Yaghi, Shadi

Background: Multiple randomized clinical trials failed to show benefit of anticoagulation over antiplatelets in the secondary prevention for embolic stroke of undetermined source (ESUS). However, the benefit of combination antithrombotic regimens remains unexplored in the same patient population. Methods: This is a subgroup analysis of a multicenter retrospective observational cohort of consecutive adult patients with ESUS (n=27 sites, 2015-2024). Comparisons were made between patients treated with single (SAPT) or dual antiplatelet therapy (DAPT), exclusive anticoagulation (AC) (direct oral anticoagulant, vitamin K antagonist, low molecular weight heparin) and combination anticoagulation and antiplatelet therapy initiated within the first 7 days of index stroke. The primary composite outcome of recurrent ischemic stroke, major bleeding, or death was assessed using unadjusted and adjusted Cox proportional hazards regression. Secondary outcomes were individual outcomes of recurrent ischemic stroke, major bleeding, or death. Results: Of the 2201 included patients, 1456 (66.1%) were on SAPT, 527 (23.9%) were on DAPT, 195 (8.8%) were on exclusive AC and 23 (1.0%) were on AC+AP (all of which were on DAPT). Patients treated with AC+AP were older (median 66 years [IQR 51-78]), more likely to have history of hypertension, stroke, hyperlipidemia, PFO and left atrial enlargement. Compared to SAPT, all treatment strategies were associated with similar risk of the primary outcomes in the unadjusted and adjusted cox regression. Similarly, there was no difference in individual outcomes including recurrent stroke, major bleeding and death in the adjusted cox regression. However, there was an increased risk of major bleeding with AC+AP in the unadjusted cox regression (HR 4.0, [95% CI 1.2-12.8], p=0.02) but not in the adjusted model when compared to SAPT. Also, DAPT was associated with lower risk of death than SAPT in the unadjusted model (HR 0.61 [95% CI 0.4-0.8],p=0.005) but not the adjusted model. Additionally, when adjusted by the HASBLED score, there was no difference in major bleeding when AC+AP was compared to SAPT. Conclusion: Over 90% of ESUS patients in this cohort were prescribed SAPT or DAPT. Antithrombotic therapy with DAPT, exclusive AC, or AC+AP was not associated with any lower risk of recurrent ischemic stroke, major bleeding and death compared with SAPT in an unselected cohort of ESUS patients.

Introduction: Four randomized clinical trials have not demonstrated the superiority of anticoagulation over antiplatelet therapy in the prevention of recurrent embolic stroke of undetermined source (ESUS). In this multicenter observational cohort study, we evaluated long-term outcomes associated with various antithrombotic strategies according to potential embolic sources. Methods: A multicenter retrospective observational cohort of consecutive adult patients with ESUS was queried (n=27 sites). Comparisons were made between patients treated with single or combination antiplatelet therapy versus anticoagulation (direct oral anticoagulant, vitamin K antagonist, low molecular weight heparin) with or without antiplatelet therapy initiated within 7 days of stroke. The primary composite outcome of recurrent stroke, major bleeding, or death was assessed using unadjusted and adjusted Cox proportional hazards regression, with clustering by site. Causal inference was assessed using inverse probability of treatment weighted regression adjustment (IPTWRA), accounting for propensity for antiplatelet treatment, with effect estimates summarized as the average treatment effect (ATE) over time (in days). Adjusted models accounted for age, stroke severity, vascular risk factors, and major categories of potential embolic sources. Results: Of the 2201 included patients (n=218 treated with anticoagulation) followed over a median of 564 days (interquartile range [IQR] 154-1124), the median age was 65y (IQR 54-74) and 49.8% were female. Patients treated with anticoagulation were older with more frequent previous stroke, concomitant left ventricular dysfunction, and more severe deficits. Over 4541 person-years of follow-up, the annualized incidence rate of the primary outcome was 14.6% (95% confidence interval [CI], 13.6%-15.8%). Compared to anticoagulation, antiplatelet(s) use was not associated with a lower risk of the primary outcome in the adjusted Cox model (HR 0.91, 95% CI, 0.64-1.29) or in the IPTWRA model (average treatment effect 0.14, 95% CI, -1376.6 to 1376.9). Major bleeding events trended toward significance in the adjusted Cox model (HR 0.51, 95% CI 0.25-1.04) but were no different with IPTWRA (ATE 58.9, 95% CI, -125.4 to 243.2). Conclusions: These results validate the observations of randomized trials indicating a lack of benefit of anticoagulation over antiplatelet therapy in ESUS. A more detailed analysis of heterogeneity of treatment effect is under way.

