Association of Plaque Inflammation With Stroke Recurrence in Patients With Unproven Benefit From Carotid Revascularization.

BACKGROUND AND OBJECTIVES: In pooled analyses of endarterectomy trials for symptomatic carotid stenosis, several subgroups experienced no net benefit from revascularization. The validated symptomatic carotid atheroma inflammation lumen-stenosis (SCAIL) score includes stenosis severity and inflammation measured by PET and improves the identification of patients with recurrent stroke compared with lumen-stenosis alone. We investigated whether the SCAIL score improves the identification of recurrent stroke in subgroups with uncertain benefit from revascularization in endarterectomy trials. METHODS: We did an individual-participant data pooled analysis of 3 prospective cohort studies (Dublin Carotid Atherosclerosis Study [DUCASS], 2008-2011; Biomarkers and Imaging of Vulnerable Atherosclerosis in Symptomatic Carotid Artery Disease [BIOVASC], 2014-2018; Barcelona Plaque Study, 2015-2018). Eligible patients had a recent nonsevere (modified Rankin Scale score ≤3) anterior circulation ischemic stroke/TIA and ipsilateral mild carotid stenosis (<50%); ipsilateral moderate carotid stenosis (50%-69%) plus at least 1 of female sex, age <65 years, diabetes mellitus, TIA, or delay >14 days to revascularization; or monocular loss of vision. Patients underwent coregistered carotid 18F-fluorodeoxyglucosePET/CT angiography (≤7 days from inclusion). The primary outcome was 90-day ipsilateral ischemic stroke. Multivariable Cox regression modeling was performed. RESULTS: We included 135 patients. All patients started optimal modern-era medical treatment at admission, and 62 (45.9%) underwent carotid revascularization (36 within the first 14 days and 26 beyond). At 90 days, 18 (13.3%) patients had experienced at least 1 stroke recurrence. The risk of recurrence increased progressively according to the SCAIL score (0.0% in patients scoring 0-1, 15.1% scoring 2-3, and 26.7% scoring 4-5; p = 0.04). The adjusted (age, smoking, hypertension, diabetes, carotid revascularization, antiplatelets and statins) hazard ratio for ipsilateral recurrent stroke per 1-point SCAIL increase was 2.16 (95% CI 1.32-3.53; p = 0.002). A score ≥2 had a sensitivity of 100% for recurrence. DISCUSSION: The SCAIL score improved the identification of early recurrent stroke in subgroups who did not experience benefit in endarterectomy trials. Randomized trials are needed to test whether a combined stenosis-inflammation strategy will improve selection for carotid revascularization when benefit is currently uncertain. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, in patients with recent anterior circulation ischemic stroke who do not benefit from carotid revascularization, the SCAIL score accurately distinguishes those at risk for recurrent ipsilateral ischemic stroke.

A Risk Score Including Carotid Plaque Inflammation and Stenosis Severity Improves Identification of Recurrent Stroke.

Background and Purpose- In randomized trials of symptomatic carotid endarterectomy, only modest benefit occurred in patients with moderate stenosis and important subgroups experienced no benefit. Carotid plaque 18F-fluorodeoxyglucose uptake on positron emission tomography, reflecting inflammation, independently predicts recurrent stroke. We investigated if a risk score combining stenosis and plaque 18F-fluorodeoxyglucose would improve the identification of early recurrent stroke. Methods- We derived the score in a prospective cohort study of recent (<30 days) non-severe (modified Rankin Scale score ≤3) stroke/transient ischemic attack. We derived the SCAIL (symptomatic carotid atheroma inflammation lumen-stenosis) score (range, 0-5) including 18F-fluorodeoxyglucose standardized uptake values (SUVmax <2 g/mL, 0 points; SUVmax 2-2.99 g/mL, 1 point; SUVmax 3-3.99 g/mL, 2 points; SUVmax ≥4 g/mL, 3 points) and stenosis (<50%, 0 points; 50%-69%, 1 point; ≥70%, 2 points). We validated the score in an independent pooled cohort of 2 studies. In the pooled cohorts, we investigated the SCAIL score to discriminate recurrent stroke after the index stroke/transient ischemic attack, after positron emission tomography-imaging, and in mild or moderate stenosis. Results- In the derivation cohort (109 patients), recurrent stroke risk increased with increasing SCAIL score (P=0.002, C statistic 0.71 [95% CI, 0.56-0.86]). The adjusted (age, sex, smoking, hypertension, diabetes mellitus, antiplatelets, and statins) hazard ratio per 1-point SCAIL increase was 2.4 (95% CI, 1.2-4.5, P=0.01). Findings were confirmed in the validation cohort (87 patients, adjusted hazard ratio, 2.9 [95% CI, 1.9-5], P<0.001; C statistic 0.77 [95% CI, 0.67-0.87]). The SCAIL score independently predicted recurrent stroke after positron emission tomography-imaging (adjusted hazard ratio, 4.52 [95% CI, 1.58-12.93], P=0.005). Compared with stenosis severity (C statistic, 0.63 [95% CI, 0.46-0.80]), prediction of post-positron emission tomography stroke recurrence was improved with the SCAIL score (C statistic, 0.82 [95% CI, 0.66-0.97], P=0.04). Findings were confirmed in mild or moderate stenosis (adjusted hazard ratio, 2.74 [95% CI, 1.39-5.39], P=0.004). Conclusions- The SCAIL score improved the identification of early recurrent stroke. Randomized trials are needed to test if a combined stenosis-inflammation strategy improves selection for carotid revascularization where benefit is currently uncertain.

