Citations

Background and Purpose: Studies of carotid artery disease have suggested that high-grade stenosis can affect cognition, even without stroke. The presence and degree of cognitive impairment in such patients have not been reported and compared with a demographically matched population-based cohort. Methods: We studied cognition in 1000 consecutive CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) patients, a treatment trial for asymptomatic carotid disease. Cognitive assessment was after randomization but before assigned treatment. The cognitive battery was developed in the general population REGARDS Study (Reasons for Geographic and Racial Differences in Stroke), involving Word List Learning Sum, Word List Recall, and Word List fluency for animal names and the letter F. The carotid stenosis patients were >45 years old with ≥70% asymptomatic carotid stenosis and no history of prevalent stroke. The distribution of cognitive performance for the patients was standardized, accounting for age, race, and education using performance from REGARDS, and after further adjustment for hypertension, diabetes, dyslipidemia, and smoking. Using the Wald Test, we tabulated the proportion of Z scores less than the anticipated deviate for the population-based cohort for representative percentiles. Results: There were 786 baseline assessments. Mean age was 70 years, 58% men, and 52% right-sided stenosis. The overall Z score for patients was significantly below expected for higher percentiles ( P <0.0001 for 50th, 75th, and 95th percentiles) and marginally below expected for the 25th percentile ( P =0.015). Lower performance was attributed largely to Word List Recall ( P <0.0001 for all percentiles) and for Word List Learning (50th, 75th, and 95th percentiles below expected, P ≤0.01). The scores for left versus right carotid disease were similar. Conclusions: Baseline cognition of patients with severe carotid stenosis showed below normal cognition compared to the population-based cohort, controlling for demographic and cardiovascular risk factors. This cohort represents the largest group to date to demonstrate that poorer cognition, especially memory, in this disease. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02089217.

Abstract Background The multicenter prospective CREST‐2 Registry (C2R) provides recent experience in performing carotid artery stenting (CAS) for interventionists to ensure safe performance of CAS. Objective To determine the periprocedural safety of CAS performed using a transradial approach relative to CAS performed using a transfemoral approach. Methods Patients with ≥70% asymptomatic and ≥50% symptomatic carotid stenosis, ≤80 years of age and at standard or high risk for carotid endarterectomy (CEA) are eligible for the C2R. The primary endpoint was a composite of severe access‐related complications. Comparisons were made using propensity‐score matched logistic regression. Results The mean age of the cohort was 67.6 ± 8.2 years and 1906 (35.1%) were female. Indications for CAS included 4063 (74.9%) for primary atherosclerosis. A total of 2868 (52.8%) cases underwent CAS for asymptomatic disease. Transradial access was used in 213 (3.9%) patients. The transradial cohort had lower use of general anesthesia (1.5% vs. 6.3%, p = 0.007) and higher use of distal embolic protection (96.7% vs. 89.4%, p = 0.0004). There were no significant differences between radial and femoral access groups in terms of a composite of major access‐related complications (0% vs. 1.1%) or a composite of periprocedural stroke or death (3.3% vs. 2.4%; OR = 1.4 [confidence intervals 0.6, 3.1]; p = 0.42). Conclusion We found no significant differences in rates of major access‐related complications or periprocedural stroke or death with CAS performed using transradial compared to transfemoral access. Our results support incorporation of the transradial approach to clinical trials comparing CAS to other revascularization techniques.

Introduction: Abdominal aortic aneurysm (AAA) rupture is associated with high mortality and morbidity. The U.S. Preventive Services Task Force recommends one-time ultrasound screening for AAA in men age 65-75 who have ever smoked. Little is known about other high-risk subpopulations. Recent linkage and genome-wide association studies confirm a shared genetic risk between AAA and intracranial aneurysms (IA). We tested the hypothesis that sonographic screening for AAA in individuals known to have IA is cost-effective. Methods: A decision tree model was developed to compare costs and outcomes of AAA screening compared to no screening in a hypothetical cohort of patients with IA. Event probabilities, utilities, and costs included in the model were derived through a comprehensive literature review. Expected outcomes of screening vs. no screening were measured in terms of quality-adjusted life years (QALY), lifetime costs and the overall cost-effectiveness ratio. Sensitivity analyses were performed to assess the effects of ranging baseline variables, within plausible minimum and maximum values, on model outcomes, as well as to identify thresholds of model variables where a decision alternative was dominated (both more expensive and less effective than the alternative). Results: In our base-case analysis, screening for AAA provided an additional 0.1055 QALYs (28.1521-screening, 28.0466-no screening) at an additional lifetime cost of $3.62 ($374.57-screening and $370.95-no screening). This yielded an incremental cost-effectiveness ratio (ICER) of $34.31/QALY. In sensitivity analyses, a prevalence of AAA in the IA population ≥ 7.5%, sensitivity of ultrasound screening ≥ 91%, or extrapolating the risk of AAA rupture to 6 years each caused the screening arm to dominate the model. Conclusion: Based on this model, screening for AAA in individuals with IA is cost-effective with an ICER of $34.31/QALY. This is well below accepted societal thresholds estimated to be less than $50,000/QALY. The sensitive variables in the model, particularly co-prevalence of IA and AAA, favored screening within conservative estimates from the literature. Prospective study evaluating the co-prevalence of IA and AAA will further elucidate the value of dedicated screening.

