Introduction: Careful selection and timely activation of clinical sites in multicenter clinical trials is critical for successful enrollment, subject safety, and generalizability of results. Methods: In the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2), a multidisciplinary Site Selection Committee evaluated applicants referred via participation in CREST, CREST principal investigators (PIs) and other investigators, StrokeNet and industry partners. Data for consideration included performance metrics in CREST and other carotid trials and a site selection questionnaire containing information on the investigators as well as quantitative data on carotid procedures performed. Any FDA warning letters were reviewed. Results: The Committee met bi-weekly for 36 months (n=64 meetings). Applications from 176 sites between March 2014 and July 2016 were evaluated: 153 were approved, 7 are under Committee review, 5 were approved but withdrew, 5 were placed on a waiting list, and 6 were rejected. One-hundred-four sites have completed the regulatory and training requirements to randomize: 51 (49%) academic medical centers, 31 (30%) private hospital-based centers, 16 (15%) private office-based practices, and 6 (6%) Veterans Administration medical centers. The mean times from application-to- approval was 5.2 weeks (interquartile range, 1.9, 6.2), and from approval-to-randomization status was 46.7 weeks (interquartile range, 35.4, 51.7). Specialties of the 104 site PIs are vascular surgery for 35 (33.7%), cardiology for 30 (28.8%), neurology for 25 (24%), neurosurgery for 8 (7.7%), interventional radiology for 4 (3.8%), and interventional neuroradiology for 2 (1.9%). Conclusions: Careful site selection is time-consuming for prospective sites and for trial leadership. Times from application-to-site-approval were modest (mean = 5.2 weeks), in contrast to the times for completing regulatory and training requirements (mean = 46.7 weeks). However, subject enrollment by teams from a wide range of medical centers led by a multi-disciplinary cohort of PIs will promote the generalizability of trial results.

Objective: To summarize the site selection process in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2). Background: Careful selection and timely activation of clinical sites in multicenter clinical trials is critical for successful enrollment, subject safety, and generalizability of results. Design/Methods: In CREST-2, a multidisciplinary Site Selection Committee evaluated applicants referred via participation in CREST, CREST principal investigators (PIs) and other investigators, StrokeNet and industry partners. Data for consideration included performance metrics in CREST and other carotid trials and a site selection questionnaire containing information on the investigators as well as quantitative data on carotid procedures performed. Results: The Committee met bi-weekly for 36 months (n=64 meetings). Applications from 176 sites between March 2014 and July 2016 were evaluated: 153 were approved, 7 are under Committee review, 5 were approved but withdrew, 5 were placed on a waiting list, and 6 were rejected. One-hundred-four sites have completed the regulatory and training requirements to randomize: 51 (49%) academic medical centers, 31 (30%) private hospital-based centers, 16 (15%) private office-based practices, and 6 (6%) Veterans Administration medical centers. The mean times from application-to-approval was 5.2 weeks (interquartile range, 1.9, 6.2), and from approval-to-randomization status was 46.7 weeks (interquartile range, 35.4, 51.7). Specialties of the 104 site PIs are vascular surgery for 35 (33.7%), cardiology for 30 (28.8%), neurology for 25 (24%), neurosurgery for 8 (7.7%), interventional radiology for 4 (3.8%), and interventional neuroradiology for 2 (1.9%). Conclusions: Careful site selection is time-consuming for prospective sites and for trial leadership. The mean time from application-to-site-approval was 5.2 weeks, and the mean time for completing regulatory and training requirements was 46.7 weeks. However, subject enrollment by teams from a wide range of medical centers led by a multi-disciplinary cohort of PIs will promote the generalizability of trial results. Disclosure: Dr. Demaerschalk has nothing to disclose. Dr. Brown has nothing to disclose. Dr. Howard has nothing to disclose. Dr. Tom has nothing to disclose. Dr. Longbottom has nothing to disclose. Dr. Voeks has nothing to disclose. Dr. Kadiric has nothing to disclose. Dr. Meschia has received personal compensation in an editorial capacity for the European Journal of Neurology. Dr. Brott has received personal compensation for activities with 3D Communications and Edwards Lifesciences, LLC as a consultant.

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.

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 ( P inter >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.