Estimated stroke risk, yield, and number needed to screen for atrial fibrillation detected through single time screening: a multicountry patient-level meta-analysis of 141,220 screened individuals.

BACKGROUND: The precise age distribution and calculated stroke risk of screen-detected atrial fibrillation (AF) is not known. Therefore, it is not possible to determine the number needed to screen (NNS) to identify one treatable new AF case (NNS-Rx) (i.e., Class-1 oral anticoagulation [OAC] treatment recommendation) in each age stratum. If the NNS-Rx is known for each age stratum, precise cost-effectiveness and sensitivity simulations can be performed based on the age distribution of the population/region to be screened. Such calculations are required by national authorities and organisations responsible for health system budgets to determine the best age cutoffs for screening programs and decide whether programs of screening should be funded. Therefore, we aimed to determine the exact yield and calculated stroke-risk profile of screen-detected AF and NNS-Rx in 5-year age strata. METHODS AND FINDINGS: A systematic review of Medline, Pubmed, and Embase was performed (January 2007 to February 2018), and AF-SCREEN international collaboration members were contacted to identify additional studies. Twenty-four eligible studies were identified that performed a single time point screen for AF in a general ambulant population, including people ≥65 years. Authors from eligible studies were invited to collaborate and share patient-level data. Statistical analysis was performed using random effects logistic regression for AF detection rate, and Poisson regression modelling for CHA2DS2-VASc scores. Nineteen studies (14 countries from a mix of low- to middle- and high-income countries) collaborated, with 141,220 participants screened and 1,539 new AF cases. Pooled yield of screening was greater in males across all age strata. The age/sex-adjusted detection rate for screen-detected AF in ≥65-year-olds was 1.44% (95% CI, 1.13%-1.82%) and 0.41% (95% CI, 0.31%-0.53%) for <65-year-olds. New AF detection rate increased progressively with age from 0.34% (<60 years) to 2.73% (≥85 years). Neither the choice of screening methodology or device, the geographical region, nor the screening setting influenced the detection rate of AF. Mean CHA2DS2-VASc scores (n = 1,369) increased with age from 1.1 (<60 years) to 3.9 (≥85 years); 72% of ≥65 years had ≥1 additional stroke risk factor other than age/sex. All new AF ≥75 years and 66% between 65 and 74 years had a Class-1 OAC recommendation. The NNS-Rx is 83 for ≥65 years, 926 for 60-64 years; and 1,089 for <60 years. The main limitation of this study is there are insufficient data on sociodemographic variables of the populations and possible ascertainment biases to explain the variance in the samples. CONCLUSIONS: People with screen-detected AF are at elevated calculated stroke risk: above age 65, the majority have a Class-1 OAC recommendation for stroke prevention, and >70% have ≥1 additional stroke risk factor other than age/sex. Our data, based on the largest number of screen-detected AF collected to date, show the precise relationship between yield and estimated stroke risk profile with age, and strong dependence for NNS-RX on the age distribution of the population to be screened: essential information for precise cost-effectiveness calculations.

Carotid Plaque Inflammation Imaged by 18F-Fluorodeoxyglucose Positron Emission Tomography and Risk of Early Recurrent Stroke.

