Brott, Thomas G.

Background: Hormone replacement therapy (HRT) was among factors considered in a post-hoc assessment of the risk of revascularization by carotid artery stenting (CAS) or carotid endarterectomy (CEA) in women enrolled in CREST. Methods: Of the 872 women in CREST, 775 (89%) were post-menopausal and current HRT status was known in 739 (95%). The study composite outcome was defined as any stroke, myocardial infarction, or death during the periprocedural period, plus ipsilateral stroke over a 4-year follow-up period. Treatment groups were combined and differences in the composite outcome were assessed by current HRT at baseline. Results: There were 77/739 (10%) current HRT users. HRT users were more likely to be symptomatic at baseline than non-users (65% vs. 52%; p = 0.027), and were less likely to be diabetic (19% vs. 32%; p = 0.024). However, they were similar in most other factors including age, race, hypertension, dyslipidemia, smoking status, and length of follow-up (p > 0.10). There were no (0) periprocedural events among the 77 HRT users while there were 43 (6.5%) events among the 662 non-users (p = 0.017). Among those event-free at the end of the periprocedural period, there was little evidence of an impact of baseline HRT on the risk of ipsilateral stroke with 2 (2.6%) post-procedural events among 77 HRT users and 12 (1.9%) among 619 non-users. Conclusion: We found that women on current HRT have lower periprocedural risk associated with CAS or CEA than non-users, but little difference in risk after the procedural period. The mechanism for this unexpected finding is elusive. We urge caution in the interpretation of this post-hoc observation and encourage replication or refutation by other revascularization studies with similar data.

Background: Optimum management of carotid stenosis, both symptomatic (sx) and asymptomatic (asx), remains controversial despite clinical trials evaluating Carotid Endarterectomy (CEA) and Carotid Stenting (CAS). Objective: We compared attitudes in management of carotid stenosis between experts in Europe (EU), and North America (NA). Methods: From April 2011 to July 2012, a 3-round, email-Delphi survey was sent to members of the European Stroke Organisation (n=390) and to a list of NA stroke neurologists developed at the University of Texas at Houston Stroke Program (n=289). Those completing the survey were shown all responses broken down by EU/NA after each of the first 2 survey rounds. Continent specific consensus was defined a priori to be > 80% agreement. Results: 100 (15%, of which 73% EU) participated in all 3-Delphi rounds, 19% of all EU vs 9% NA (χ2=11.62, p=0.0007): 76% male; 69% treating between 1-8 new cases of carotid stenosis per month. In the final round, EU reached consensus in 7/11 statements (3 reached in phase-I), while NA did in 4/11 (1 reached in phase-I).Ninety-percent of EU vs 70% of NA (χ2=8.09, p=0.017) disagreed that CAS and CEA are equivalent treatments for sx carotid stenosis, and stated that CEA is superior. There remains a significant difference between EU and NA when considering ipsilateral stroke and death < 30 days as primary outcome (χ2=12.18, p=0.007). Sixty-nine-percent of NA agreed that there is a stronger indication for CAS over CEA in patients < 65 years for sx carotid stenosis whereas 55% of EU (χ2=11.39, p=0.023) disagreed with the statement. When asked how likely they would recommend CEA for an asx carotid stenosis, 81% of EU and 80% of NA said ‘sometimes’. When asked how likely they would recommend CAS for an asx carotid stenosis, 62% of NA said ‘sometimes’ vs 60% of EU said ‘never’(χ2=3.54, p=0.06). Conclusion: There are several clear differences in attitudes regarding the management of carotid stenosis between EU and NA: EU has a stronger attitude towards superiority of CEA while in NA there is more equipoise between the two treatments. Areas of lack of consensus may provide direction for future clinical trials.

