Brott, Thomas G.

Objective: The overall risk of ischemic stroke from a chronically occluded internal carotid artery (COICA) is around 5%-7% per year despite receiving the best medical therapy. We propose a radiographic classification of COICA that can be used as a guide to determine the technical success and safety of endovascular recanalization for symptomatic COICA. Methods: The radiographic images of 100 consecutive subjects with COICA were analyzed. A new classification of COICA was proposed based on the morphology, location of occlusion, and presence or absence of reconstitution of the distal ICA. The classification was used to predict successful revascularization in 32 symptomatic COICAs in 31 patients. Patients were included in the study if they had a COICA with ischemic symptoms refractory to medical therapy. Results: Four types (A-D) of radiographic COICA were identified. Types A and B were more amenable to safe revascularization than types C and D. Recanalization was successful at a rate of 68.75% (22/32 COICAs; type A: 8/8; type B: 8/8; type C: 4/8; type D: 2/8). The perioperative complication rate was 18.75% (6/32; type A: 0/8 [0%]; type B: 1/8 [12.50%]; type C: 3/8 [37.50%], type D: 2/8 [25.00%]). None of these complications led to permanent morbidity or death. Twenty (64.52%) of 31 subjects had improvement in their symptoms at the 2-6 months' follow-up. A statistically significant decrease in systolic blood pressure (SBP) was noted in 17/21 (80.95%) patients who had successful revascularization, which persisted on follow-up (p = 0.0001). The remaining 10 subjects in whom revascularization failed had no significant changes in SBP (p = 0.73). Conclusions: The pilot study suggested that our proposed classification of COICA may be useful as an adjunctive guide to determine the technical feasibility and safety of revascularization for symptomatic COICA using endovascular techniques. Additionally, successful revascularization may lead to a significant decrease in SBP postprocedure. A Phase 2b trial in larger cohorts to assess the efficacy of endovascular revascularization using our COICA classification is warranted.

Introduction: Robust leptomeningeal collaterals protect brain from ischemia, yet the determinants of poor collaterals remains unclear. We aimed to identify predictors of poor collaterals in patients with large-vessel occlusive stroke. Methods: We analyzed 112 consecutive patients with middle cerebral artery ± internal carotid artery occlusion from 2012-2016 who presented within 6 hours after stroke symptoms onset. Collaterals on baseline CT-angiogram (poor collaterals ≤50% filling, good collaterals >50% filling) were reviewed blinded to clinical data. Pre-specified predictors of poor collaterals were analyzed with adjusted logistic regression models: including known predictors (age, vascular risk factors and metabolic derangements) and hypothesized predictors (low cardiac output, elevated inflammatory markers, and imaging evidence for chronic cerebral small-vessel disease and chronic steno-occlusive arterial disease). Results: The mean age was 67± 16 years, there were 48% women, 57% white, and median NIHSS was 15 (IQR 11-20). Poor collaterals at baseline were detected in 48%. Multivariable modeling identified that age (aOR 1.8 per 10 years; 95% CI 1.3-2.6; p<0.001), black race (aOR 2.1; 95% CI 1.0-4.5; p=0.043), high blood glucose level (aOR 2.4 per 100 mg/dl; 95% CI 1.1-5.1; p=0.029), and high WMH burden (aOR 6.1; 95%CI 1.8-20.4; p=0.003) were independent predictors of poor collaterals. Associations between low cardiac output, elevated inflammatory markers, intracranial atherosclerosis and poor collaterals did not reach statistical significance (Table). Conclusions: We have identified that advanced age, black race, hyperglycemia, and white matter hyperintensities are predictors of poor collaterals. Independent replication study at another institution is ongoing to further explore the hypothesized predictors.

