The Challenge of Examining Social Determinants of Health in People Living With Tourette Syndrome.

BACKGROUND: To examine the association between race, ethnicity, and parental educational attainment on tic-related outcomes among Tourette Syndrome (TS) participants in the Tourette Association of America International Consortium for Genetics (TAAICG) database. METHODS: 723 participants in the TAAICG dataset aged ≤21 years were included. The relationships between tic-related outcomes and race and ethnicity were examined using linear and logistic regressions. Parametric and nonparametric tests were performed to examine the association between parental educational attainment and tic-related outcomes. RESULTS: Race and ethnicity were collapsed as non-Hispanic white (N=566, 88.0%) versus Other (N=77, 12.0%). Tic symptom onset was earlier by 1.1 years (P < 0.0001) and TS diagnosis age was earlier by 0.9 years (P = 0.0045) in the Other group (versus non-Hispanic white). Sex and parental education as covariates did not contribute to the differences observed in TS diagnosis age. There were no significant group differences observed across the tic-related outcomes in parental education variable. CONCLUSIONS: Our study was limited by the low number of nonwhite or Hispanic individuals in the cohort. Racial and ethnic minoritized groups experienced an earlier age of TS diagnosis than non-Hispanic white individuals. Tic severity did not differ between the two groups, and parental educational attainment did not affect tic-related outcomes. There remain significant disparities and gaps in knowledge regarding TS and associated comorbid conditions. Our study suggests the need for more proactive steps to engage individuals with tic disorders from all racial and ethnic minoritized groups to participate in research studies.

2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association.

BACKGROUND: The American Heart Association (AHA), in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, nutrition, sleep, and obesity) and health factors (cholesterol, blood pressure, glucose control, and metabolic syndrome) that contribute to cardiovascular health. The AHA Heart Disease and Stroke Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, brain health, complications of pregnancy, kidney disease, congenital heart disease, rhythm disorders, sudden cardiac arrest, subclinical atherosclerosis, coronary heart disease, cardiomyopathy, heart failure, valvular disease, venous thromboembolism, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The AHA, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States and globally to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2024 AHA Statistical Update is the product of a full year's worth of effort in 2023 by dedicated volunteer clinicians and scientists, committed government professionals, and AHA staff members. The AHA strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year's edition includes additional global data, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains. RESULTS: Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

Heart Disease and Stroke Statistics-2023 Update: A Report From the American Heart Association.

BACKGROUND: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The American Heart Association, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2023 Statistical Update is the product of a full year's worth of effort in 2022 by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. The American Heart Association strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year's edition includes additional COVID-19 (coronavirus disease 2019) publications, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains. RESULTS: Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

Hemorrhagic Stroke in Children and Adults With Sickle Cell Anemia: The Post-STOP Cohort.

BACKGROUND: Hemorrhagic stroke in young patients with sickle cell anemia remains poorly characterized. METHODS: The Post-STOP (Stroke Prevention Trial in Sickle Cell Anemia) retrospective study collected follow-up data on STOP and STOP II clinical trial cohorts. From January 2012 to May 2014, a team of analysts abstracted data from medical records of prior participants (all with sickle cell anemia). Two vascular neurologists reviewed data to confirm hemorrhagic strokes defined as spontaneous intracerebral, subarachnoid, or intraventricular hemorrhage. Incidence rates were calculated using survival analysis techniques Results: Follow-up data were collected from 2850 of 3835 STOP or STOP II participants. Patients (51% male) were a median of 19.1 (interquartile range, 16.6-22.6) years old at the time of last known status. The overall hemorrhagic stroke incidence rate was 63 per 100 000 person-years (95% CI, 45-87). Stratified by age, the incidence rate per 100 000 person-years was 50 (95% CI, 34-75) for children and 134 (95% CI, 74-243) for adults >18 years. Vascular abnormalities (moyamoya arteriopathy, aneurysm or cavernous malformation) were identified in 18 of 35 patients with hemorrhagic stroke. CONCLUSIONS: The incidence rate of hemorrhagic stroke in patients with sickle cell anemia increases with age. Structural vascular abnormalities such as moyamoya arteriopathy and aneurysms are common etiologies for hemorrhage and screening may be warranted.