Background: Carotid revascularization was addressed by NASCET and ACAS. NASCET showed a 2-year stroke and death of 32.3% in medical patients and a 15.8% incidence in surgical patients (16.5% absolute/51% relative reduction). Similarly, ACAS revealed an 11% 5-year risk in medical patients and 5.1% in surgical patients (5.9% absolute reduction/53% relative reduction). Absolute risk (rather than relative risk) reduction is of prime interest to the patient. However, in these studies, treatment efficacy was assessed on a relative basis, and these procedures were equally efficacious (51% vs. 53% relative risk). The higher event rates in the symptomatic patients resulted in a larger absolute risk reduction in NASCET (16.5% vs. 5.9%). CREST is the only carotid revascularization study to include both symptomatic and asymptomatic patients undergoing CEA or carotid artery stenting (CAS), and we looked at absolute and relative risks associated with both procedures. Methods: Treatment differences in CREST by symptomatic status were reviewed and interaction terms analyzed. Results: Symptomatic periprocedural stroke and death rates were 6% for CAS vs. 3.2% for CEA (2.8% absolute/47% relative difference/p = 0.02), and were 2.5% for CAS vs. 1.4% for CEA (1.2% absolute/53% relative difference/p = 0.15) for asymptomatic. While treatment differences in periprocedural rates were significant for symptomatic but not asymptomatic patients, there was no difference in treatment efficacy as determined by relative risk reduction. Even the most prominent interaction terms were clearly not significant, p > 0.38. Discussion: There is no evidence of a CAS-CEA difference in treatment efficacy by symptomatic status in CREST. There are significant findings in symptomatic patients. This is likely a product of an increased background rate of events in this strata. While symptomatic status can identify a subgroup with an increased background rate, other factors (e.g. age or stenosis) could identify subgroups of asymptomatic patients with high event rates and large absolute treatment differences.

Background: Considerable disagreement exists among experts regarding the appropriate extent of diagnostic testing after ischemic stroke (IS). Evidence-based data guiding stroke evaluation for individual patients according to the underlying phenotype are unknown. We sought to determine the yield of cardiac and arterial evaluations for identifying an alternative major stroke etiology in patients with a given phenotype in the NINDS Stroke Genetics Network (SiGN). Methods: SiGN is a consortium of IS studies at 22 US and European sites aiming to identify stroke susceptibility genes. Adjudicators certified in Causative Classification of Stroke (CCS) system determined major etiologic stroke phenotypes based on chart review. All diagnostic data entered into the CCS software were stored in a confidential database. We determined the probability of identifying an alternative major abnormality based on cardiac (history, EKG, echocardiography) and arterial [intracranial (IC), extracranial (EC)] evaluations in 3 stroke phenotypes: lacunar infarct (LI), large artery atherosclerosis (LAA), and cardiac embolism (CE). Proportions of alternative major etiologies were calculated in patients with complete evaluations in each phenotype. Results: The analyses included 15720 patients. Among these, 2299 had phenotypic subtype of LI (1660 with cardiac and 1691 with arterial evaluations); 4228 had CE (2451 with arterial evaluation); and 2613 had LAA (2047 with cardiac evaluation). Cardiac evaluation revealed a major cardiac source of embolism in 12.3% of patients with LI and 20.3% with LAA. Echocardiography demonstrated an additional major structural cardiac source not seen by history/examination/EKG in 1.9% and 1.6% in LI and LAA respectively. Arterial evaluation led to the identification of ≥50%ipsilateral stenosis in 13.5% (IC: 8.9%, EC: 5.8%) of patients with LI and 17% (IC: 8.1%, EC: 11.3%) of those with CE. In LI patients with complete cardiac and vascular evaluations, 24.1% had an alternative major stroke etiology. Conclusions: A considerable proportion of IS patients with LI, LAA, and CE harbor an alternative major etiology. In the future, these results can be used to generate evidence-based and cost-effective evaluation and management strategies.