Introduction: Participation by American Indian and Alaska Natives (AI/AN) in clinical research may improve AI/AN health outcomes and generalizability of the research. Hypothesis: Cultural beliefs have a strong impact on willingness of AI/AN to participate in research. Methods: We developed a survey to identify if cultural beliefs impact perception of clinical research and the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) protocol. Stroke neurologists and CREST-2 investigators participated in the design of the survey. Participants were stratified based on AI/AN self-identification and level of education. Likert-scale responses were tested with the Mann Whitney-U test and dichotomous responses with the Chi-Square test. Results: There were 102 participants: 61% female, mean age 39, and 37% AI/AN. Eight questions evaluated understanding of research concepts within CREST-2; 89% of these responses were correct, with no significant difference in responses between AI/AN and non-AI/AN or between low (n=42) and high (n=60) education. Compared to other ethnic groups, AI/AN identify more with their culture (p=0.002) and consider cultural beliefs when making health care decisions (p=0.005), including participating in a research study (p=0.002). Using the same questions, we found no difference between respondents with low or high education.(Figure 1) Conclusion: These data support our hypothesis that cultural beliefs have a strong impact on AI/AN willingness to participate in research. It is important for researchers to consider cultural beliefs when designing recruitment strategies for AI/AN populations. Future work will address how cultural beliefs affect AI/ANs’ understanding of and willingness to participate in clinical research.

Objective: Cultural beliefs have a strong impact on willingness of AI/AN to participate in research. Background: Participation by American Indian and Alaska Natives (AI/AN) in clinical research may improve AI/AN health outcomes and generalizability of the research. Methods: We developed a survey to identify if cultural beliefs impact perception of clinical research and the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) protocol. Stroke neurologists and CREST-2 investigators participated in the design of the survey. Participants were stratified based on AI/AN self-identification and level of education. Likert-scale responses were tested with the Mann Whitney-U test and dichotomous responses with the Chi-Square test. Results: There were 102 participants: 61[percnt] female, mean age 39, and 37[percnt] AI/AN. Eight questions evaluated understanding of research concepts within CREST-2; 89[percnt] of these responses were correct, with no significant difference in responses between AI/AN and non-AI/AN or between low (n=42) and high (n=60) education. Compared to other ethnic groups, AI/AN identify more with their culture (92[percnt] vs 65[percnt] p=0.002) and consider cultural beliefs when making health care decisions (69[percnt] vs 39[percnt] p=0.005), including participating in a research study (56[percnt] vs 28[percnt] p=0.002). Using the same questions, we found no difference between respondents with low or high education. Conclusions: These data support our hypothesis that cultural beliefs have a strong impact on AI/AN willingness to participate in research. It is important for researchers to consider cultural beliefs when designing recruitment strategies for AI/AN populations. Future work will address how cultural beliefs affect AI/ANs’ understanding of and willingness to participate in clinical research. Disclosure: Dr. Bennett has nothing to disclose. Dr. Aitken has nothing to disclose. Dr. Longbottom has nothing to disclose. Dr. Brown has nothing to disclose. Dr. De Havenon has nothing to disclose. Dr. Majersik has nothing to disclose. Dr. Majersik has nothing to disclose.

Background: With patients living a decade or longer post-procedure, long-term data are needed to assess the durability of carotid artery stenting versus carotid endarterectomy. Identifying characteristics of those consenting or declining to continue in long-term follow-up may suggest strategies to improve retention in clinical trials. Purpose: This report describes differences between patients choosing or declining to continue follow-up for up to 10 years in the Carotid Revascularization Endarterectomy versus Stenting Trial. Methods: Following completion of the primary outcome, patients who were in active Carotid Revascularization Endarterectomy versus Stenting Trial follow-up were asked to continue beyond their original 4-year commitment for a maximum of 10 years. The characteristics of those who consented were compared with those who declined. Univariate and multivariable logistic regression were used for analysis, and backwards stepwise logistic regression (the most parsimonious model) was used to determine the factors associated with continuation. Results: Of the 1921 active Carotid Revascularization Endarterectomy versus Stenting Trial participants for whom consent to extend follow-up was requested, 1695 (88%; mean age: 68.4) consented; 226 (12%; mean age: 69.6) declined. Of those who did not consent versus those who consented, 66% versus 48% were symptomatic at baseline (p < 0.0001), at follow-up 28% versus 20% were smokers (p = 0.009), 85% versus 90% were hypertensive (p = 0.01), and 84% versus 94% were dyslipidemic (p < 0.0001). Additional factors that differed between those who did not consent and those who consented included the mean number of years in the study at time of consent (4.8 years vs 3.7 years (p = <0.0001)) and patients from sites that enrolled <30 patients compared to sites randomizing 30 or more (70% vs 52% (p < 0.0001)). Multivariable logistic regression indicated that those with lesser odds of consenting to the extended follow-up were older (odds ratio: 0.80; 95% confidence interval: 0.67, 0.96), more likely to be symptomatic (odds ratio: 0.58; 95% confidence interval: 0.42, 0.80), smokers (odds ratio: 0.48; 95% confidence interval: 0.34, 0.70), were in the study 5+ years versus <3 (odds ratio: 0.21; 95% confidence interval: 0.13, 0.34), and at a site that randomized <30 patients (odds ratio: 0.46; 95% confidence interval: 0.33, 0.63), while patients with dyslipidemia at follow-up had increased odds of consenting (odds ratio: 2.28 (1.47, 3.54)). Conclusion: Symptomatic status, increasing age, randomized at lower volume centers, and longer time in follow-up were associated with reduced odds of consenting to long-term follow-up. Identifying factors associated with reduced willingness to extend participation long-term can suggest targeted strategies to improve retention in future clinical trials.

