Citations

Background: CREST, a randomized trial comparing carotid artery stenting (CAS) with endarterectomy (CEA) in symptomatic and asymptomatic patients, reported in 2010 that the two procedures were similar for the composite endpoint of stroke, myocardial infarction, or death. Data on temporal trends in the use of these procedures in the US are limited, particularly by sex, race, and geographic region. We reviewed trends in utilization of CAS and CEA for ischemic stroke patients. Methods: Ischemic stroke hospitalizations (ICD-9 433, 434, 436) were identified for patients aged ≥18 years from the Nationwide Inpatient Sample 2007-2011 (N=480,375). Annual trends of CAS and CEA were estimated using mixed models that adjusted for patient age and comorbidities. Models were stratified by sex, race (white, black, other), and 9 geographic regions. Results: Overall, the proportion of stroke patients who received CAS remained relatively stable over time (2.7% in 2007 to 2.8% in 2011) while the proportion who received CEA decreased (from 21.0% to 16.3%). CAS rates increased in the three Central Regions (East North, East South, and West South) but decreased in New England; CEA declines were similar across regions. In adjusted analyses, CAS rates increased slightly for white men, decreased for men and women of other race, but remained stable for the remaining groups (Figure); CEA rates decreased for all sex-race groups. These patterns by sex and race subgroups were generally consistent across geographic regions. Conclusions: The proportion of hospitalized stroke patients receiving CEA decreased over time while CAS rates remained relatively stable, with slight increases seen in the Central regions of the US. There are sex-race differences in the proportion of patients who receive these procedures, but these patterns are largely similar across regions.

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.

Background: The CREST trial demonstrated that for patients at standard risk of surgical complications, there was no significant difference in the primary composite outcome of periprocedural death, MI, or stroke, or late ipsilateral stroke between carotid artery stenting (CAS) and carotid endarterectomy (CEA), although CAS had a higher rate of stroke, and CEA had a higher rate of MI. The economic implications of these two strategies are unknown. Methods: We performed a prospective health economic study alongside the CREST trial. Costs were assessed from the perspective of the US health care system in 2008 dollars using a combination of resource-based and event-based methods. Costs for carotid revascularization procedures were based on measured resource use and unit costs derived from a sample of study hospitals. Non-procedural costs for these hospitalizations were estimated using hospital billing data (charges) and cost-center-specific cost-to-charge-ratios. Costs for follow-up events were estimated using national average DRG reimbursements. The primary analysis was based on a modified intention-to-treat population for which the assigned procedure was attempted (n=1212 CAS; 1193 CEA). Results: CAS was associated with higher total procedural costs (Δ=$675, see Table), driven mainly by higher costs for disposable supplies. Length of stay was shorter for CAS, with associated reductions in non-procedural hospital costs (Δ = -$436). Total cost for the index hospitalization remained slightly higher for CAS (Δ=$239) with similar differences at 1 year. Conclusions: For patients at standard risk of surgical complications, total 1-year costs are slightly higher for CAS vs. CEA, driven largely by higher initial procedural costs. Cost-utility analysis will be performed to determine whether differences in quality of life observed in CREST render CAS an economically attractive strategy. CAS (n= 1212) CEA (n=1193) Δ CAS - CEA (95% CI via bootstrap) Index Procedure Costs, $ Excluding MD Fees 6782 ± 1412 5743 ± 1370 1039 (926, 1148) MD Fees 1114 ± 240 1478 ± 108 -364 (-379, -349) Total 7896 ± 1551 7221 ± 1450 675 (555, 800) Index Hospital Stay 7159 ± 5108 7595 ± 7482 -436 (-951, -59) TOTAL Index Hosp Costs 15055 ± 5539 14816 ± 7709 239 (-302, 778) Index Hosp LOS (days) ICU LOS 0.7 ± 1.1 0.8 ± 1.4 -0.1 (-0.24, -0.04) Non-ICU LOS 1.9 ± 3.2 2.2 ± 4.1 -0.2 (-0.55, 0.06) TOTAL LOS 2.6 ± 3.3 3.0 ± 4.5 -0.4 (-0.7, -0.06) 1-year Rehosp Costs: Repeat Revasc - CAS 295 ± 2097 273 ± 2126 -21 (-142, 201) Repeat Revasc - CEA 287 ± 2088 477 ± 2510 -190 (-371, -11) Ipsilateral Stroke 556 ± 3273 384 ± 2580 172 (-75, 402) TIA 48 ± 520 33 ± 487 16 (-25, 56) Death 63 ± 846 45 ± 779 18 (-49, 85) TOTAL Rehosp costs 1321 ± 4827 1293± 4502 28 (-334, 396) TOTAL 1-year costs 16375 ± 7730 16108 ± 9030 267 (-366, 961)