Background: The importance of physical activity in preventing major vascular events has received increased attention in the past decade. Due to the inclusion of the INTERVENT lifestyle modification program, the CREST2 trial provides a unique opportunity to study physical activity profiles in patients with severe asymptomatic extracranial carotid stenosis. Hypothesis: Based on data from a trial of intracranial stenosis patients, we aimed to evaluate the hypothesis that <40% of carotid stenosis subjects will have optimal physical activity levels. We also assessed key subgroups to determine patterns of physical activity. Methods: We analyzed 1087 CREST2 participants with baseline data on physical activity. The Physician-based Assessment and Counseling for Exercise (PACE) score is recorded for each patient and dichotomized as “in target” (4-8 points) or “out of target” (<4 points). A PACE score of <4 indicates a subject who does not engage in regular exercise. Results are analyzed for the entire trial. Chi square testing and t-tests were performed for evaluation of subgroup differences. Results: The mean age of the study population is 69.5±7.8 years (60% male). The median PACE score at baseline is 4.0 (mean 3.8±2.1; IQR 2 to 6). The Table shows baseline characteristics of patients by mean PACE score. Being male, not having diabetes mellitus, having a body mass index <30kg/m2, being a non-smoker, and not having a history of peripheral arterial disease were associated with significantly higher mean PACE scores (P<0.01). Conclusions: We have defined several patient groups with asymptomatic carotid stenosis that have suboptimal physical activity. These results provide opportunities for targeted efforts to improve primary stroke prevention. These baseline data will also allow investigators to determine if trial involvement and the INTERVENT program leads to improvement in the level of physical activity.

Objectives: Assessment of carotid disease is most commonly performed with duplex ultrasonography (DUS). Measures of plaque area and tissue composition from DUS images may identify patients at risk for future neurologic events, and may assess the effects of vascular risk-factor modification (by measuring change in plaque area and/or tissue constituents). We quantified plaque area and tissue constituents from DUS images of CREST-2 participants at baseline and correlated them with their baseline vascular risk factors. Methods: CREST-2 consists of two multicenter, randomized trials in patients with asymptomatic ≥70% carotid stenosis comparing intensive medical management (IMM) plus endarterectomy or stenting vs IMM alone. Baseline B-mode DUS images from 500 patients underwent manual plaque outlining and automatic pixel brightness assessment. Plaque area, grayscale median (GSM), Gray-Weale score for heterogeneity, and areas for intraplaque hemorrhage and lipid were the output parameters. We computed the parameter estimates (95% confidence intervals) for baseline patient characteristics (age, sex, race, diabetes, smoking, BMI, blood pressure and LDL levels) versus plaque characteristics. Results: High-risk plaque features (larger plaque area, lower GSM , lower Gray-Weale scores, or larger areas of hemorrhage and lipid) were present in older patients, males, and those with elevated diastolic blood pressure and LDL levels (Table). Conclusions: In a randomized trial of asymptomatic patients with high-grade carotid stenosis, DUS-based computation of plaque geometry and tissue composition is feasible. Elevated diastolic blood pressure and LDL levels at baseline are associated with high-risk plaque characteristics. These novel findings identify potentially modifiable targets for aggressive treatment to reduce stroke-risk in patients with carotid stenosis.

Introduction: A 3.4% (95% CI: 2.1% to 4.7%) higher peri-procedural stroke and death risk has been previously documented for those treated with carotid artery stenting (CAS) relative to those treated with carotid endarterectomy (CEA). However, the CAS versus CEA treatment differences in long-term outcomes and the post-procedure durability have not been described. Methods: Data from the 4 largest CAS-versus-CEA randomized trials for treatment of symptomatic carotid atherosclerosis (EVA-3S, SPACE, ICSS, and CREST) were pooled, and treatment differences assessed for the outcome of any stroke or death during a 120-day peri-procedural period, plus ipsilateral stroke afterward. Results: Long-term follow-up was analysed for 4754 patients. Median length of follow-up across the studies ranged from 2.0 to 6.9 years, with 88 peri-procedural and 55 post-procedural events among those CEA-treated, and 169 and 64 for those CAS-treated. After the peri-procedural period, the annual rates of stroke following CAS was 0.6% (95% CI: 0.5 to 0.8) and following CEA 0.6% (95% CI: 0.5 to 0.8), resulting in non-significant durability differences of less than 1% over the period extending up to 9 years (see Table). The previously-documented 3.4% higher peri-procedural event rate in the CAS group contributed to a significant 3.1% (95% CI: 1.6% to 4.7%) treatment difference at 1-year, and the aforementioned similar durability implied that this significant difference remained relatively constant over the period extending up to 9 years (see table). Conclusions: The post-procedure durability of CAS and CEA were similar, both with event rates below 1%. The similarity of post-procedure events rates implies that the previously-documented higher peri-procedural in the CAS group is “carried forward” with a higher risk of outcomes extending to 9-years.