OBJECTIVE: To describe differences between patients choosing or declining extended CREST follow-up (≤10 years). BACKGROUND: Long-term data are needed to assess the durability of CEA versus CAS. Identifying characteristics of those asked to extend participation may suggest mechanisms to improve long-term retention. DESIGN/METHODS: Following completion of the primary outcome, active CREST participants were asked to extend their original four-year commitment up to ten years. Characteristics of those who consented were compared with those who declined. Univariate and multivariable logistic regression were used for analysis; backwards stepwise logistic regression was used to determine the factors associated with continuation. RESULTS: Of 1921 active participants for whom extended follow-up consent was requested, 1695 (89[percnt]; mean age 68.4) consented; 226 (12[percnt]; mean age 69.6) declined. Of those who consented versus those who declined, 48[percnt] vs. 65[percnt] were symptomatic at baseline (p<0.0001), 24[percnt] vs. 35[percnt] were smokers (p=0.001), 87[percnt] vs. 81[percnt] were dyslipidemic (p=0.01) and 29[percnt] vs. 36[percnt] were diabetic (p=0.5). Additional differences between those who consented versus declined included mean years followed at time of consent (3.7 years vs. 4.8 years (p=30 patients versus sites randomizing <30 (48[percnt] vs. 30[percnt] (p<0.0001)). Multivariable logistic regression indicated that those with lower odds of consenting were older (OR 0.75; 95[percnt] CI 0.63, 0.91), more likely symptomatic (OR 0.56; 95[percnt] CI 0.41, 0.78), smokers (OR 0.45; 95[percnt] CI 0.32, 0.63), diabetic (OR 0.70; 95[percnt] CI 0.51, 0.95), followed 5+ years vs. <3 (OR 0.21;95[percnt] CI 0.13, 0.73) and randomized at sites with <30 patients (OR 0.48;95[percnt]CI 0.35, 0.66). CONCLUSIONS: Symptomatic status, increasing age, higher levels of atherosclerotic risk factors, randomized at lower volume centers, and longer time in follow-up, were associated with declining long-term participation. Identifying factors associated with reduced willingness to extend participation can suggest targeted mechanisms to improve long-term retention. Funding: NINDS (US) [R01 NS038384] Disclosure: Dr. Sheffet has nothing to disclose. Dr. Mackey has nothing to disclose. Dr. Brooks has nothing to disclose. Dr. Clark has nothing to disclose. Dr. Hill has received personal compensation for activities with Boehringer Ingelheim and Pfizer, Inc. as advisory board member. Dr. Voeks has nothing to disclose. Dr. Hughes has nothing to disclose. Dr. Tom has nothing to disclose. Dr. Longbottom has nothing to disclose. Dr. Howard has nothing to disclose. Dr. Brott has received personal compensation for activities with 3D Communications and Edwards Lifesciences as a consultant.

