Citations

Background and Purpose: The CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) consists of 2 parallel randomized stroke prevention trials in patients with asymptomatic high-grade stenosis of the cervical carotid artery. The purpose of this report is to detail the outcomes of a health screening effort to increase trial enrollment of women and minorities. Methods: Life Line screening (LLS) conducts nationwide screening for vascular disease. Screenings within a 50-mile radius of each CREST-2 center were identified for participation in a joint CREST-LLS program over the course of one year (November 2018 to October 2019) whereby patients with an abnormal carotid ultrasound were referred to the local CREST-2 center for further workup, management, and potential consideration for trial enrollment. Results: LLS completed the screening of 588 198 individuals in 29 732 zip codes across the United States. Of those, 230 021 individuals were screened at events occurring near a CREST-2 clinical center and 646 (0.3%) were found to have abnormal carotid ultrasound findings. Each of the 646 individuals was contacted by CREST-LLS program staff for permission to be referred to their local CREST-2 center; 200 (31%) consented to be contacted by CREST-2. Of those, 39 (19.5%) agreed to be, and were, evaluated at their local CREST-2 center. High-grade stenosis was confirmed in 27 patients. A total of 3 patients were eligible for the trial and were enrolled, one woman but no racial/ethnic minorities. Conclusions: The LLS program appears to identify community-living individuals with high-grade carotid stenosis through ultrasonography. However, the prevalence of abnormal carotid findings was low. In addition, screening and offering participation into the CREST-2 trial had no substantial impact on the proportion of women and minorities enrolled in the trial. Additional innovative strategies are needed to promote enrollment of diverse patients with carotid stenosis into stroke prevention trials.

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.

Background: Carotid endarterectomy (CEA) is the leading procedure for carotid stenosis, yet national data on trends in rates and outcomes are limited. We determined CEA rates among Medicare beneficiaries and evaluated mortality and readmission over 8 years. Methods: We used Medicare fee-for-service data to identify beneficiaries aged ≥65y who had their first CEA (ICD-9 38.12) from 2003-2010 and calculated annual rates per 100,000 person-years (PY). We fit mixed models to assess trends in patient-level outcomes, adjusting for demographics, comorbidities, and symptomatic status. We also evaluated hospital-level trends by calculating risk-standardized mortality (RSMR) and readmission (RSRR) rates. A spatial mixed model adjusted for age, sex, and race was fit to calculate county-specific risk-standardized CEA rates in 2003-2004. Results: There were 505,966 unique CEA hospitalizations. The annual number of CEA discharges decreased from 81,604 in 2003 to 47,597 in 2010 (42% decrease), though the patient characteristics remained largely similar. The national CEA rate was 283 per 100,000 PY in 2003, and there was considerable geographic variability (Figure A). This rate decreased each year to a low of 172 per 100,000 PY in 2010. The rate of stroke or death within 30 days decreased from 3.2 to 2.7%, with a significant adjusted annual reduction of 3% (Figure B). Annual reductions in other short- and long-term outcomes were similar, ranging from 2-3%. The median hospital-level 30-day RSMR decreased over time from 0.99 to 0.57%, while the variation between hospitals increased (interquartile range of 0.7-1.67 percentage points). The 30-day RSRR decreased from 11.0 to 10.1%, but there was more homogeneity across hospitals and years. Conclusions: CEA use among Medicare patients decreased dramatically from 2003-2010, while mortality and readmission outcomes improved. The relative importance of biological and sociological mechanisms for these trends merits further study.

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: 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.

Objectives The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) showed no difference in the composite endpoint of stroke, myocardial infarction, or death between carotid artery stenting (CAS) and carotid endarterectomy (CEA) in patients with symptomatic or asymptomatic carotid stenosis (CS). We compared restenosis or occlusion, and repeat revascularization, between CAS and CEA over 2 years of follow-up. Methods Restenosis, occlusion, and repeat revascularization were assessed at 1, 6, 12 and 24 months post-randomization. Hemodynamically significant restenosis (≥70% diameter reduction) was defined by a peak systolic velocity (PSV) ≥300 cm/second on standardized duplex ultrasonography (DUS), occlusion by an absence of flow within the target artery on DUS, and repeat revascularization by any additional procedure (CEA, angioplasty or CAS) performed on the index artery. Studies were performed in CREST-certified laboratories and interpreted in the CREST Ultrasound Core Lab. Patients included in this report were those who received their assigned treatment within 30 days of randomization and had an ultrasound reviewed at the Core Lab (n=2191). Treatment differences were assessed using proportional hazards models adjusting for age, sex, and symptomatic status. Results In the analytic cohort, 1086 patients received CAS and 1105 received CEA. Over 2 years 113 patients developed restenosis, 56 (rate 5.8%) in the CAS group and 57 (rate 5.8%) in the CEA group; and 8 developed an occlusion, 3 (rate 0.3 %) in the CAS group and 5 (rate 0.5%) in the CEA group. The combined restenosis-occlusion rate was 6.0% (n=58) for CAS and 6.3% (n=62) for CEA (HR=0.90, 95% CI=0.63-1.29, p=0.58). Forty-three patients of the 2191 underwent repeat revascularization (20 CAS, 23 CEA, p=0.69) of which 28 had restenosis by our criteria and so were included ( Figure ). Stroke occurred in 13 (4 CAS; 9 CEA) of the 120 patients with restenosis or occlusion; 1 of the 4 CAS strokes occurred after restenosis was detected, and 5 of 9 CEA strokes occurred after restenosis was detected. Conclusions This analysis of carotid restenosis is the largest reported to date from any randomized clinical trial. Restenosis and occlusion were infrequent and similar up to 2 years following CAS or CEA among 2191 patients. The rates of revascularization likewise did not differ between CAS and CEA. Follow-up out to 10 years is ongoing. Figure. Kaplan-Meier curves of restenosis and occlusion over 2 years.