Treatment of carotid stenosis in asymptomatic, nonoctogenarian, standard risk patients with stenting versus endarterectomy trials.

OBJECTIVE: Asymptomatic carotid stenosis is the most frequent indication for carotid endarterectomy (CEA) in the United States. Published trials and guidelines support CEA indications in selected patients with longer projected survival and when periprocedural complications are low. Transfemoral carotid artery stenting with embolic protection (CAS) is a newer treatment option. The objective of this study was to compare outcomes in asymptomatic, nonoctogenarian patients treated with CAS vs CEA. METHODS: Patient-level data was analyzed from 2544 subjects with ≥70% asymptomatic carotid stenosis who were randomized to CAS or CEA in addition to standard medical therapy. One trial enrolled 1091 (548 CAS, 543 CEA) and another enrolled 1453 (1089 CAS, 364 CEA) asymptomatic patients less than 80 years old (upper age eligibility). Independent neurologic assessment and routine cardiac enzyme screening were performed. The prespecified, primary composite endpoint was any stroke, myocardial infarction, or death during the periprocedural period or ipsilateral stroke within 4 years after randomization. RESULTS: There was no significant difference in the primary endpoint between CAS and CEA (5.3% vs 5.1%; hazard ratio, 1.02; 95% confidence interval, 0.7-1.5; P = .91). Periprocedural rates for the components are (CAS vs CEA): any stroke (2.7% vs 1.5%; P = .07), myocardial infarction (0.6% vs 1.7%; P = .01), death (0.1% vs 0.2%; P = .62), and any stroke or death (2.7% vs 1.6%; P = .07). After this period, the rates of ipsilateral stroke were similar (2.3% vs 2.2%; P = .97). CONCLUSIONS: In a pooled analysis of two large randomized trials of CAS and CEA in asymptomatic, nonoctogenarian patients, CAS achieves comparable short- and long-term results to CEA.

Baseline Cognitive Impairment in Patients With Asymptomatic Carotid Stenosis in the CREST-2 Trial.

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.

Rationale, Design, and Implementation of Intensive Risk Factor Treatment in the CREST2 Trial.

BACKGROUND AND PURPOSE: The CREST2 trial (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis) is comparing intensive medical management (IMM) alone to IMM plus revascularization with carotid endarterectomy or transfemoral carotid artery stenting for preventing stroke or death within 44 days after randomization or ipsilateral ischemic stroke thereafter. There are extensive clinical trial data on outcomes after revascularization of asymptomatic carotid stenosis, but not for IMM. As such, the experimental treatment in CREST2 is IMM, which is described in this article. METHODS: IMM consists of aspirin 325 mg/day and intensive risk factor management, primarily targeting systolic blood pressure <130 mm Hg (initially systolic blood pressure <140 mm Hg) and LDL (low-density lipoprotein) cholesterol <70 mg/dL. Secondary risk factor targets focus on tobacco smoking, non-HDL (high-density lipoprotein), HbA1c (hemoglobin A1c), physical activity, and weight. Risk factor management is performed by site personnel and a lifestyle coaching program delivered by telephone. We report interim risk factor data on 1618 patients at baseline and last follow-up through 24 months. RESULTS: The mean baseline LDL of 80.5 mg/dL improved to 66.7 mg/dL. The mean baseline systolic blood pressure of 139.7 mm Hg improved to 130.3 mm Hg. The proportion of patients in-target improved from 43% to 61% for systolic blood pressure <130 mm Hg and from 45% to 67% for LDL<70 mg/dL (both changes P<0.001). CONCLUSIONS: The rigorous multimodal approach to intensive stroke risk factor management in CREST2 has resulted in significant improvements in risk factor control that will enable a comparison of cutting-edge medical care to revascularization in patients with asymptomatic carotid stenosis. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02089217.