Background An increased risk of periprocedural stroke and death has been reported for older patients treated with carotid stenting (CAS). Selection of patients for CAS could be improved if patient or artery characteristics responsible for this higher risk could be identified. Methods The 1123 CREST patients randomized to CAS who received CAS within 30-days were analyzed. From the CREST sites, risk factors for atherosclerosis (hypertension, diabetes, and dyslipidemia) and arterial characteristics by angiography (lesion length, eccentric lesions, ulcerated lesions, and percent stenosis) were assessed. From the CREST core labs, potential mediators of the age effect included peak systolic velocity (ultrasound core, available on 853 patients) and arterial characteristics (angiographic core, available on 1042 patients, narrow/no ulcer or wide mouth, lesion location, and distal tortuosity). Mediation analysis assessed impact of adjustment for these factors on the magnitude of the estimated increased risk for CAS at older ages. Results After adjustment for sex and symptomatic status, there was a 1.72-times (95% CI: 1.26 - 2.37) increased risk of periprocedural stroke and death associated with each decade of patient age. Adjustment for lesion length as assessed in the clinical center significantly attenuated this increased risk at older ages to 1.66 (95% CI: 1.20 - 2.29, p = 0.039), an 8.3% attenuation. No other factor showed evidence as a contributor to the periprocedural increased risk of stroke and death in older patients (p > 0.10). Conclusion These data suggest that a longer carotid artery lesion length is a significant contributor to the increased risk of CAS in the elderly. However, attenuation of the age effect was modest, less than a 10% change in the hazard ratios. Other potential mediators such as tortuosity and atherosclerosis of the aortic arch and great vessels were not assessed. Non-anatomic factors that are more common with advancing age such as cerebral white matter disease and subclinical dementia were also not assessed and may play a role in how elderly patients respond to ischemic insults.

Background: We have previously reported that carotid artery stenting (CAS) carries a higher stroke risk than carotid endarterectomy (CEA) in patients over the age of 70. The question arises if advanced age is a surrogate for other factors? If so, can those factors be separately identified such that advanced chronological age alone would not be considered a contra-indication for CAS? Here we consider whether the CAS/CEA choice could be guided by other factors known in the clinical center at the time of patient evaluation, independent of age, in order to provide optimal 4-year outcomes. Methods: Demographic factors (age, sex and race), symptomatic status, patient risk factors (hypertension, diabetes, dyslipidemia, smoking), and arterial characteristics (percent stenosis) were available on 2,502 patients. Additional detailed arterial characteristics (ulcerated plaque, distal tortuosity, sequential lesions, circumferential calcification) were available on 1141 CAS and 438 CEA patients. Potential differential treatment efficacy was assessed by the addition of factor-by-treatment interaction terms to a proportional hazard model containing established predictors of outcome (treatment, symptomatic status, sex, age and age-by-treatment interaction). Results: No other factor was found to mitigate advanced age with evidence of additional treatment effect modification of 4-year outcome (p > 0.10). Discussion: Beyond the previously described differential treatment efficacy by age, there were no other patient or arterial characteristic detected to identify patient subgroups that would differentially benefit from the choice of CAS versus CEA. Our inability to identify factors to guide treatment choices could be due to the low number of stroke and death events, incomplete information regarding arterial characteristics in the CEA population, or the potential exclusion of “high risk” groups (such as those with severe arterial tortuosity) from the study.