Background: It is known that there are discrepancies between insurance status and access to care for a variety of health conditions. In addition, differences have been shown in initial in-hospital management of stroke as well as outcomes in the acute setting. We sought to examine the relationship between insurance status and risk of recurrent stroke, major bleeding or death following an incident cryptogenic stroke. Methods: Patients with cryptogenic stroke included in a multicenter (n=27 sites) retrospective observational cohort and complete insurance status were evaluated for a primary composite outcome of recurrent stroke, major bleeding, or death. Insurance providers were categorized by Private/Veterans Administration, Medicare, Other, and Medicaid/pending/None, with the primary carrier ranked in that order when multiple insurance carriers applied. Descriptive statistics and an adjusted Cox proportional hazards regression were used to associate the primary insurance provider with the composite outcome, and with each unique secondary outcome, adjusting for age, stroke severity, pre-stroke disability, atherosclerotic risk factors, and potential embolic sources (e.g., patent foramen ovale). Results: Of the 2201 patients, 2006 (91.1%) had reported insurance information and were followed for a median of 1.50 years (interquartile range [IQR 0.41 - 2.99y]). The majority of patients were primary Medicare beneficiaries (42.3%), followed by private insurance (36.7%), Medicaid/none (18.1%) and Other (2.9%). Although there were important differences in demographic and neurodiagnostic results across insurance groups, compared to Private/VA beneficiaries, beneficiaries for Medicaid/pending/none had a higher rate of the composite outcome in adjusted regression (adjusted hazard ratio [HR] 1.35, 95% confidence interval [CI], 1.07-1.69) which was driven largely by the higher rate of recurrent stroke (adjusted HR 1.33, 95%CI, 1.02-1.73) with no significant difference in rate of major bleeding or death (p>0.05 for both). Conclusions: Independent of age, race, pre-existing disability, and atherosclerotic risk factors, insurance status was independently predictive of recurrent stroke in this diverse cohort of cryptogenic stroke.

Introduction: Malignancy represents an important subgroup of embolic stroke of undetermined source (ESUS). We aim to compare infarct features, potential embolic sources, and long-term outcomes in ESUS patients with and without malignancy. Methods: In this pre-specified secondary analysis of the Cardiac Abnormalities in Stroke Prevention and Recurrence (CASPR) retrospective cohort study, active cancers were identified by site investigators and adjudicated as malignant if they were non-squamous or non-basal cell skin cancers. We compared the prevalence of various potential embolic sources (e.g., patent foramen ovale, left ventricular dysfunction, post-stroke atrial fibrillation) among patients with and without malignancy. The risk of recurrent stroke, major bleeding, or death was evaluated using adjusted Cox proportional hazards models, accounting for age, sex, vascular risk factors, competing potential embolic sources, and initial treatment with anticoagulation versus non-anticoagulant (e.g., antiplatelet) regimen. Results: Of the 2201 patients followed over a median of 564 days, 236 (10.7%) were diagnosed with cancer at the time of stroke. Patients with malignancy were older, more frequently hypertensive and did not differ with regards to prevalence of specific infarct patterns or potential cardiac embolic sources. No difference was observed in the composite outcome of recurrent stroke, major bleeding, or death (adjusted HR 1.02, 95% CI, 0.71-1.46). Age (adjusted HR per year 1.02, 95% CI, 1.01-1.03), baseline stroke severity (adjusted HR 1.03 per NIHSS point, 95% CI, 1.01-1.05), prior stroke (adjusted HR 1.68, 95% CI, 1.38-2.05), and multi-territorial infarct pattern (adjusted HR 1.67, 95% CI, 1.33-2.08) were significantly associated with this composite outcome, but anticoagulation was not. There was a nominally lower rate of major bleeding with malignancy (adjusted HR 0.45, 95% CI, 0.19-1.04), a significantly higher rate of death (adjusted HR 1.58, 95% CI, 1.09-2.30), but no significant difference in recurrent ischemic stroke (p=0.31). Conclusions: Patients with malignancy and ESUS had higher mortality but did not differ in recurrent stroke risk or major bleeding when compared to patients without malignancy. Anticoagulation was not independently associated with better outcomes. Further analysis of infarct topology and risk factors may better identify patients for whom anticoagulation may benefit.