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

Introduction: The relative performance of carotid artery stenting (CAS) and carotid endarterectomy (CEA) among Medicare beneficiaries in routine clinical practice has not been established. Objective: To compare the performance of CAS relative to CEA among Medicare beneficiaries. Methods: We linked Medicare data (2000-2009) to the Society for Vascular Surgery’s Vascular Registry (SVS-VR; 2005-2008) and to the NCDR® Carotid Artery Revascularization and Endarterectomy Registry (CARE; 2006-2008/9). Medicare patients aged ≥66 years undergoing CAS or CEA were followed from the procedure date for the outcomes of death, stroke/transient ischemic attack (TIA), peri-procedural myocardial infarction (MI) or a composite endpoint for these outcomes. We derived high-dimensional propensity scores using registry and Medicare data to control for patient-level factors and adjusted for provider-level factors including past-year CAS/CEA physician and hospital volume, hospital ownership, teaching affiliation, and hospital size in a Cox regression model comparing CAS to CEA. Results: Among 5,254 SVS-VR (1,999 CAS and 3,255 CEA) and 4,055 CARE (2,824 CAS and 1,231 CEA) patients, CAS patients were more often at higher surgical risk (SVS-VR: 96.7% vs. 44.5%; CARE: 71.3% vs. 44.7%) and had a higher comorbidity burden. Crude outcome risks for death and stroke/TIA were lower for CEA. Adjusting for patient-level factors drove estimates downwards for CAS relative to CEA but only after further adjustment for provider-level factors did the performance of CAS and CEA become comparable on all outcomes (figure 1). Conclusion: Performance of CAS and CEA among Medicare beneficiaries was comparable after accounting for patient- and provider-level factors, which is consistent with landmark trials. Further studies are needed to understand the role of heterogeneity in provider-level characteristics.

Introduction: Left ventricular assist device (LVAD) is known to extend survival in patients with advanced heart failure but it is associated with intracranial cranial hemorrhage (ICH). In the last decade, the use of LVAD substantially increased along with advances in LVAD technology, but there is limited data regarding the trends of ICH risk and predictors in patients with LVAD. Methods: We included the patients aged≥18 years with primary diagnosis of LVAD hospitalized in the US from 2005 to 2014 using the National Inpatient Sample. We computed the survey weighted percentages with ICH across the 10-year study period and assessed whether the proportions changed over time. Predictors of ICH were evaluated using the multivariable logistic regression model. All analyses were appropriately adjusted for the survey design variables to account for the complex survey design. Results: Of 33,246 hospitalizations, 568 (1.7%) had ICH. The number of LVAD placement has increased from 873 in year 2005 to 5,175 in year 2014. However, the risk of ICH remained largely unchanged from 1.7% to 2.3% (linear trend: p=0.604). The adjusted odds of ICH was increased with the presence one of the following variables: female sex (odds ratio [OR]: 1.58, 95% confidence interval [CI] 1.03-2.43), history of ischemic stroke (OR: 3.13, 95% CI 1.86-5.28), and Charlson Comorbidity Index (CCI) of ≥3 (OR: 77.40, 95% CI 10.03-597.60). Conclusions: Despite advances in LVAD technology and its increased use in patients with advanced heart failure, the risk of ICH has remained relatively unchanged. High CCI and history of ischemic stroke were associated with higher odds of ICH in patients with LVAD. With the advent of magnetically levitated centrifugal-flow LVAD, future trend of ICH may change and further research efforts are needed to prevent ICH in patients with LVAD.

