Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). METHODS: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). FINDINGS: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. INTERPRETATION: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. FUNDING: Bristol Myers Squibb and Janssen Research & Development.

Endovascular Therapy for Basilar Artery Occlusion: Among the First to Conceptualize, Last to Prove.

In 1981, the dismal outcomes of patients with basilar artery occlusion (BAO) inspired the first reports of intra-arterial thrombolytic treatment in BAO. These reports were among the first to conceptualize that opening an artery could help patients with large vessel occlusion stroke. Whereas multiple anterior circulation LVO trials demonstrated the efficacy of endovascular therapy starting in 2014, proof of benefit for BAO was lacking until 2022. In this commentary, we reflect on how the BASICS (Basilar Artery International Cooperation Study) and BEST (Basilar Artery Occlusion: Endovascular Interventions vs Standard Medical Treatment) trials lay the foundations for clinical trials in BAO, subsequently leading to the positive results of the ATTENTION (Endovascular Treatment for Acute Basilar-Artery Occlusion) and BAOCHE (Basilar Artery Occlusion Chinese Endovascular) trials.

Rationale and design of the AXIOMATIC-SSP phase II trial: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention.

BACKGROUND: Individuals with ischemic stroke or transient ischemic attack (TIA) have a high early risk of ischemic stroke despite dual antiplatelet therapy. The risk of ischemic stroke, and associated disability, represents a significant unmet clinical need. Genetic variants resulting in reduced factor XI levels are associated with reduced risk for ischemic stroke but are not associated with increased intracranial bleeding. Milvexian is an oral small-molecule inhibitor of FXIa that binds activated factor XI with high affinity and selectivity and may reduce the risk of stroke when added to antiplatelet drugs without significant bleeding. We aimed to evaluate the dose-response relationship of milvexian in participants treated with dual antiplatelets. METHODS: We began a phase II, double-blinded, randomized, placebo-controlled trial at 367 sites in 2019. Participants (N = 2366) with ischemic stroke (National Institutes of Health Stroke Scale score ≤7) or high-risk TIA (ABCD2 score ≥6) were randomized to 1 of 5 doses of milvexian or placebo for 90 days. Participants also received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg for 90 days. The efficacy endpoint was the composite of ischemic stroke or incident infarct on magnetic resonance imaging. Major bleeding, defined as type 3 or 5 bleeding according to the Bleeding Academic Research Consortium, was the safety endpoint. Participant follow-up will end in 2022. CONCLUSION: The AXIOMATIC-SSP trial will evaluate the dose-response of milvexian for ischemic stroke occurrence in participants with ischemic stroke or TIA.

Microbleeds and the Effect of Anticoagulation in Patients With Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Randomized Clinical Trial.