AbstractObjectiveAbout 25% of patients with acute ischemic stroke (AIS) present within the intravenous thrombolytic (IVT) therapeutic window of <4.5 h. This study is to elucidate the safety and efficacy of IVT in the extended therapeutic window (ETW) in patients with AIS.MethodsUsing PRISMA guidelines, a systematic review was conducted using PubMed, Embase, and Scopus. A rigorous risk of bias assessment was conducted using the RoB2 tool. Rates of excellent and good functional outcome (mRS 0–1 and mRS 0–2) at 90 days, symptomatic intracranial hemorrhage (sICH), and mortality at 90 days were pooled using generalized linear mixed model and compared with controls. Meta‐analyses were conducted employing random‐effect models with risk ratio (RR) and 95% confidence intervals (CIs). Subgroup analysis was performed to assess the effect of imaging modalities used for patient selection.ResultsEight randomized controlled trials (n = 2221, 59% male) were included. At 90 days IVT showed higher rates of functional recovery: mRS 0–1: RR 1.21 95% CI 1.1–1.34, p < 0.001, and mRS 0–2: RR 1.11 95% CI 1.03–1.18, p = 0.004. Rate of mortality at 90 day was not different between groups: RR 1.17 95% CI 0.93–1.48, p = 0.17. However, the rate of sICH was higher among IVT group: RR 2.93 95% CI 1.53–5.6, p = 0.001. Subgroup analysis showed higher mRS 0–1 among patients who were selected based on perfusion imaging (p < 0.05).InterpretationThe use of IVT in AIS in ETW is beneficial especially with the use of perfusion imaging for patients' selection.

Background and Objectives: Acute small subcortical infarcts (SSI) result in high rates of early neurological deterioration (END) despite best medical management. Those with SSI-related END have worse functional outcomes after stroke leading to increased morbidity. Presently, it is unknown in a robust manner the incidence or risk factors for END within this demographic. The aim of this study was to perform a systematic review and meta-analysis to understand the incidence and risk factors of SSI-related END. Methods: We searched PubMed, Cochrane Library, and Google Scholar between January 1, 2000, and June 1, 2022, including both retrospective cross-sectional and prospective observational studies. The primary outcome was development of END based on publishing authors’ definition. Abstracted data included age, sex, cohort size, diagnoses of hypertension, hyperlipidemia, diabetes mellitus, study definition of END and SSI, and presence of branch atheromatous disease (BAD) and lesion diameter. Results: We identified 31 studies enrolling 6376 patients. Most studies were conducted in East Asia (27/31, 87%) and had a least some concern for risk of bias. Funnel plot illustrated a high level of publication bias favoring high incidence studies. END was commonly defined as ≥ 2 overall NIHSS change or ≥ 1 motor change within 3 to 7 days from admission (average: 5 days). A pooled proportion of END was 22% (95%CI 0.19 - 0.25, I2 = 91.2%, 31 studies). Meta-regression identified that female sex [risk ratio (RR) 1.23, 95%CI 1.09-1.39, I2=30.8%, 31 studies], diabetes mellitus (RR 1.16 95%CI 1.01-1.33, I2=38.4%, 30 studies), and BAD (RR 1.99 95%CI 1.61-2.46, I2=50.7%, 17 studies) as risk factors for END. Discussion: Our data identified primarily within an East Asian cohort that risk factors for SSI-related END include diabetes mellitus and branch atheromatous disease with a pooled prevalence of END occurring in 1 in 4 patients. Future studies are needed to understand treatment and preventative strategies for this patient population.

ObjectiveTo evaluate clinical outcomes of endovascular thrombectomy (EVT) for acute basilar artery occlusion (BAO) using population‐level data from the United States.MethodsWeighted discharge data from the National Inpatient Sample were queried to identify adult patients with acute BAO during the period of 2015 to 2019 treated with EVT or medical management only. Complex samples statistical methods and propensity‐score adjustment using inverse probability of treatment weighting (IPTW) were performed to assess clinical endpoints.ResultsAmong 3,950 BAO patients identified, 1,425 (36.1%) were treated with EVT [mean age 66.7 years, median National Institute of Health Stroke Scale (NIHSS) score 22]. On unadjusted analysis, 155 (10.9%) EVT patients achieved favorable functional outcomes (discharge disposition to home without services), while 515 (36.1%) experienced in‐hospital mortality, and 20 (1.4%) developed symptomatic intracranial hemorrhage (sICH). Following propensity‐score adjustment by IPTW accounting for age, stroke severity, and comorbidity burden, EVT was independently associated with favorable functional outcome [adjusted odds ratio (aOR) 1.25, 95% confidence interval (CI) 1.07, 1.46; p = 0.004], but not with in‐hospital mortality or sICH. In an IPTW‐adjusted sub‐group analysis of patients with NIHSS scores >20, EVT was associated with both favorable functional outcome (discharge disposition to home or to acute rehabilitation) (aOR 1.55, 95% CI 1.24, 1.94; p < 0.001) and decreased mortality (aOR 0.78, 95% CI 0.69, 0.89; p < 0.001), but not with sICH.InterpretationThis retrospective population‐based analysis using a large national registry provides real‐world evidence of a potential benefit of EVT in acute BAO patients. ANN NEUROL 2023;94:55–60

Importance In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P &amp;lt; .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P &amp;lt; .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P &amp;lt; .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.