Introduction: Robust leptomeningeal collaterals protect the brain from ischemia, yet the determinants of poor collaterals have not been established. We aimed to identify predictors of poor collaterals in patients with large vessel occlusive stroke. Methods: Consecutive patients with large vessel occlusive stroke who underwent thrombectomy at 2 academic medical centers (derivation cohort/validation cohort) from 2012-2017 were included. Poor collaterals were defined as ≤50% filling on CT angiogram. Pre-specified predictors of poor collaterals were analyzed with adjusted logistic regression models: demographics (age, sex, race), risk factors (hypertension, diabetes, atrial fibrillation, smoking), hemodynamics (blood pressure, cardiac output, troponin), metabolic (hyperglycemia, hyponatremia, uremia), hematologic (anemia, leukocytosis, thrombocytosis) and neuroimaging evidence of chronic cerebral small-vessel disease and chronic steno-occlusive arterial disease. Results: Of the 248 total patients, poor collaterals were detected in 107 (43%). Mean age was 71±14y vs. 63±16y in patients with poor vs good collaterals, respectively (p<.001). There were 136 patients in the derivation cohort; 54 (48%) patients with poor collaterals. Multivariable modeling identified that older age (OR 1.8, p<.001), hyperglycemia (OR 2.4, p=.029) and white matter hyperintensities (WMH) (OR 6.1, p=.003) were independent predictors of poor collaterals in the derivation cohort. The validation cohort consisted of 136 patients; 53 (39%) had poor collaterals, of which older age (OR 1.4, p=.015), thrombocytosis (OR 24.0, p=.012), and WMH (OR 6.7, p=.018) were significant predictors of poor collaterals. Age and WMH were the only significant predictors of poor collaterals across the derivation and validation cohorts. When pooled the cohorts, older age (OR=1.5, p<.001), thrombocytosis (OR=7.6, p=.001) and WMH (OR=6.4, p<.001) were significant predictors of poor collaterals. Conclusions: We have identified that advanced age, WMH, and thrombocytosis are predictors of poor collaterals. Future studies to explore the effect of vascular aging on collateral therapeutics are indicated.

Introduction: Cilostazol has promise as an alternative to aspirin for secondary stroke prevention given its vasodilatory and anti-inflammatory properties in addition to platelet aggregation inhibition. We conducted a systematic review and meta-analysis to estimate the comparative effectiveness and safety of cilostazol compared to aspirin for stroke prevention in patients with previous stroke or TIA. Hypothesis: Cilostazol is more effective than aspirin in preventing recurrent ischemic stroke with lower risk of intracranial hemorrhage and bleeding. Methods: We searched PubMed and the Cochrane Central Register of Controlled Trials from inception to 2019. Randomized clinical trials that compared cilostazol vs aspirin and reported the endpoints of ischemic stroke, intracranial hemorrhage and bleeding were included. A random-effects estimate was computed based on Mantel-Haenszel methods. The pooled estimates with 95% confidence intervals were compared between cilostazol and aspirin and displayed as forest plots (Figure). Results: The search identified 5 randomized clinical trials comparing cilostazol vs aspirin for secondary stroke prevention that enrolled 7,240 patients from primarily Asian countries (3,615 received cilostazol and 3,625 received aspirin). The pooled results from the random-effects model showed that cilostazol was associated with significantly lower risk of recurrent ischemic stroke (Hazard ratio [HR] 0.70; 95%CI, 0.54-0.89), intracranial hemorrhage (HR 0.41; 95%CI, 0.25-0.65) and bleeding (HR 0.71; 95%CI, 0.55-0.91). See forest plots. Conclusion: This meta-analysis suggests cilostazol is more effective than aspirin in the prevention of recurrent ischemic stroke with lower risk of intracranial hemorrhage and bleeding. Confirmatory randomized trials of cilostazol for secondary stroke prevention to be performed in more generalizable populations are needed.

Introduction: Left atrial enlargement (LAE) is associated with atrial fibrillation, a frequent cause of large vessel occlusion (LVO) leading to ischemic stroke. Leptomeningeal collaterals protect tissue from ischemia, but the association between collaterals and structural heart disease is not well described. We aim to investigate the association between LAE and cerebral collaterals during acute LVO when microvasculature, vasodilation, and chronotropic competence are critically important. Hypothesis: Left atrial enlargement is associated with poor collaterals. Methods: We reviewed consecutive patients presenting with middle cerebral and internal carotid LVO who underwent thrombectomy from 2012 to 2017. Patients with CT angiogram of the head and echocardiogram were included. Poor collaterals were defined as ≤ 50% filling on CT angiogram. LAE was defined as left atrial volume index ≥ 35 mL/m 2 . Multivariate logistic regression analysis was performed to evaluate the relationship between LAE and poor collaterals with adjustment for age and hypertension. Results: There were 128 eligible patients. The mean age was 68± 15 years, median NIHSS was 17, and 51 (39.8%) had LAE. Baseline characteristics are described in the table. Poor collaterals were observed in 50 (39%) patients. Patients with LAE were more likely to have poor collaterals compared to those with normal left atrial size (52.9% vs. 29.9%, p=0.009). After adjusting for age and hypertension, a trend towards association remained (OR 2.00, p=0.089). Conclusion: Our results indicate that patients with LVO and LAE were more likely to have poor collaterals. Further research is warranted to determine the cause of the association. One possibility is shared pathophysiology affecting both cardiac and cerebral vasculature such as microvascular disease or endothelial dysfunction. Alternatively, structural heart disease causing chronotropic incompetence may lead to poor collateral filling.

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.