Background: Stroke symptoms in the general population are common (≈18% of adults 45+) and are associated with future stroke. These symptoms may also identify a broad spectrum of clinically-undetected vascular conditions. Methods: Stroke symptoms (sudden weakness, numbness, unilateral or general loss of vision, and loss of ability to communicate or understand) and time to self-reported hospitalization for any cardiovascular (CVD) reason (heart, stroke, or TIA) or stroke were assessed in the REGARDS Study (a national, population-based, longitudinal study of 30,239 African-American and white adults > 45 years enrolled 2003-2007). The symptom-hospitalization association was assessed by proportional hazards analysis in persons stroke/TIA-free at baseline, with adjustment for demographics (age, race and sex), further adjustment for SES (income and education), CVD risk factors (smoking, hypertension, diabetes, dyslipidemia, atrial fibrillation and heart disease), and “perceived health status.” Results: Over an average follow-up of 5.6 years, presence of any stroke symptom was associated with greater risk of hospitalization for stroke (11% versus 6%; HR = 1.68; 95% CI: 1.52 - 1.85), a risk only modestly attenuated by adjustment for SES (HR = 1.59; 95% CI: 1.44 - 1.76), risk factors (HR = 1.44; 95% CI: 1.29 - 1.60), and perceived health (HR = 1.37; 95% CI: 1.23 - 1.53). However, presence of any stroke symptom was more strongly related to hospitalization for CVD (42% vs. 24%; HR = 1.92; 95 CI: 1.82 - 2.03), only modestly mediated by adjustment for SES (HR = 1.82; 95% CI: 1.73 - 1.93), risk factors (HR = 1.66; 95% CI: 1.57 - 1.76), and perceived health (HR = 1.57; 95% CI: 1.48 - 1.66). Conclusions: Stroke symptoms appear to be a marker not only for stroke risk, but also for general CVD. Simple questions can identify 18% of the general population that have over a 40% chance of hospitalization for CVD over a 5-year horizon. Implications for potential intervention to reduce risk are profound.

Background: Recruitment and phenotyping constitute major costs in stroke genetics research. Clinical trial datasets that include biological samples provide an opportunity to leverage richly phenotyped cases for genomic research. However, the heterogeneity of stroke and methodological differences across studies present challenges. We developed and validated a systematic method of mapping data abstracted from a multicenter randomized clinical trial to the inputs of the CCS stroke subtyping system for the SiGN study. Methods: The SiGN Phenotype Committee and the Secondary Prevention of Small Subcortical Strokes (SPS3) research team systematically reviewed SPS3 case report forms (CRF) to identify key elements required to generate CCS subtyping, and drafted and refined mapping rules using a derivation set of 30 charts. The resultant algorithm was compared to manual entry of clinical information into the CCS in a test set of 30 randomly selected charts. This identified problems due to multiple versions of CRFs (up to 7 versions) and prompted revision of the mapping rules. We assessed the revised algorithm in an independent test set. Results: None of the subtype classifications agreed in the initial testing prompting revision to allow capture information from different versions of the CRFs. The revised mapping algorithm applied to the same test set performed well; 29/30 agreed - 20 small artery occlusion (SAO) evident, 4 SAO possible, 2 SAO probable and 3 supra-aortic large artery atherosclerosis evident). The one chart that disagreed was classified as SAO evident by manual entry but as undetermined by the data mapping rules. In the 2nd independent test set, 30/30 agreed: 22 SAO evident, 4 SAO possible, 3 supra-aortic large artery atherosclerosis evident and 1 undetermined unknown - incomplete evaluation. Conclusions: We created mapping rules using CRFs from a clinical trial to allow reliable subtype classification using the CCS. Issues related to multiple iterations of CRFs presented challenges. Highly phenotyped stroke cases from clinical trials represent a cost-effective opportunity for genomic research.