Impact of COVID-19 on Clinical Research and Inclusion of Diverse Populations.

The randomized clinical trial (RCT) has long been recognized as the 'gold standard' for developing evidence for clinical treatments and vaccines; however, the successful implementation and translation of these findings is predicated upon external validity. The generalization of RCT findings are jeopardized by the lack of participation of at-risk groups such as African Americans, with long-recognized disproportional representation. Distinct factors that deter participation in RCTs include distrust, access, recruitment strategies, perceptions of research, and socioeconomic factors. While strategies have been implemented to improve external validity with greater participation among all segments of the population in RCTs, the coronavirus disease 2019 (COVID-19) pandemic may exacerbate disparities in RCT participation with the potential impact of delaying treatment development and vaccine interventions that are applicable and generalizable. Thus, it is essential to include diverse populations in such strategies and RCTs. This Perspective aims to direct attention to the additional harm from the pandemic as well as a refocus on the unresolved lack of inclusion of diverse populations in conducting RCTs.

The CREST-2 experience with the evolving challenges of COVID-19: A clinical trial in a pandemic.

The coronavirus disease 2019 pandemic has disrupted the lives of whole communities and nations. The multinational multicenter National Institute of Neurological Disorders and Stroke Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial stroke prevention trial rapidly experienced the effects of the pandemic and had to temporarily suspend new enrollments and shift patient follow-up activities from in-person clinic visits to telephone contacts. There is an ethical obligation to the patients to protect their health while taking every feasible step to ensure that the goals of the trial are successfully met. Here, we describe the effects of the pandemic on the trial and steps that are being taken to mitigate the effects of the pandemic so that trial objectives can be met.

Factors influencing credentialing of interventionists in the CREST-2 trial.

BACKGROUND: The Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) is a pair of randomized trials assessing the relative efficacy of carotid revascularization in the setting of intensive medical management (IMM) in patients with asymptomatic high-grade atherosclerotic stenosis. One of the trials assesses IMM with or without carotid artery stenting (CAS). Given the low risk of stroke in nonrevascularized patients receiving IMM, it is essential that there be low periprocedural risk of stroke for CAS if it is to show incremental benefit. Thus, credentialing of interventionists to ensure excellence is vital. This analysis describes the protocol-driven approach to credentialing of CAS interventionists for CREST-2 and its outcomes. METHODS: To be eligible to perform stenting in CREST-2, interventionists needed to be credentialed on the basis of a detailed Interventional Management Committee (IMC) review of data from their last 25 consecutive cases during the past 24 months along with self-reported lifetime experience case numbers. When necessary, additional prospective cases performed in a companion registry were requested after webinar training. Here we review the IMC experience from the first formal meeting on March 21, 2014 through October 14, 2017. RESULTS: The IMC had 102 meetings, and 8311 cases submitted by 334 interventionists were evaluated. Most were either cardiologists or vascular surgeons, although no single specialty made up the majority of applicants. The median total experience was 130 cases (interquartile range [IQR], 75-266; range, 25-2500). Only 9% (30/334) of interventionists were approved at initial review; approval increased to 46% (153/334) after submission of new cases with added training and re-review. The median self-reported lifetime case experience for those approved was 211.5 (IQR, 100-350), and the median number of cases submitted for review was 30 (IQR, 27-35). The number of CAS procedures performed per month (case rate) was the only factor associated with approval during the initial cycle of review (P < .00001). CONCLUSIONS: Identification of interventionists who were deemed sufficiently skilled for CREST-2 has required substantial oversight and a controlled system to judge current skill level that controls for specialty-based practice variability, procedural experience, and periprocedural outcomes. High-volume interventionists, particularly those with more recent experience, were more likely to be approved to participate in CREST-2. Primary approval was not affected by operator specialty.

Ischemic stroke in children and young adults with sickle cell disease in the post-STOP era.