Importance: The reported associations of cerebral microbleeds with recurrent stroke and intracerebral hemorrhage have raised concerns regarding antithrombotic treatment in patients with a history of stroke and microbleeds on magnetic resonance imaging. Objective: To characterize microbleeds in embolic strokes of undetermined source (ESUS) and report interactions between microbleeds and the effects of random assignment to anticoagulant vs antiplatelet therapy. Design, Setting, and Participants: Subgroup analyses of the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs Aspirin to Prevent Embolism in ESUS (NAVIGATE ESUS) international, double-blind, randomized, event-driven phase 3 clinical trial. Participants were enrolled between December 2014 and September 2017 and followed up for a median of 11 months. The study setting included 459 stroke recruitment centers in 31 countries. Patients aged 50 years or older who had neuroimaging-confirmed ESUS between 7 days and 6 months before screening were eligible. Of these 7213 NAVIGATE ESUS participants, 3699 (51%) had information on cerebral microbleeds reported on their baseline clinical magnetic resonance imaging and were eligible for these analyses. Patients with a prior history of symptomatic intracerebral hemorrhage were excluded from the NAVIGATE ESUS trial. Interventions: Rivaroxaban, 15 mg, compared with aspirin, 100 mg, daily. Main Outcomes and Measures: The primary outcome was recurrent stroke. Secondary outcomes were ischemic stroke, intracerebral hemorrhage, and all-cause mortality. Results: Microbleeds were present in 395 of 3699 participants (11%). Of patients with cerebral microbleeds, mean (SD) age was 69.5 (9.4) years, 241 were men (61%), and 201 were White (51%). Advancing age (odds ratio [OR] per year, 1.03; 95% CI, 1.01-1.04), East Asian race/ethnicity (OR, 1.57; 95% CI, 1.04-2.37), hypertension (OR, 2.20; 95% CI, 1.54-3.15), multiterritorial infarcts (OR, 1.95; 95% CI, 1.42-2.67), chronic infarcts (OR, 1.78; 95% CI, 1.42-2.23), and occult intracerebral hemorrhage (OR, 5.23; 95% CI, 2.76-9.90) were independently associated with microbleeds. The presence of microbleeds was associated with a 1.5-fold increased risk of recurrent stroke (hazard ratio [HR], 1.5; 95% CI, 1.0-2.3), a 4-fold risk of intracerebral hemorrhage (HR, 4.2; 95% CI, 1.3-13.9), a 2-fold risk of all-cause mortality (HR, 2.1; 95% CI, 1.1-4.3), and strictly lobar microbleeds with an approximately 2.5-fold risk of ischemic stroke (HR, 2.3; 95% CI, 1.3-4.3). There were no interactions between microbleeds and treatment assignments for recurrent stroke, ischemic stroke, or all-cause mortality. The HR of intracerebral hemorrhage on rivaroxaban was similar between persons with microbleeds (HR, 3.1; 95% CI, 0.3-30.0) and persons without microbleeds (HR, 3.0; 95% CI, 0.6-14.7; interaction P = .97). Conclusions and Relevance: Microbleeds mark an increased risk of recurrent stroke, ischemic stroke, intracerebral hemorrhage, and mortality in ESUS but do not appear to influence effects of rivaroxaban on clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02313909.

Proposal for Updated Nomenclature and Classification of Potential Causative Mechanism in Patent Foramen Ovale-Associated Stroke.

Importance: Recent epidemiologic and therapeutic advances have transformed understanding of the role of and therapeutic approach to patent foramen ovale (PFO) in ischemic stroke. Patent foramen ovale is likely responsible for approximately 5% of all ischemic strokes and 10% of those occurring in young and middle-aged adults. Observations: Randomized clinical trials have demonstrated that, to prevent recurrent ischemic stroke in patients with PFO and an otherwise-cryptogenic index ischemic stroke, PFO closure is superior to antiplatelet medical therapy alone; these trials have provided some evidence that, among medical therapy options, anticoagulants may be more effective than antiplatelet agents. Conclusions and Relevance: These new data indicate a need to update classification schemes of causative mechanisms in stroke, developed in an era in which an association between PFO and stroke was viewed as uncertain. We propose a revised general nomenclature and classification framework for PFO-associated stroke and detailed revisions for the 3 major stroke subtyping algorithms in wide use.

Prevalence of Retinal Emboli and Acute Retinal Artery Occlusion in Acute Ischemic Stroke.