Background and Purpose: NINDS Stroke Genetics Network (SiGN) is an international consortium of ischemic stroke studies that aims to generate high quality phenotype data to identify the genetic basis of ischemic stroke subtypes. The goal of this analysis is to characterize the etiopathogenetic basis of ischemic stroke in the consortium. Methods: This analysis included 16,954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries. 52 trained and certified adjudicators used the web-based Causative Classification of Stroke System for etiologic stroke classification through chart reviews to determine both phenotypic (abnormal test findings categorized in major etiologic groups without weighting towards the most likely cause in the presence of multiple etiologies) and causative subtypes in each subject. Classification reliability was assessed with blinded re-adjudication of 1509 randomly selected cases. Findings: The figure shows the distribution of etiologic categories. Overall, only 40% to 54% of cases with a given major ischemic stroke etiology (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (kappa 0·72, 95%CI:0·69-0·75) and phenotypic classifications (kappa 0·73, 95%CI:0·70-0·75). Conclusions: This study provides high quality data on etiologic stroke subtypes and demonstrates that etiologic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes suggests that the presence of an abnormality in a stroke patient does not necessarily mean that it is the cause of stroke.

Background Carotid artery stent (CAS) placement may be used as an alternative to carotid endarterectomy in selected patients with symptomatic and asymptomatic carotid artery disease. Perhaps because stroke is an uncommon event after CAS, the angiographic predictors of stroke have been incompletely described. Methods A total of 1070 catheter-based angiograms were centrally reviewed in patients undergoing CAS enrolled in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). Of these patients, 43 (4%) experienced periprocedural stroke. Angiograms were reviewed using qualitative and quantitative methodology before and after CAS. Reviews were done blinded to patient outcomes and strokes were adjudicated by a central committee blinded to results of angiography. The view showing the greatest carotid stenosis severity was selected. Extreme tortuosity was defined as 2 severe bends >90 degrees (maximum angulation/20 mm segment) beyond the target lesion, sequential lesions as lesions separated by ≥10 mm, and narrow mouth ulcer as a discrete area of contrast extension beyond the normal arterial lumen with a narrow inlet into the ulceration. Results The internal carotid artery reference diameter was 4.2 ± 0.8 mm, the minimal lumen diameter was 1.1 ± 0.6 mm, and the baseline % diameter stenosis was 74.1 ± 11.6%. There were no differences in vessel size or severity of the stenosis in patients with and without stroke. Morphologic predictors significantly related to the risk of subsequent stroke are listed in the Table . Calcification, lesion eccentricity, baseline flow, and distance from the bifurcation were not predictive of periprocedural stroke (p > 0.05). Conclusion In CREST, four angiographic variables were found to increase risk for stroke during and within 30 days after CAS: severe distal tortuosity, sequential lesions, lesion length > 20 mm, and narrow mouth ulcer. Angiographic characteristics beyond percent stenosis may help in patient selection in terms of best revascularization option.

Objectives: Identification of gene variants of stroke subtypes is important for the development of tailored ischemic stroke therapies among various ethnic groups. Valid and reliable determination of ischemic stroke subtype is essential for achieving this goal and to standardize a classification scheme across multi-center studies and different populations. Causative Classification System for Ischemic Stroke (CCS) is a novel computerized subclassification tool developed to improve reliability and accuracy of classifying stroke types. The CCS algorithm relies on both phenotypic and causative stroke variables. A Hispanic subset of the SiGN, an important and distinct target population with greater risk of certain stroke subtypes, was evaluated with Trial of Org 10172 in Acute Stroke Treatment (TOAST) and CCS and the agreement between the two classification systems was analyzed. Methods: Over 6000 subjects at 15 sites across US and Europe were enrolled, with TOAST and CCS locally adjudicated. Blood collection and central data quality control (10% central readjudication) were performed on all participants. A subset of Hispanics was analyzed for the purpose of this study and the agreement between the TOAST and CCS were assessed by kappa statistic. Findings: Hispanics (n=595, 10.9%) compared to non-Hispanics (n=5457) were more likely to be younger (63.7 vs. 64.0), male (55% vs. 46%) and have fewer of the traditional stroke risk factors HTN (54% vs. 64%), Afib (11% vs. 14%), DM(23% vs. 25%), CAD(16% vs. 20%) and smoking(19% vs. 22%). While the TOAST showed no differences between stroke subtypes for Hispanic vs. non-Hispanics, in CCS, Hispanics were classified with more of large vessel (22% vs. 20%), cardioembolic (37% vs. 30%) and small vessel strokes (13% vs. 9%) and fewer with undetermined etiology (28% vs. 40%) as compared to non-Hispanics. TOAST and CCS offered moderate correlation across all stroke types in Hispanics: kappa of 0.66 for large artery atherosclerosis, 0.58 for cardioembolic, and 0.58 for small artery occlusion. Conclusion: CCS offers a more sensitive and accurate system for subphenotyping of strokes in Hispanics who tended to have relatively fewer risk factors and unclassified strokes. Further studies correlating the two classification systems and their relation to genotyping data are warranted.