The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) trials established routine transcranial Doppler ultrasound (TCD) screening, with indefinite chronic red cell transfusions (CRCT) for children with abnormal TCD as standard of care. Implementation failures and limitations to the STOP protocol may contribute to continued ischemic stroke occurrence. In the "Post-STOP" study, we sought to assess the impact of the STOP protocol on the incidence of ischemic stroke in a multicenter cohort of former STOP and/or STOP 2 trial participants. A central team abstracted data for 2851 (74%) of the 3835 children who took part in STOP and/or STOP 2. Data included TCD and neuroimaging results, treatment, laboratory data, and detailed clinical information pertaining to the stroke. Two stroke neurologists independently confirmed each stroke using pre-specified imaging and clinical criteria and came to consensus. Among the 2808 patients who were stroke-free at the start of Post-STOP with available follow-up, the incidence of first ischemic stroke was 0.24 per 100 patient-years (95% CI, 0.18, 0.31), with a mean (SD) duration of follow-up of 9.1 (3.4) [median 10.3, range (0-15.4)] years. Most (63%) strokes occurred in patients in whom the STOP protocol had not been properly implemented, either failure to screen appropriately with TCD (38%) or failure to transfuse adequately patients with abnormal TCD (25%). This study shows that substantial opportunities for ischemic stroke prevention remain by more complete implementation of the STOP Protocol.

Does the Association of Diabetes With Stroke Risk Differ by Age, Race, and Sex? Results From the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

OBJECTIVE: Given temporal changes in diabetes prevalence and stroke incidence, this study investigated age, race, and sex differences in the diabetes-stroke association in a contemporary prospective cohort, the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. RESEARCH DESIGN AND METHODS: We included 23,002 non-Hispanic black and white U.S. adults aged ≥45 years without prevalent stroke at baseline (2003-2007). Diabetes was defined as fasting glucose ≥126 mg/dL, random glucose ≥200 mg/dL, or use of glucose-lowering medication. Incident stroke events were expert adjudicated and available through September 2017. RESULTS: The prevalence of diabetes was 19.1% at baseline. During follow-up, 1,018 stroke events occurred. Among adults aged <65 years, comparing those with diabetes to those without diabetes, the risk of stroke was increased for white women (hazard ratio [HR] 3.72 [95% CI 2.10-6.57]), black women (HR 1.88 [95% CI 1.22-2.90]), and white men (HR 2.01 [95% CI 1.27-3.27]) but not black men (HR 1.27 [95% CI 0.77-2.10]) after multivariable adjustment. Among those aged ≥65 years, diabetes increased the risk of stroke for white women and black men, but not black women (HR 1.05 [95% CI 0.74-1.48]) or white men (HR 0.86 [95% CI 0.62-1.21]). CONCLUSIONS: In this contemporary cohort, the diabetes-stroke association varied by age, race, and sex together, with a more pronounced effect observed among adults aged <65 years. With the recent increase in the burden of diabetes complications at younger ages in the U.S., additional efforts are needed earlier in life for stroke prevention among adults with diabetes.

Long-term outcomes of stenting and endarterectomy for symptomatic carotid stenosis: a preplanned pooled analysis of individual patient data.