OBJECTIVE: In population-based studies asymptomatic retinal emboli occur in .32%-2.9% of people. Retinal artery occlusion (RAO) may occur concurrently with cerebral stroke but the frequency is unknown. No study has examined how commonly retinal emboli occur in the acute stroke population. We aimed to assess the prevalence of retinal emboli and RAO at the time of carotid territory ischemic stroke. METHODS: Patients were enrolled prospectively after onset of symptoms consistent with the diagnosis of carotid territory ischemic stroke. Every participant underwent pharmacologic dilation of both pupils and bedside funduscopic examination. Emboli were classified as cholesterol, calcific, platelet/fibrin, or other and categorized by the side of occurrence. Stroke was classified as atheroembolic, cardioembolic, embolic stroke of undetermined source, lacunar, or other. Acute RAO was diagnosed by direct visualization of ischemic retinal whitening. RESULTS: Sixty-five patients were enrolled with a mean age of 59.2 years; 23 were female (35.4%). Eleven of 65 subjects (16.9%) had retinal emboli visible on funduscopy; all were cholesterol emboli except a single platelet/fibrin embolus in a patient with atheroembolic source. Six patients (9%) had acute RAO and no RAO was seen in the lacunar or undetermined source subgroups. CONCLUSIONS: Retinal emboli occurred more than 10 times more frequently in the acute stroke patient than in large population-based studies. RAOs also occurred concurrently with ischemic stroke. Although emboli were seen in patients with atheroembolic and cardioembolic sources, all patients with carotid disease had emboli in the ipsilateral eye. Future studies are required to determine if the presence of retinal emboli or RAO may help elucidate an etiology in patients suffering from embolic stroke of undetermined source.

Sex Differences in Outcome After Endovascular Stroke Therapy for Acute Ischemic Stroke.

Background and Purpose- We determined the effect of sex on outcome after endovascular stroke thrombectomy in acute ischemic stroke, including lifelong disability outcomes. Methods- We analyzed patients treated with the Solitaire stent retriever in the combined SWIFT (Solitaire FR With the Intention for Thrombectomy), STAR (Solitaire FR Thrombectomy for Acute Revascularization), and SWIFT PRIME (Solitaire FR With the Intention for Thrombectomy as Primary Endovascular Treatment) cohorts. Ordinal and logistic regression were used to examine known factors influencing outcome after endovascular stroke thrombectomy and study the effect of sex on the association between these factors and outcomes, including age and time to reperfusion. Years of optimal life after thrombectomy were defined as disability-adjusted life years and calculated by projecting disability through adjusted poststroke life expectancy by sex. Results- Among 389 patients treated with endovascular stroke thrombectomy, 55% were females, and median National Institutes of Health Stroke Scale was 17 (interquartile range, 8-28). There were no differences between females versus males in presenting deficit severity (National Institutes of Health Stroke Scale score, 17 versus 17, P=0.21), occlusion location (69% versus 64% M1, P=0.62), presenting infarct extent (Alberta Stroke Program Early CT Score 8 versus 8, P=0.24), rate of substantial reperfusion (Thrombolysis in Cerebral Infarction 2b/3, 87% versus 83%, P=0.37), onset to reperfusion time (294 versus 302 minutes, P=0.46). Despite older ages (69 versus 64, P<0.001) and higher rate of atrial fibrillation (45% versus 30%, P=0.002) for females compared with males, adjusted rates of functional independence at 90 days were similar (odds ratio, 1.0; 95% CI, 0.6-1.6). After adjusting for age at presentation and stroke severity, females had more years of optimal life (disability-adjusted life year) after endovascular stroke thrombectomy, 10.6 versus 8.5 years (P<0.001). Conclusions- Despite greater age and higher rate of atrial fibrillation, females experienced comparable functional outcomes and greater years of optimal life after intervention compared with males.

Time Course for Benefit and Risk of Clopidogrel and Aspirin After Acute Transient Ischemic Attack and Minor Ischemic Stroke.