BACKGROUND: Recent genome-wide association studies (GWAS) have identified a number of novel SNPs associated with blood pressure and hypertension-related traits although studies were very large (approaching 80K participants) and effect sizes were modest with per allele effect sizes as small variants as a single millimeter of mercury difference in blood pressure. However, because hypertension is the most potent modifiable risk factor for ischemic stroke, lowering blood pressure by a few mm Hg can translate into measurable decrease in stroke risk. METHODS: We investigated 22 hypertension (HTN) associated SNPs in a case-control analysis of ischemic stroke in multiple stroke studies including the Siblings With Ischemic Stroke Study (SWISS), the Ischemic Stroke Genetics Study (ISGS), the Bio-Repository of DNA in Stroke (BRAINS), the Vitamin Intervention for Stroke Prevention (VISP) trial, and the Women's Health Initiative (WHI). SWISS/ISGS/BRAINS were analyzed together and included subtype information. Genotyping was funded through the individual studies, the Genomics and Randomized Trials Network (GARNET) consortium, and the SHARe (SNP Health Association Resource). All studies had both raw and imputed GWAS data. Analyses included the following phenotypes: all ischemic stroke, stroke subtypes, and age-at-stroke-onset and were stratified by race. Analyses were minimally adjusted for age, sex and principal components 1 & 2. Alpha was set at 0.05. RESULTS: Eleven of the SNPs from the HTN GWAS were associated with ischemic stroke in European ancestry from one or more of the study populations. Two SNPs on chromosome 12 and one on chromosome 21 were associated in multiple European ancestry cohorts. No SNP was associated in all studies. A SNP previously associated with HTN in African ancestry populations was associated with stroke in African-Americans. Analysis of subtypes found associations with small vessel disease and cardioembolic stroke but not large artery disease. The case-only age-at-stroke-onset analysis also found associations for the two SNPs on chromosome 12. CONCLUSION: These data suggest that candidate SNPs from a HTN GWAS may be associated with ischemic stroke and warrant further investigation. Racial differences were observed. Replication in populations from the other SiGN (Stroke Genetics Network), GENEVA (Gene Environment Association Studies) consortium, and the ISGC (International Stroke Genetics Consortium) studies are underway.

Background The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) enrolled 2502 patients between December of 2000 and mid-July of 2008. We analyzed temporal changes in outcomes for both CEA and CAS over the course of this study. Methods Enrollment was divided into 3 consecutive epochs (5 years, 14 months, and 16 months), each with approximately 834 patients ( Table ). Rates for the primary outcome of death, stroke, and myocardial infarction (DSMI) and for death and stroke (DS) during the periprocedural period were calculated. Poisson regression was used to adjust rates for age, sex, dyslipidemia, and symptomatic status, all of which were found to influence outcomes. Results For CAS, there was a 26% decline in DSMI (6.2% → 4.6%) and a 35% decline in DS (5.5% → 3.6%). For both composite endpoints in CEA there was no consistent pattern ( Table ). As CREST progressed, it enrolled younger patients, more men, patients more likely to be dyslipidemic and enrolled more asymptomatic patients (all p < 0.05). Adjustment for these changes mediated the improvement in event rates for the CAS patients, and had no consistent effect on CEA event rates ( Table ). Conclusion Periprocedural safety for CAS improved over time in CREST. Changes were inconsistent for CEA. Improvements for CAS in part appear to reflect changes in patient selection related to age, sex, and risk factors, as adjustment for those variables attenuated the decline in rates. Linking rates to operator experience was not feasible because of the large number of new interventionalists and surgeons entering CREST over time.