BACKGROUND: The risk of periprocedural stroke or death is higher after carotid artery stenting (CAS) than carotid endarterectomy (CEA) for the treatment of symptomatic carotid stenosis. However, long-term outcomes have not been sufficiently assessed. We sought to combine individual patient-level data from the four major randomised controlled trials of CAS versus CEA for the treatment of symptomatic carotid stenosis to assess long-term outcomes. METHODS: We did a pooled analysis of individual patient-level data, acquired from the four largest randomised controlled trials assessing the relative efficacy of CAS and CEA for treatment of symptomatic carotid stenosis (Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis trial, Stent-Protected Percutaneous Angioplasty of the Carotid Artery versus Endarterectomy trial, International Carotid Stenting Study, and Carotid Revascularization Endarterectomy versus Stenting Trial). The risk of ipsilateral stroke was assessed between 121 days and 1, 3, 5, 7, 9, and 10 years after randomisation. The primary outcome was the composite risk of stroke or death within 120 days after randomisation (periprocedural risk) or subsequent ipsilateral stroke up to 10 years after randomisation (postprocedural risk). Analyses were intention-to-treat, with the risk of events calculated using Kaplan-Meier methods and Cox proportional hazards analysis with adjustment for trial. FINDINGS: In the four trials included, 4775 patients were randomly assigned, of whom a total of 4754 (99·6%) patients were followed up for a maximum of 12·4 years. 21 (0·4%) patients immediately withdrew consent after randomisation and were excluded. Median length of follow-up across the studies ranged from 2·0 to 6·9 years. 129 periprocedural and 55 postprocedural outcome events occurred in patients allocated CEA, and 206 and 57 for those allocated CAS. After the periprocedural period, the annual rates of ipsilateral stroke per person-year were similar for the two treatments: 0·60% (95% CI 0·46-0·79) for CEA and 0·64% (0·49-0·83) for CAS. Nonetheless, the periprocedural and postprocedural risks combined favoured CEA, with treatment differences at 1, 3, 5, 7, and 9 years all ranging between 2·8% (1·1-4·4) and 4·1% (2·0-6·3). INTERPRETATION: Outcomes in the postprocedural period after CAS and CEA were similar, suggesting robust clinical durability for both treatments. Although long-term outcomes (periprocedural and postprocedural risks combined) continue to favour CEA, the similarity of the postprocedural rates suggest that improvements in the periprocedural safety of CAS could provide similar outcomes of the two procedures in the future. FUNDING: None.

Duration of asymptomatic status and outcomes following carotid endarterectomy and carotid artery stenting in the Carotid Revascularization Endarterectomy vs Stenting Trial.

BACKGROUND: Most carotid revascularization studies define asymptomatic as symptom-free for more than 180 days; however, it is unknown if intervention carries similar risk among those currently asymptomatic but with previous symptoms (PS) vs those who were always asymptomatic (AA). METHODS: We compared the periprocedural and 4-year risks of PS vs AA patients in the Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) randomized to carotid endarterectomy (CEA) or carotid artery stenting (CAS)/angioplasty. Proportional hazards models adjusting for age, sex, and treatment were used to assess the risk of periprocedural stroke and/or death (S+D; any S+D during periprocedural period), stroke and death at 4 years (any S+D within the periprocedural period and ipsilateral stroke out to 4 years) and the primary end point at 4 years (any stroke, death, and myocardial infarction within the periprocedural period and ipsilateral stroke out to 4 years). Analysis was performed pooling the CEA-treated and CAS-treated patients, and separately for each treatment. RESULTS: Of 1181 asymptomatic patients randomized in CREST, 1104 (93%) were AA and 77 (7%) were PS. There was no difference in risk when comparing the AA and PS cohorts in the pooled CAS+CEA population for periprocedural S+D (2.0% vs 1.3%), S+D at 4 years (3.6% vs 3.2%), or the primary end point (5.2% vs 5.8%). There were also no differences among those assigned to CEA (periprocedural S+D, 1.5% vs 0%; S+D at 4 years, 2.7% vs 0%; or primary end point, 5.1% vs 2.4%) or CAS (periprocedural S+D, 2.5% vs 2.8%; S+D at 4 years, 4.4% vs 6.9%; or primary end point, 5.3% vs 9.8%) when analyzed separately. CONCLUSIONS: In CREST, only a small minority of asymptomatic patients had previous ipsilateral symptoms. The outcomes of periprocedural S+D, periprocedural S+D, and ipsilateral stroke up to 4 years, and the primary end point did not differ for AA patients compared with PS patients.

Influence of multiple stents on periprocedural stroke after carotid artery stenting in the Carotid Revascularization Endarterectomy versus Stent Trial (CREST).