BACKGROUND: In patients with acute minor ischemic stroke or high-risk transient ischemic attack enrolled in the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke [POINT] Trial), the combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage in comparison to aspirin alone. METHODS: In a secondary analysis of POINT (N=4881), we assessed the time course for benefit and risk from the combination of clopidogrel and aspirin. The primary efficacy outcome was a composite of ischemic stroke, myocardial infarction, or ischemic vascular death. The primary safety outcome was major hemorrhage. Risks and benefits were estimated for delayed times of treatment initiation using left-truncated models. RESULTS: Through 90 days, the rate of major ischemic events was initially high then decreased markedly, whereas the rate of major hemorrhage remained low but relatively constant throughout. With the use of a model-based approach, the optimal change point for major ischemic events was 21 days (0-21 days hazard ratio 0.65 for clopidogrel-aspirin versus aspirin; 95% CI, 0.50-0.85; P=0.0015, in comparison to 22-90 days hazard ratio, 1.38; 95% CI, 0.81-2.35; P=0.24). Models showed benefits of clopidogrel-aspirin for treatment delayed as long as 3 days after symptom onset. CONCLUSIONS: The benefit of clopidogrel-aspirin occurs predominantly within the first 21 days, and outweighs the low, but ongoing risk of major hemorrhage. When considered with the results of the CHANCE trial (Clopidogrel in High-Risk Patients With Non-disabling Cerebrovascular Events), a similar trial treating with clopidogrel-aspirin for 21 days and showing no increase in major hemorrhage, these results suggest that limiting clopidogrel-aspirin use to 21 days may maximize benefit and reduce risk after high-risk transient ischemic attack or minor ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Recurrent Stroke With Rivaroxaban Compared With Aspirin According to Predictors of Atrial Fibrillation: Secondary Analysis of the NAVIGATE ESUS Randomized Clinical Trial.

Importance: The NAVIGATE ESUS randomized clinical trial found that 15 mg of rivaroxaban per day does not reduce stroke compared with aspirin in patients with embolic stroke of undetermined source (ESUS); however, it substantially reduces stroke risk in patients with atrial fibrillation (AF). Objective: To analyze whether rivaroxaban is associated with a reduction of recurrent stroke among patients with ESUS who have an increased risk of AF. Design, Setting, and Participants: Participants were stratified by predictors of AF, including left atrial diameter, frequency of premature atrial contractions, and HAVOC score, a validated scheme using clinical features. Treatment interactions with these predictors were assessed. Participants were enrolled between December 2014 and September 2017, and analysis began March 2018. Intervention: Rivaroxaban treatment vs aspirin. Main Outcomes and Measures: Risk of ischemic stroke. Results: Among 7112 patients with a mean (SD) age of 67 (9.8) years, the mean (SD) HAVOC score was 2.6 (1.8), the mean (SD) left atrial diameter was 3.8 (1.4) cm (n = 4022), and the median (interquartile range) daily frequency of premature atrial contractions was 48 (13-222). Detection of AF during follow-up increased for each tertile of HAVOC score: 2.3% (score, 0-2), 3.0% (score, 3), and 5.8% (score, >3); however, neither tertiles of the HAVOC score nor premature atrial contractions frequency impacted the association of rivaroxaban with recurrent ischemic stroke (P for interaction = .67 and .96, respectively). Atrial fibrillation annual incidence increased for each tertile of left atrial diameter (2.0%, 3.6%, and 5.2%) and for each tertile of premature atrial contractions frequency (1.3%, 2.9%, and 7.0%). Among the predefined subgroup of patients with a left atrial diameter of more than 4.6 cm (9% of overall population), the risk of ischemic stroke was lower among the rivaroxaban group (1.7% per year) compared with the aspirin group (6.5% per year) (hazard ratio, 0.26; 95% CI, 0.07-0.94; P for interaction = .02). Conclusions and Relevance: The HAVOC score, left atrial diameter, and premature atrial contraction frequency predicted subsequent clinical AF. Rivaroxaban was associated with a reduced risk of recurrent stroke among patients with ESUS and moderate or severe left atrial enlargement; however, this needs to be independently confirmed before influencing clinical practice.

Thyroid cartilage compression causing stroke.