Background: Historical data suggest that patients with recently symptomatic carotid stenosis are at high risk of early recurrent stroke. Guidelines therefore recommend revascularization within 2 weeks of symptoms. We assessed the risk of stroke or death occurring before revascularization in modern trials of symptomatic carotid stenosis. Methods: We pooled data of all individual patients with symptomatic carotid stenosis randomised to stenting (CAS) or endarterectomy (CEA) in the EVA-3S, SPACE, ICSS and CREST trials. The outcome event (OE) was death or any stroke occurring between randomization and treatment by CAS or CEA, or up to 120 days after randomization among patients not undergoing treatment in this period. Results: 4707 patients were included in the analysis. Median time from qualifying event until randomization was 18 (interquartile range 7-50) days. Median time from randomization until treatment was 6 (2-11) days in the CAS group, and 7 (3-12) days in the CEA group (p<0.001). 31% of patients in the CAS group and 27% in the CEA group underwent revascularization within 14 days of the qualifying event. The OE occurred in 21 patients (CAS: 8, CEA: 13), all within 31 days of randomization (Kaplan Meier estimate: 2.4%, standard error 0.7%; fig.), including 18 non-fatal strokes, 1 fatal stroke, and 2 non-stroke related deaths. In 2 of the patients, the date of the qualifying event was unknown, in 8 patients the OE occurred within 14 days of the qualifying event and in 11 patients >14 days after the qualifying event. All patients with the OE had severe (70-99% degree) stenosis. No other baseline variables predicted the OE. Discussion: Despite the fact that less than a third of patients underwent revascularization within 14 days of the qualifying event, only 2.4% of patients had a recurrent stroke or died before treatment. The risk is lower than expected from historical data, which may reflect advances in medical therapy. Patients at risk are those with severe degree of stenosis.

Purpose: The safety of revascularization for asymptomatic carotid stenosis, and the efficacy of medical therapy for stroke prevention have improved. Therefore, results of prior randomized trials may not apply to current treatment decisions. The NINDS-funded CREST-2 will compare carotid endarterectomy and intensive medical therapy (IMT) versus IMT alone (n=1240), and carotid stenting and IMT versus IMT alone (n=1240) in asymptomatic patients with≥70% stenosis. Materials & Methods: CREST-2 consists of two parallel randomized clinical trials to be conducted at a target of ≈120 centers, including within NINDS StrokeNet. The composite primary outcome is stroke or death during the peri-procedural period or ipsilateral ischemic stroke thereafter up to 4 years. Blinded assessment of cognition will be done periodically. Centrally directed IMT includes tight control of blood pressure (systolic target <140 mm Hg) and cholesterol (LDL target <70 mg/dl) as well as lifestyle coaching. Results: As of June 12, 2015, 94 centers have been approved by the Site Selection Committee. Credentialing is ongoing, with 198 approved surgeons and 64 approved interventionists; 124 additional conditionally approved interventionists will be able to submit additional cases for review under the CREST-2 Registry. The Centers for Medicare and Medicaid will offer CAS reimbursement for Registry enrollees. As of June 12, 2015, there are 39 actively enrolling centers, and 37 patients have been randomized. Conclusion: CREST-2 is designed to identify the best approach for asymptomatic carotid stenosis. The first patient was randomized in December, 2014. An update will be provided regarding the numbers of patients randomized, centers certified, as well as surgeons and interventionists fully approved. Registration: ClinicalTrials.gov Identifier: NCT02089217

Background: Perfusion weighted imaging on MRI (MRP) and computerized tomography perfusion (CTP) are increasingly required to manage large vessel disease. Computerized algorithms can quantify perfusion data, but the programs are expensive and not widely used outside acute stroke evaluation. We aimed to determine how well human observers can identify asymmetries in cerebral perfusion images compared with an automated computer algorithm. Methods: Ten clinicians experienced in treating carotid artery disease (4 vascular neurologists, 3 neuroradiologists, 1 vascular surgeon, 1 neurosurgeon, 1 interventional radiologist) were given 28 post-processed, color-coded, axial-slice MRP scans from patients in the Carotid Revascularization Endovascular versus Stenting Trial - Hemodynamics (CREST-H) study. All patients had >70%, unilateral, asymptomatic carotid artery stenosis and had varying degrees of time-to-peak (TTP) delay on the side of stenosis, ranging from 0 to 2 secs, quantified by a semi-automated system that computes quantitative perfusion maps, using deconvolution of tissue and arterial signals (Olea, Cambridge, MA). A minimum volume of 10cc was required for a given TTP delay. Clinicians were asked to determine asymmetry (y/n) and side of occlusion for each case. Number of correct responses that matched the computer output were tallied. Results: We averaged correct responses by the 10 clinicians for cases at each increment of TTP delay; (Figure). At TTP delays ≥1.5 seconds, accuracy was ≥80%. At 1.25 sec accuracy fell to 60%, and at ≤ 1 sec, accuracy was ≤50%. For TTP=0 (no asymmetry), accuracy was 71%. Conclusions: Visual impression of hemodynamic asymmetry among experienced clinicians was reasonably accurate for TTP delays ≥1.5 seconds, but declined with more subtle asymmetries. Depending on the clinical impact of TTP delays (for CREST-H: correlation with cognitive decline), experienced clinicians may perform as well as an automated algorithm.