BACKGROUND: In the Carotid Revascularization Endarterectomy versus Stent Trial (CREST), carotid artery atherosclerotic lesion length and nature of the lesions were important factors that predicted the observed difference in stroke rates between carotid endarterectomy and carotid artery stenting (CAS). Additional patient-related factors influencing CAS outcomes in CREST included age and symptomatic status. The importance of the operator's proficiency and its influence on periprocedural complications have not been well defined. We evaluated data from CREST to determine the impact of use of multiple stents, which we speculate may be related to technical proficiency. METHODS: CREST includes CAS performed for symptomatic ≥50% carotid stenosis and asymptomatic ≥70% stenosis. Both symptomatic and asymptomatic patients were enrolled in the trial and in the lead-in registry. Data from patients enrolled in the CREST registry and randomized trial from 2000 to 2008 were reviewed for patient- and lesion-related characteristics along with number of stents deployed. The occurrence of 30-day stroke and demographic and clinical features were recorded. Odds ratios for 30-day stroke associated with the use of multiple stents were calculated in univariate analysis and on multivariable analysis after adjustment for demographics (age, sex, symptomatic status), lesion characteristics (length, ulceration, eccentric, percentage stenosis), and risk factors (diabetes, hypertension, dyslipidemia, and smoking). RESULTS: The registry (n = 1531) and trial (n = 1121) enrolled 2652 patients undergoing CAS. The mean age was 69 years; 36% were women, and 38% were symptomatic. The mean diameter stenosis was 78%, and the mean lesion length was 18 mm (±standard deviation, 8 mm). Risk factors included hypertension (85%), diabetes (32%), dyslipidemia (84%), and smoking (23%). All patients received Acculink stents (Abbott Vascular, Abbott Park, Ill) that were 20, 30, or 40 mm in length (straight or tapered) and Accunet (Abbot Vascular) embolic protection when possible. Most patients received one stent (n = 2545), whereas 98 patients received two stents and 9 patients received three stents (P < .001) to treat the lesion. Patients receiving more than one stent were older (P = .01) but did not differ in other demographic or risk factors. Strokes occurred in 118 (4.5%) of all CAS procedures, in 102 (4%) with the use of one stent, and in 16 (15%) with the use of two or three stents. After adjustment for demographics, lesion characteristics, and risk factors, the use of more than one stent resulted in 2.90 odds (95% confidence interval, 1.49-5.64) for a stroke. CONCLUSIONS: Although we know that lesion characteristics (length, ulceration) play an important role in CAS outcomes, in this early experience with carotid stenting, a significant and independent relationship existed between the number of stents used and procedural risk of CAS. We postulate that this was an indicator of the operator's inexperience with the procedure.

Developing a risk-based composite neurologic outcome for a trial of hydroxyurea in young children with sickle cell disease.

BACKGROUND: Studies of interventions to prevent the many neurological complications of sickle cell disease must take into account multiple outcomes of variable severity, with limited sample size. The goals of the studies presented were to use investigator preferences across outcomes to determine an attitude-based weighting of relevant clinical outcomes and to establish a valid composite outcome for a clinical trial. METHODS: In Study 1, investigators were surveyed about their practice regarding hydroxyurea therapy and opinions about outcomes for the "Hydroxyurea to Prevent the Central Nervous System Complications of Sickle Cell Disease Trial" (HU Prevent), and their minimally acceptable relative risk reduction for the two outcome components, motor and neurocognitive deficits. In Study 2, HU Prevent investigators provided overall weights for these two components. In Study 3, they provided more granular rankings, ratings, and maximum number acceptable to harm. A weighted composite outcome, the Stroke Consequences Risk Score, was constructed that incorporates the major neurologic complications of sickle cell disease. The Stroke Consequences Risk Score represents the 3-year risk of suffering the adverse consequences of stroke. In Study 4, the results of the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP2) and Silent Infarct Transfusion Trials were reanalyzed in light of the composite outcome. RESULTS: In total, 22 to 27 investigators participated per study. In Study 1, across three samplings between 2009 and 2015, the average minimally acceptable relative risk reduction ranged from 0.36 to 0.50, at or below the target effect size of 0.50. In 2015, 21 (91%) reported that a placebo-controlled trial is reasonable; 23 (100%), that it is ethical; and 22 (96%), that they would change their practice, if the results of the trial were positive. In Studies 2 and 3, the weight elicited for a cognitive decline (of 10 IQ points) from the overall assessment was 0.67 (and for motor deficit, the complementary 0.33); from ranking, 0.6; from rating, 0.58; and from maximal number acceptable to harm, 0.5. Using data from two major clinical trials, Study 4 demonstrated the same conclusions as the original trials using the Stroke Consequences Risk Score, with smaller p-values for both reanalyses. An assessment of acceptability was performed as well. CONCLUSION: This set of studies provides the rationale, justification, and validation for the use of a weighted composite outcome and confirms the need for the phase III HU Prevent study. Surveys of investigators in multi-center studies can provide the basis of clinically meaningful outcomes that foster the translation of study results into practice while increasing the efficiency of a study.