We describe the diagnostic workup and surgical treatment of a patient presenting with the unique case of vertebral artery (VA) occlusion subsequent to head flexion leading to compression of an aberrant VA by the ipsilateral superior cornu of the thyroid cartilage. Imaging revealed ischemic infarcts as well as the presence of an aberrant right VA, which was compressed by the ipsilateral superior cornu of the thyroid cartilage upon neck flexion. The patient was managed with laryngoplasty involving removal of the right superior cornu of the thyroid cartilage. Laryngoscope, 129:E445-E448, 2019.

SCAI expert consensus statement on operator and institutional requirements for PFO closure for secondary prevention of paradoxical embolic stroke: The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists.

Until recently, evidence to support Patent Foramen Ovale (PFO) closure for secondary prevention of recurrent stroke has been controversial. Publication of high-quality evidence from randomized clinical trials and the subsequent FDA approval of two devices for percutaneous PFO closure is expected to increase the volume of PFO closure procedures not only in the United States but worldwide. As this technology is disseminated broadly to the public, ensuring the safe and efficacious performance of PFO closure is essential to mitigate risk and avoid unnecessary procedures. This document, prepared by a multi-disciplinary writing group convened by the Society for Cardiovascular Angiography and Interventions and including representatives from the American Academy of Neurology, makes recommendations for institutional infrastructure and individual skills necessary to initiate and maintain an active PFO/stroke program, with emphasis on shared decision making and patient-centered care.

Hemodynamic Markers in the Anterior Circulation as Predictors of Recurrent Stroke in Patients With Intracranial Stenosis.

Background and Purpose- Although aggressive medical therapy was superior to stenting in the SAMMPRIS trial (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis), the stroke rate in the medical arm was still high. The aim of this study was to determine the association between hemodynamic markers (borderzone infarct pattern and impaired collateral flow on baseline imaging) and rates of recurrent stroke in patients treated medically in SAMMPRIS. Methods- This was a post hoc analysis of patients whose qualifying event for SAMMPRIS was an infarct in the territory of a stenotic middle cerebral artery or intracranial carotid artery. Infarcts were adjudicated as involving primarily internal or cortical borderzone territories, the core middle cerebral artery territory, or perforator territories, and collateral flow was assessed according to a standard scale (American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology). Log-rank tests and χ2 tests were performed to assess associations of infarct patterns and collateral flow with rates of recurrent stroke. Results- Of 101 patients who qualified, 14 of 53 (26.4%) with borderzone infarcts, 2 of 24 (8.3%) with core middle cerebral artery infarcts, and 3 of 24 (12.5%) with perforator infarcts had a recurrent stroke in the territory (P=0.14 for comparing the 3 groups, P=0.052 for borderzone versus nonborderzone). Of 82 patients with collateral flow assessment, 30 of 43 (70%) with borderzone infarcts, 7 of 19 (37%) with core middle cerebral artery infarcts, and 11 of 20 (55%) with perforator infarcts had impaired collateral flow distal to the stenosis (P=0.049). Patients with borderzone infarcts and impaired collateral flow had the highest risk of recurrent stroke (37%). Conclusions- Borderzone infarcts and impaired collateral flow identify a subgroup of patients with intracranial stenosis who are at particularly high risk of recurrent stroke on medical treatment. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00576693.

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.

BACKGROUND: Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. METHODS: NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. FINDINGS: Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22-1·36), and the risk was similar for those without known PFO (1·06; 0·84-1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51-8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69-4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24-0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. INTERPRETATION: Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. FUNDING: Bayer and Janssen.

Cerebral amyloid angiopathy: diagnosis and potential therapies.