Background and Purpose- Plaque inflammation contributes to stroke and coronary events. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) identifies plaque inflammation-related metabolism. Almost no prospective data exist on the relationship of carotid 18F-FDG uptake and early recurrent stroke. Methods- We did a multicenter prospective cohort study BIOVASC (Biomarkers/Imaging Vulnerable Atherosclerosis in Symptomatic Carotid disease) of patients with carotid stenosis and recent stroke/transient ischemic attack with 90-day follow-up. On coregistered carotid 18F-FDG PET/computed tomography angiography, 18F-FDG uptake was expressed as maximum standardized uptake value (SUVmax) in the axial single hottest slice. We then conducted a systematic review of similar studies and pooled unpublished individual-patient data with 2 highly similar independent studies (Dublin and Barcelona). We analyzed the association of SUVmax with all recurrent nonprocedural stroke (before and after PET) and with recurrent stroke after PET only. Results- In BIOVASC (n=109, 14 recurrent strokes), after adjustment (for age, sex, stenosis severity, antiplatelets, statins, diabetes mellitus, hypertension, and smoking), the hazard ratio for recurrent stroke per 1 g/mL SUVmax was 2.2 (CI, 1.1-4.5; P=0.025). Findings were consistent in the independent Dublin (n=52, hazard ratio, 2.2; CI, 1.1-4.3) and Barcelona studies (n=35, hazard ratio, 2.8; CI, 0.98-5.5). In the pooled cohort (n=196), 37 recurrent strokes occurred (29 before and 8 after PET). Plaque SUVmax was higher in patients with all recurrence ( P<0.0001) and post-PET recurrence ( P=0.009). The fully adjusted hazard ratio of any recurrent stroke was 2.19 (CI, 1.41-3.39; P<0.001) and for post-PET recurrent stroke was 4.57 (CI, 1.5-13.96; P=0.008). Recurrent stroke risk increased across SUVmax quartiles (log-rank P=0.003). The area under receiver operating curve for all recurrence was 0.70 (CI, 0.59-0.78) and for post-PET recurrence was 0.80 (CI, 0.64-0.96). Conclusions- Plaque inflammation-related 18F-FDG uptake independently predicted future recurrent stroke post-PET. Although further studies are needed, 18F-FDG PET may improve patient selection for carotid revascularization and suggest that anti-inflammatory agents may have benefit for poststroke vascular prevention.

A Systematic Review of the Causes and Management of Nonthrombotic Embolic Stroke of Tissue Origin.

INTRODUCTION: Various bodily tissues have been reported to enter the arterial circulation and embolize to the brain resulting in ischemic stroke. Most frequently nonthrombotic embolic stroke (NTES) of tissue origin is iatrogenic or related to an underlying disease process. With the increase in elective surgery and intravascular procedures, NTES may increase in prevalence. AIM: To compile a summary of the background, incidence, presentation, and treatment of NTES of tissue origin, by conducting a systematic review of the current literature. SUMMARY OF REVIEW: We searched EMBASE and MEDLINE for articles on NTES of tissue origin published in English with no restriction on publication date (search date June 2017). 800 articles were identified and screened and 159 articles were ultimately reviewed in full text and included in qualitative analysis. Articles deemed relevant were assessed by a second reviewer to confirm compatibility with the inclusion criteria. References of included articles were reviewed for relevant publications. We categorized the pathology of the emboli into the following groups: amniotic fluid (4 publications), tumour (60 publications), fat (43 publications), cholesterol (19 publications), and intravascular debris (12 publications). We then summarized the available literature on each cause of NTES. CONCLUSIONS: NTES of tissue origin is an uncommon but important diagnosis to consider particularly in younger stroke patients and in certain clinical settings. Treatment for NTES is currently anecdotal and based on small case series. Embolectomy may emerge as the therapy of choice due to the longer treatment timeframe and heterogeneity of the emboli.

Screening for Atrial Fibrillation: A Report of the AF-SCREEN International Collaboration.