Background and Purpose— We investigated whether procedural stroke or death risk of carotid artery stenting (CAS) compared with carotid endarterectomy (CEA) is different in patients with and without history of coronary heart disease (CHD) and whether the treatment-specific impact of age differs. Methods— We combined individual patient data of 4754 patients with symptomatic carotid stenosis from 4 randomized trials (EVA-3S [Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis], SPACE [Stent-Protected Angioplasty Versus Carotid Endarterectomy], ICSS [International Carotid Stenting Study], and CREST [Carotid Revascularization Endarterectomy Versus Stenting Trial]). Procedural risk was defined as any stroke or death ≤30 days after treatment. We compared procedural risk between both treatments with Cox regression analysis, stratified by history of CHD and age (<70, 70–74, ≥75 years). History of CHD included myocardial infarction, angina, or coronary revascularization. Results— One thousand two hundred ninety-three (28%) patients had history of CHD. Procedural stroke or death risk was higher in patients with history of CHD. Procedural risk in patients treated with CAS compared with CEA was consistent in patients with history of CHD (8.3% versus 4.6%; hazard ratio [HR], 1.96; 95% CI, 0.67–5.73) and in those without (6.9% versus 3.6%; HR, 1.93; 95% CI, 1.40–2.65; P interaction =0.89). In patients with history of CHD, procedural risk was significantly higher after CAS compared with CEA in patients aged ≥75 (CAS-to-CEA HR, 2.78; 95% CI, 1.32–5.85), but not in patients aged <70 (HR, 1.71; 95% CI, 0.79–3.71) and 70 to 74 years (HR, 1.09; 95% CI, 0.45–2.65). In contrast, in patients without history of CHD, procedural risk after CAS was higher in patients aged 70 to 74 (HR, 3.62; 95% CI, 1.80–7.29) and ≥75 years (HR, 2.64; 95% CI, 1.52–4.59), but equal in patients aged <70 years (HR, 1.05; 95% CI, 0.63–1.73; 3-way P interaction =0.09). Conclusions— History of CHD does not modify procedural stroke or death risk of CAS compared with CEA. CAS might be as safe as CEA in patients with history of CHD aged <75 years, whereas for patients without history of CHD, risk after CAS compared with CEA was only equal in those aged <70 years.

Background: The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) previously reported increased mortality in patients who sustained a periprocedural stroke or cardiac event (myocardial infarction [MI] or biomarker only) in follow-up to 4 years. We now extend these observations to 10 years. Methods and Results: CREST is a randomized controlled trial designed to compare the outcomes of carotid stenting versus carotid endarterectomy. Proportional hazards models were used to assess the association between mortality and periprocedural stroke, MI, or biomarker-only events. For 10-year follow-up, patients with periprocedural stroke were at 1.74× the risk of death compared with those without stroke (adjusted hazard ratio [HR]=1.74; 95% CI, 1.21–2.50; P <0.003). This increased risk was driven by increased early (between 0 and 90 days) mortality (adjusted HR=14.41; 95% CI, 5.33–38.94; P <0.0001), with no significant increase in late (between 91 days and 10 years) mortality (adjusted HR=1.40; 95% CI, 0.93–2.10; P =0.11). Patients with a protocol MI were at 3.61× increased risk of death compared with those without MI (adjusted HR=3.61; 95% CI, 2.28–5.73; P <0.0001), with an increased hazard both early (adjusted HR=8.20; 95% CI, 1.86–36.2; P =0.006) and late (adjusted HR=3.40; 95% CI, 2.09–5.53; P <0.0001). Patients with a biomarker-only event were at 2.04× increased risk overall (adjusted HR=2.04; 95% CI, 1.09–3.84; P =0.03) than those without MI, with an increased early hazard (adjusted HR=8.44; 95% CI, 1.09–65.5; P =0.04) and a suggestive but nonsignificant association toward higher 91-day to 10-year risk (1.88; 95% CI, 0.97–3.64; P =0.062) contributing to the increased risk. Conclusions: In the CREST trial, patients with periprocedural events demonstrate a substantial increase in future mortality to 10 years. For stroke, this risk is largely confined to an early time frame while periprocedural MI or biomarker-only events confer a continuous increased mortality for 10 years. Strategies to reduce periprocedural events and to optimize the evaluation and management of patients with cardiac events should be considered in efforts to reduce not only early but also long-term mortality. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00004732.