INTRODUCTION: Cerebral amyloid angiopathy (CAA) is characterized by the pathologic deposition of amyloid-beta within cortical and leptomeningeal arteries, arterioles, capillaries and, in rare cases, the venules of the brain. It is often associated with the development of lobar intracerebral hemorrhages (ICHs) but may cause other neurologic symptoms or be asymptomatic. Magnetic resonance imaging characteristics, such as lobar microbleeds, support a diagnosis of CAA and assist with hemorrhage risk assessments. Immunosuppressants are used to treat rarer inflammatory forms of CAA. For the more common forms of CAA, the use of antihypertensive medications can prevent ICH recurrence while the use of antithrombotics may increase hemorrhage risk. Anti-amyloid approaches to treatment have not yet been investigated in phase 3 trials. Areas covered: A literature search was conducted using MEDLINE on the topics of imaging, biomarkers, ICH prevention and treatment trials in CAA, focusing on its current diagnosis and management and opportunities for future therapeutic approaches. Expert commentary: There is likely a significant unrecognized burden of CAA in the elderly population. Continued research efforts to discover biomarkers that allow the early diagnosis of CAA will enhance the opportunity to develop treatment interventions.

Impact of Stroke Call on the Stroke Neurology Workforce in the United States: Possible Challenges and Opportunities.

BACKGROUND: The Stroke & Vascular Neurology Section of the American Academy of Neurology was charged to identify challenges to the recruitment and retention of stroke neurologists and to make recommendations to address any identified problems. The Section initiated this effort by determining the impact of stroke on-call requirements as a barrier to the recruitment and retention of vascular neurologists. METHODS: This is a cross-sectional survey of a sample of US Neurologists providing acute stroke care. RESULTS: Of the 900 neurologists who were sent surveys, 313 (35%) responded. Of respondents from institutions providing stroke coverage, 71% indicated that general neurologists and 45% indicated that vascular neurologists provided that service. Of those taking stroke call, 36% agreed with the statement, "I spent too much time on stroke call," a perception that was less common among those who took less than 12-hour shifts (P < .0001); 21% who participated in stroke call were dissatisfied with their current job. Forty-six percent indicated that their stroke call duties contributed to their personal feeling of "burnout." CONCLUSIONS: Although the reasons are likely multifactorial, our survey of neurologists providing stroke care suggests that over-burdensome on-call responsibilities may be contributing to the vascular neurology workforce burnout and could be affecting recruitment and retention of vascular neurologists. Strategies to reduce the lifestyle impact of stroke call may help address this problem.

The Influence of ß-Adrenergic Receptor Kinase-1 on Stroke-induced Immunodeficiency Syndrome.

BACKGROUND: Immunodeficiency in acute ischemic stroke (AIS) is thought to be a result of norepinephrine suppression of the lymphoid tissue. The possible differences in the distribution of lymphocytes after stroke may be due to differences in responsiveness of lymphocyte ß-adrenergic receptors to their kinase (BARK-1). OBJECTIVE: The objective was to quantify the influence of lymphocyte BARK-1 on stroke-induced immunodeficiency in AIS patients. METHODS: A prospective clinical cohort study was conducted (N = 44). Measures included age, gender, race, risk factors for stroke, stroke severity, comorbidities, presence of infection, white blood cell counts and differential proportions, and lymphocyte BARK-1. Student t tests, effect sizes, and linear and logistic regressions were conducted to test the study objective. The study was approved by the Oregon Health & Science University Institutional Review Board. RESULTS: There were significant changes in all white blood cells and differential proportions and in the National Institutes of Health Stroke Scale from admission to 48 hours after onset of stroke deficits. Higher BARK-1 influenced the lower lymphocyte proportion at 48 hours, independent of age, P < .0001. Furthermore, BARK-1 also was associated with an increase in the likelihood of having sustained or stroke-induced immunodeficiency at 48 hours: odds ratio, 2.41; 95% confidence interval, 1.10-5.25; P = .027, and odds ratio, 2.79; 95% confidence interval, 1.03-7.52; P = .043, respectively. In all backward stepwise selection of factors, BARK-1 was the only factor consistently retained in the models. CONCLUSIONS: ß-Adrenergic receptor kinase-1 has a significant quantifiable influence on lymphocyte proportion at 48 hours and on the classification of sustained stroke-induced immunodeficiency. CLINICAL IMPLICATIONS: ß-Adrenergic stimulation influences immunodeficiency in AIS.