Periprocedural Stroke and Myocardial Infarction as Risks for Long-Term Mortality in CREST.

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.

Challenge and Yield of Enrolling Racially and Ethnically Diverse Patient Populations in Low Event Rate Clinical Trials.

BACKGROUND AND PURPOSE: We report patient enrollment and retention by race and ethnicity in the CREST (Carotid Revascularization Endarterectomy Versus Stent Trial) and assess potential effect modification by race/ethnicity. In addition, we discuss the challenge of detecting differences in study outcomes when subgroups are small and the event rate is low. METHODS: We compared 2502 patients by race, ethnicity, baseline characteristics, and primary outcome (any periprocedural stroke, death, or myocardial infarction and subsequent ipsilateral stroke up to 10 years). RESULTS: Two hundred forty (9.7%) patients were minority by race (6.1%) or ethnicity (3.6%); 109 patients (4.4%) were black, 32 (1.3%) Asian, 2332 (93.4%) white, 11 (0.4%) other, and 18 (0.7%) unknown. Ninety (3.6%) were Hispanic, 2377 (95%) non-Hispanic, and 35 (1.4%) unknown. The rate of the primary end point for all patients was 10.9%±0.9% at 10 years and did not differ by race or ethnicity (Pinter>0.24). CONCLUSIONS: The proportion of minorities recruited to CREST was below their representation in the general population, and retention of minority patients was lower than for whites. Primary outcomes did not differ by race or ethnicity. However, in CREST (like other studies), the lack of evidence of a racial/ethnic difference in the treatment effect should be interpreted with caution because of low statistical power to detect such a difference. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732.

Factors Associated With Time to Site Activation, Randomization, and Enrollment Performance in a Stroke Prevention Trial.

BACKGROUND AND PURPOSE: Multicenter clinical trials attempt to select sites that can move rapidly to randomization and enroll sufficient numbers of patients. However, there are few assessments of the success of site selection. METHODS: In the CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trials), we assess factors associated with the time between site selection and authorization to randomize, the time between authorization to randomize and the first randomization, and the average number of randomizations per site per month. Potential factors included characteristics of the site, specialty of the principal investigator, and site type. RESULTS: For 147 sites, the median time between site selection to authorization to randomize was 9.9 months (interquartile range, 7.7, 12.4), and factors associated with early site activation were not identified. The median time between authorization to randomize and a randomization was 4.6 months (interquartile range, 2.6, 10.5). Sites with authorization to randomize in only the carotid endarterectomy study were slower to randomize, and other factors examined were not significantly associated with time-to-randomization. The recruitment rate was 0.26 (95% confidence interval, 0.23-0.28) patients per site per month. By univariate analysis, factors associated with faster recruitment were authorization to randomize in both trials, principal investigator specialties of interventional radiology and cardiology, pre-trial reported performance >50 carotid angioplasty and stenting procedures per year, status in the top half of recruitment in the CREST trial, and classification as a private health facility. Participation in StrokeNet was associated with slower recruitment as compared with the non-StrokeNet sites. CONCLUSIONS: Overall, selection of sites with high enrollment rates will likely require customization to align the sites selected to the factor under study in the trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02089217.