Introduction: Patients with carotid stenosis may have silent cerebrovascular disease due to chronic hypoperfusion and atheroembolism. If so, progression of silent disease may be preventable through revascularization. We aim to evaluate the association between carotid stenosis/occlusion and cerebral small vessel disease (SVD) burden ipsilateral to the cervical carotid stenosis. Methods: Patients age ≥40 years with carotid stenosis or occlusion on carotid ultrasound who underwent MRI brain and intracranial angiogram with gradable SVD on MRI from 2011-2015 were included. Severity of carotid stenosis was defined using NASCET criteria as 50-69% (moderate), 70-99% (high-grade), or occluded. WMH volume was quantified using an automated artificial intelligence algorithm applied to axial T2 FLAIR images. Images were also scored for presence of chronic lacune, cerebral microbleeds (CMB), and silent infarcts using STRIVE criteria. Differences in WMD volume between hemispheres ipsilateral and contralateral to the carotid stenosis were calculated, and prevalence of SVD and silent infarct were compared across severities of carotid stenosis. Results: Of the 183 patients, mean age was 71±10 years and 38% were female. Moderate and severe stenosis was present in 36% and 46.5%, respectively, and 18% had carotid occlusion. Mean WMH volume was 7271±522mm 3 . Patients with carotid stenosis had greater WMH volume ipsilateral to the side of carotid stenosis than the contralateral side (mean difference 224±206mm 3 ), and higher severity of stenosis was associated with greater hemispheric difference in WMH volume (moderate vs high; 164±274mm 3 vs 743±309 mm 3 , p=0.009). Silent infarcts were more prevalent in high-grade carotid stenosis than moderate grade (moderate vs high, 10.8% vs 36.5%; p=0.002). There were no differences in either lacunae or CMBs across severities. Conclusions: Greater than one third of patients with high-grade carotid stenosis had ipsilateral silent brain infarction, and the volume of WMH was greater on the side of carotid stenosis. Future analyses should consider the potential yield of screening for carotid atherosclerosis in patients with varying degrees of hemispheric WMH asymmetry.

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: In order to increase the efficiency and effectiveness of neurovascular clinical research studies, increase data quality, facilitate data sharing, help educate new clinical investigators and reduce study start-up time, the National Institute of Neurological Disorders and Stroke (NINDS) convened a Working Group (WG) that developed Version 1.0 (published 2010) Stroke-specific Common Data Elements (CDEs). Since their initial publication, intervening advances in science and initial experience with the CDEs identified a need to update them and refine guidance on their deployment. Hypothesis/Objective: The NINDS has updated guidance on uniform data structures for use in cerebrovascular research in epidemiology, clinical trials and imaging studies in order to advance the prevention, acute treatment and recovery from cerebrovascular disease. Methods: The NINDS convened experts in research and data element design drawing strongly from investigators in the NIH StrokeNet and other NINDS clinical research projects. Results: Stroke CDE leadership developed a revised process for classifying Stroke CDEs among the four hierarchical categories of Core, Supplemental - Highly Recommended, Supplemental and Exploratory. Due to the heterogeneity of stroke conditions and study types, the classification of Supplemental - Highly Recommended was used for study type (clinical trial or observational), disease type (e.g., ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage) and disease phase (primary prevention, acute, recovery and secondary prevention). Conclusion: The second iteration of NINDS CDE recommendations for neurovascular disease is an important step towards more efficient study start-up time and improved data sharing. The updated CDEs were released on the NINDS CDE website in May 2015. The information at this meeting will include examples of how the Stroke CDEs may be used by a research study, an explanation of the new CDE classifications, and examples of navigating and selecting CDEs from the NINDS CDE website. Support: This project was funded by HHSN271201200034C.

Introduction: Inclusion of asymptomatic patients in randomized trials comparing revascularization to medical therapy has been questioned if they have been previously symptomatic. Hypothesis: Duration of asymptomatic status is not associated with better outcomes following endarterectomy (CEA) or stenting (CAS). Methods: Patients in CREST were classified as asymptomatic if they had not had a TIA or stroke ipsilateral to the study artery within 6 months prior to randomization. We compared those patients who had always been asymptomatic (AA) to those who had been previously symptomatic (PS) ≥ 6 months prior to randomization. Proportional hazards models adjusting for age and treatment were used to assess risk of 30-day stroke or death (S+D), and risk of any 30-day S+D plus ipsilateral stroke at 4 years by asymptomatic status Results: Among the 1056 asymptomatic patients who received the assigned procedure within 30 days of randomization, 977 (93%) were AA and 79 (7%) were PS. There was no difference in the 30-day and 4 year outcomes (Table). Conclusion: In CREST, 93% of the asymptomatic patients were always asymptomatic. Similar outcomes for the previously symptomatic patients (7%) supports the inclusion of such patients in randomized trials comparing CEA and CAS to medical treatment.