Periprocedural heparin use in acute ischemic stroke endovascular therapy: the TREVO 2 trial.

BACKGROUND: The use of periprocedural heparin has previously been reported to be safe and potentially beneficial during thrombectomy with older generation devices. We aimed to evaluate the safety and clinical outcomes of heparin use in the stent retriever era. METHODS: A post hoc analysis of the TREVO 2 trial was performed comparing baseline characteristics and clinical outcomes between patients who received (HEP+) and those who did not receive periprocedural heparin (HEP-) while undergoing MERCI or TREVO clot retrieval. RESULTS: Of 173 patients, 58 (34%) received periprocedural heparin including 40 who received one preprocedural bolus (median 3000 units). Baseline characteristics among HEP+ and HEP- patients were similar except HEP+ patients had a lower NIH Stroke Scale (NIHSS) score (17 vs 19; p=0.04), lower IV tissue plasminogen activator use (38% vs 64%; p<0.01), and a higher median ASPECTS score (8.0 vs 7.0; p=0.02). HEP+ patients were more likely to have vertebrobasilar and middle cerebral artery (MCA)-M1 occlusions but less likely to have internal carotid artery and MCA-M2 occlusions (p=0.04). Time from symptom onset to puncture was similar in the two groups while procedure duration was longer in HEP+ patients (99 vs 83 min; p<0.01). Thrombolysis In Cerebral Infarction (TICI) 2b-3 reperfusion rates, embolization to unaffected territories, access site complications, and intracranial hemorrhages were similar between the groups. In multivariable logistic regression, a good outcome (90-day modified Rankin Scale score 0-2) was independently associated with heparin bolus use (OR 5.30; 95% CI 1.70 to 16.48), TICI 2b-3 reperfusion (OR 6.56; 95% CI 2.29 to 18.83), stent retriever use (OR 3.54; 95% CI 1.38 to 9.03) and inversely associated with intubation (OR 0.10; 95% CI 0.03 to 0.33), diabetes (OR 0.11; 95% CI 0.03 to 0.39), NIHSS (OR 0.84; 95% CI 0.75 to 0.93), time from symptom onset to puncture (OR 0.64; 95% CI 0.45 to 0.89), and heart failure (OR 0.23; 95% CI 0.06 to 0.83). CONCLUSIONS: The use of periprocedural heparin in stent retriever thrombectomy is associated with a good clinical outcome at 90 days and similar rates of symptomatic intracranial hemorrhage. Further studies are warranted. CLINICAL TRIAL REGISTRATION: URL:http://www.clinicaltrials.gov. Unique identifier: NCT01270867;Post-results.

Visual Aids for Patient, Family, and Physician Decision Making About Endovascular Thrombectomy for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Rapid decision making optimizes outcomes from endovascular thrombectomy for acute cerebral ischemia. Visual displays facilitate swift review of potential outcomes and can accelerate decision processes. METHODS: From patient-level, pooled randomized trial data, 100 person-icon arrays (Kuiper-Marshall personographs) were generated showing beneficial and adverse effects of endovascular thrombectomy for patients with acute cerebral ischemia and large vessel occlusion using (1) automated (algorithmic) and (2) expert-guided joint outcome table specification. RESULTS: For the full 7-category modified Rankin Scale, thrombectomy added to IV tPA (intravenous tissue-type plasminogen activator) alone had number needed to treat to benefit 2.9 (95% confidence interval, 2.6-3.3) and number needed to harm 68.9 (95% confidence interval, 40-250); thrombectomy for patients ineligible for IV tPA had number needed to treat to benefit 2.3 (95% confidence interval, 2.1-2.5) and number needed to harm 100 (95% confidence interval, 62.5-250). Visual displays of treatment effects on 100 patients showed: with thrombectomy added to IV tPA alone, 34 patients have better disability outcome, including 14 more normal or near normal (modified Rankin Scale, 0-1); with thrombectomy for patients ineligible for IV tPA, 44 patients have a better disability outcome, including 16 more normal or nearly normal. Displays also showed that harm (increased modified Rankin Scale final disability) occurred in 1 of 100 patients in both populations, mediated by increased new territory infarcts. The person-icon figures integrated these outcomes, and early side-effects, in a single display. CONCLUSIONS: Visual decision aids are now available to rapidly educate healthcare providers, patients, and families about benefits and risks of endovascular thrombectomy, both when added to IV tPA in tPA-eligible patients and as the sole reperfusion treatment in tPA-ineligible patients.