Background and Purpose— Stenting for symptomatic carotid stenosis (carotid artery stenting [CAS]) carries a higher risk of procedural stroke or death than carotid endarterectomy (CEA). It is unclear whether this extra risk is present both on the day of procedure and within 1 to 30 days thereafter and whether clinical risk factors differ between these periods. Methods— We analyzed the risk of stroke or death occurring on the day of procedure (immediate procedural events) and within 1 to 30 days thereafter (delayed procedural events) in 4597 individual patients with symptomatic carotid stenosis who underwent CAS (n=2326) or CEA (n=2271) in 4 randomized trials. Results— Compared with CEA, patients treated with CAS were at greater risk for immediate procedural events (110 versus 42; 4.7% versus 1.9%; odds ratio, 2.6; 95% CI, 1.9–3.8) but not for delayed procedural events (59 versus 46; 2.5% versus 2.0%; odds ratio, 1.3; 95% CI, 0.9–1.9; interaction P =0.006). In patients treated with CAS, age increased the risk for both immediate and delayed events while qualifying event severity only increased the risk of delayed events. In patients treated with CEA, we found no risk factors for immediate events while a higher level of disability at baseline and known history of hypertension were associated with delayed procedural events. Conclusions— The increased procedural stroke or death risk associated with CAS compared with CEA was caused by an excess of events occurring on the day of procedure. This finding demonstrates the need to enhance the procedural safety of CAS by technical improvements of the procedure and increased operator skill. Higher age increased the risk for both immediate and delayed procedural events in CAS, mechanisms of which remain to be elucidated. Clinical Trial Registration— URL: https://clinicaltrials.gov . Unique identifier: NCT00190398. URL: http://www.isrctn.com . Unique identifier: ISRCTN57874028. URL: http://www.isrctn.com . Unique identifier: ISRCTN25337470. URL: https://clinicaltrials.gov . Unique identifier: NCT00004732.

Background: In CREST2, intensive medical management of subjects’ vascular risk factors is overseen by the site Principal Investigator (PI) and implemented by a designated Medical Management Physician (MMP) and coordinator. These physicians have different specialties and experience with risk factor management. We sought to determine the relationship between risk factor control and PI and MMP specialty. Methods: Data on 613 patients with at least 1 follow-up visit from 105 CREST2 sites were used for these analyses. CREST2 sites were categorized based on both PI specialty and MMP specialty. Specialty of the site-designated primary MMP was used for sites with more than one MMP. We compared the percentage of patients in target at last follow-up visit for the primary risk factors, LDL < 70 mg/dL and SBP <140 mm Hg, among PI specialties and MMP specialties, using the chi-square test. Results: The table shows the number of patients by PI and MMP specialty, as well as their control of SBP and LDL. There were no significant differences in control of SBP or LDL by PI specialty. There was a trend toward an association between LDL control and MMP specialty, with higher rates of LDL control at sites with Internal Medicine MMP specialists and lower rates of control with Vascular Surgery MMPs. SBP control rates were not significantly different across MMP specialties. Conclusions: In this early analysis of risk factor control in the CREST2 study, site PI and MMP specialty did not have a significant effect on LDL and SBP during follow-up. This suggests that protocol care pathways are generalizable to diverse physicians.