Approximately 10% of ischemic strokes are associated with atrial fibrillation (AF) first diagnosed at the time of stroke. Detecting asymptomatic AF would provide an opportunity to prevent these strokes by instituting appropriate anticoagulation. The AF-SCREEN international collaboration was formed in September 2015 to promote discussion and research about AF screening as a strategy to reduce stroke and death and to provide advocacy for implementation of country-specific AF screening programs. During 2016, 60 expert members of AF-SCREEN, including physicians, nurses, allied health professionals, health economists, and patient advocates, were invited to prepare sections of a draft document. In August 2016, 51 members met in Rome to discuss the draft document and consider the key points arising from it using a Delphi process. These key points emphasize that screen-detected AF found at a single timepoint or by intermittent ECG recordings over 2 weeks is not a benign condition and, with additional stroke factors, carries sufficient risk of stroke to justify consideration of anticoagulation. With regard to the methods of mass screening, handheld ECG devices have the advantage of providing a verifiable ECG trace that guidelines require for AF diagnosis and would therefore be preferred as screening tools. Certain patient groups, such as those with recent embolic stroke of uncertain source (ESUS), require more intensive monitoring for AF. Settings for screening include various venues in both the community and the clinic, but they must be linked to a pathway for appropriate diagnosis and management for screening to be effective. It is recognized that health resources vary widely between countries and health systems, so the setting for AF screening should be both country- and health system-specific. Based on current knowledge, this white paper provides a strong case for AF screening now while recognizing that large randomized outcomes studies would be helpful to strengthen the evidence base.

Cost-Effectiveness of a National Opportunistic Screening Program for Atrial Fibrillation in Ireland.

OBJECTIVES: To evaluate the cost-effectiveness of a national atrial fibrillation screening program in Ireland involving annual opportunistic pulse palpation of all those older than 65 years during general practitioner consultations, with an electrocardiogram being performed if an irregular pulse is detected. METHODS: A probabilistic Markov model was used to simulate costs and clinical outcomes in a hypothetical cohort of men and women with and without screening over the course of 25 years, using a societal perspective. RESULTS: Screening was associated with an incremental cost-effectiveness ratio of €23,004/quality-adjusted life-year compared with routine care. Nevertheless, if the relative risk of stroke and systematic embolism in screen-detected patients is more than 12% lower than that in patients with atrial fibrillation identified through routine practice, then screening would not be considered cost-effective at a willingness-to-pay threshold of €45,000/quality-adjusted life-year. An analysis comparing alternative combinations of start age and screening interval found that less frequent screening with a later start age may be more cost-effective than an annual screening from age 65 years. CONCLUSIONS: Annual opportunistic screening of men and women aged 65 years and older in primary care in Ireland is likely to be cost-effective using conventional willingness-to-pay thresholds, assuming that those detected through screening have a comparable stroke risk profile as those detected through routine practice. Raising the start age of screening or increasing the screening interval may improve the cost-effectiveness of a prospective screening program.

Diagnostic accuracy of stroke referrals from primary care, emergency room physicians, and ambulance staff using the face arm speech test.

BACKGROUND AND PURPOSE: Timely referral of appropriate patients to acute stroke units is necessary for effective provision of skilled care. We compared the characteristics of referrals with suspected stroke to an academic acute stroke unit via 3 primary referral routes: ambulance paramedics using a rapid ambulance protocol and stroke recognition instrument, the Face Arm Speech Test; primary care doctors (PCDs); and emergency room (ER) referrals. METHODS: Patient characteristics, final diagnosis, and admission delay were recorded in all suspected acute stroke referrals in a 6-month period. RESULTS: Four hundred eighty-seven patients (356 strokes/transient ischemic attacks) were admitted by the 3 routes: 178 by ambulance, 216 by PCDs, and 93 through the ER. The proportion of nonstrokes admitted by each route was similar (23%, 29%, and 29%, respectively). Ambulance paramedics' stroke diagnosis was correct in 144 of 183 (79%) stroke patients who initially presented to them. Thirty-nine of 66 strokes/transient ischemic attacks referred via ER were taken there following initial ambulance assessment. Compared with PCDs, paramedics referred more total anterior circulation (39% versus 14%, P<0.0001) and fewer lacunar strokes (14% versus 31%, P<0.001) and admitted more patients (46% versus 12%, P<0.01) within 3 hours of symptom onset. The most common nonstroke conditions were seizures, infections and confusion, cardiovascular collapse, and cerebral tumors. Paramedics admitted more patients with seizures. CONCLUSIONS: Misdiagnosis of stroke is common in the ER and by PCDs. Paramedics using the Face Arm Speech Test achieved high levels of detection and diagnostic accuracy of stroke.