Frequency and features of embolic stroke of undetermined source in young adults.

INTRODUCTION: The sources of emboli in those with embolic stroke of undetermined source may differ in old and young. We assessed the frequency, features and potential embolic sources of younger vs. older embolic stroke of undetermined source patients in the embolic stroke of undetermined source Global Registry. PATIENTS AND METHODS: Cross-sectional study of consecutive patients over age 18 years, with recent ischaemic strokes at 19 centres conducted in 2013-2014. Characteristics of embolic stroke of undetermined source patients who aged ≤50 years were analysed and compared with embolic stroke of undetermined source patients who aged >50 years. RESULTS: Among 2144 patients with ischaemic stroke, 323 (15.1%, 95% confidence interval: 13.6-16.7%) were ≤50 years old and, 1821 >50 years. 24% (n = 78) of young vs. 15% (n = 273) of older patients met embolic stroke of undetermined source criteria. The mean age of young embolic stroke of undetermined source patients was 40 years (standard deviation +/-9), 33% were women and the most prevalent vascular risk factor was hypertension (38%). Conventional vascular risk factors were less frequent in younger embolic stroke of undetermined source patients. Fewer young embolic stroke of undetermined source patients (63%) had potential minor risk embolic sources identified vs. older embolic stroke of undetermined source patients (77%) (p = 0.02). Stroke severity on admission was similar in younger vs. older patients (National Institute of Health Stroke Scale (NIHSS) 3 vs. 4, p = 0.06). DISCUSSION: Young embolic stroke of undetermined source patients comprise an important subset of ischaemic stroke patients around the world. Severity of stroke on admission and 30-day mortality rates are similar among young and older patients. However, there are important differences between younger vs. older embolic stroke of undetermined source patients with respect to risk factors, and potential embolic sources that could affect response to anticoagulants vs. antiplatelet therapies. CONCLUSION: This study provides a benchmark for the global frequency and characteristics of young embolic stroke of undetermined source patients and shows consistent high frequency of embolic stroke of undetermined source in young adults.

Management of Symptomatic Intracranial Stenosis.

Intracranial atherosclerotic disease is a common cause of stroke worldwide, causing approximately 10 % of strokes in the USA and up to 50 % in Asian populations. Recurrent stroke risks are particularly high in those with a stenosis of 70 % or more and a recent transient ischemic attack or stroke. Warfarin has been associated with higher major hemorrhage rates and no reduction of recurrent stroke compared to aspirin in patients with symptomatic intracranial stenosis. After early trials showed the feasibility of stenting, two randomized trials compared stenting plus medical management to medical management alone in symptomatic intracranial stenosis. Stenting was linked with increased risk and showed no benefit in any subpopulation of patients. Aggressive medical management in the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial was associated with half the risk of stroke compared to that in similar patients in a previous symptomatic intracranial stenosis trial after adjustment of confounding characteristics. Aggressive medical management comprises risk factor control, including a target systolic blood pressure <140 mmHg, a low density lipoprotein <70 mg/dL, hemoglobin A1C <7.0 %, and lifestyle management that incorporates exercise, smoking cessation and weight management, and the use of antithrombotics.