OBJECTIVE: To describe differences between patients choosing or declining extended CREST follow-up (≤10 years). BACKGROUND: Long-term data are needed to assess the durability of CEA versus CAS. Identifying characteristics of those asked to extend participation may suggest mechanisms to improve long-term retention. DESIGN/METHODS: Following completion of the primary outcome, active CREST participants were asked to extend their original four-year commitment up to ten years. Characteristics of those who consented were compared with those who declined. Univariate and multivariable logistic regression were used for analysis; backwards stepwise logistic regression was used to determine the factors associated with continuation. RESULTS: Of 1921 active participants for whom extended follow-up consent was requested, 1695 (89[percnt]; mean age 68.4) consented; 226 (12[percnt]; mean age 69.6) declined. Of those who consented versus those who declined, 48[percnt] vs. 65[percnt] were symptomatic at baseline (p<0.0001), 24[percnt] vs. 35[percnt] were smokers (p=0.001), 87[percnt] vs. 81[percnt] were dyslipidemic (p=0.01) and 29[percnt] vs. 36[percnt] were diabetic (p=0.5). Additional differences between those who consented versus declined included mean years followed at time of consent (3.7 years vs. 4.8 years (p=30 patients versus sites randomizing <30 (48[percnt] vs. 30[percnt] (p<0.0001)). Multivariable logistic regression indicated that those with lower odds of consenting were older (OR 0.75; 95[percnt] CI 0.63, 0.91), more likely symptomatic (OR 0.56; 95[percnt] CI 0.41, 0.78), smokers (OR 0.45; 95[percnt] CI 0.32, 0.63), diabetic (OR 0.70; 95[percnt] CI 0.51, 0.95), followed 5+ years vs. <3 (OR 0.21;95[percnt] CI 0.13, 0.73) and randomized at sites with <30 patients (OR 0.48;95[percnt]CI 0.35, 0.66). CONCLUSIONS: Symptomatic status, increasing age, higher levels of atherosclerotic risk factors, randomized at lower volume centers, and longer time in follow-up, were associated with declining long-term participation. Identifying factors associated with reduced willingness to extend participation can suggest targeted mechanisms to improve long-term retention. Funding: NINDS (US) [R01 NS038384]

Background The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) received five years' funding ($21 112 866) from the National Institutes of Health to compare carotid stenting to surgery for stroke prevention in 2500 randomized participants at 40 sites. Aims Herein we evaluate the change in the CREST budget from a fixed to variable-cost model and recommend strategies for the financial management of large-scale clinical trials. Methods Projections of the original grant's fixed-cost model were compared to the actual costs of the revised variable-cost model. The original grant's fixed-cost budget included salaries, fringe benefits, and other direct and indirect costs. For the variable-cost model, the costs were actual payments to the clinical sites and core centers based upon actual trial enrollment. We compared annual direct and indirect costs and per-patient cost for both the fixed and variable models. Differences between clinical site and core center expenditures were also calculated. Results Using a variable-cost budget for clinical sites, funding was extended by no-cost extension from five to eight years. Randomizing sites tripled from 34 to 109. Of the 2500 targeted sample size, 138 (5·5%) were randomized during the first five years and 1387(55·5%) during the no-cost extension. The actual per-patient costs of the variable model were 9% ($13 845) of the projected per-patient costs ($152 992) of the fixed model. Conclusions Performance-based budgets conserve funding, promote compliance, and allow for additional sites at modest additional cost. Costs of large-scale clinical trials can thus be reduced through effective management without compromising scientific integrity.

Background The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) is a multicenter randomized trial of stenting versus endarterectomy in patients with symptomatic and asymptomatic carotid disease. This study assesses management of vascular risk factors. Methods and Results Management was provided by the patient's physician, with biannual monitoring results collected by the local site. Therapeutic targets were low‐density lipoprotein, cholesterol <100 mg/dL, systolic blood pressure <140 mm Hg, fasting blood glucose <126 mg/dL, and nonsmoking status. Optimal control was defined as achieving all 4 goals concurrently. Generalized estimating equations were used to compare risk factors at baseline with those observed in scheduled follow‐up visits for up to 48 months. In the analysis cohort of 2210, significant improvements in risk‐factor control were observed across risk factors for all follow‐up visits compared with baseline. At 48 months, achievement of the low‐density lipoprotein cholesterol goal improved from 59.1% to 73.6% (P<0.001), achievement of the systolic blood pressure goal improved from 51.6% to 65.1% (P<0.001), achievement of the glucose goal improved from 74.9% to 80.7% (P=0.0101), and nonsmoking improved from 74.4% to 80.9% (P<0.0001). The percentage with optimal risk‐factor control also improved significantly, from 16.7% to 36.2% (P<0.001), but nearly 2 of 3 study participants did not achieve optimal control during the study. Conclusions Site‐based risk‐factor control improved significantly in the first 6 months and over the long term in CREST but was often suboptimal. Intensive medical management should be considered for future trials of carotid revascularization. Clinical Trial Registration URL: ClinicalTrials.gov. Unique identifier: NCT00004732.

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

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

Background There is evidence that center-volume of cases affects outcomes for both carotid endarterectomy (CEA) and stenting (CAS). We sought to evaluate the effect of center-volume by site on complication rates in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). Methods In CREST, the primary composite endpoint was any stroke, myocardial infarction, or death within 30 days or ipsilateral stroke in follow-up. Certification was achieved by 477 surgeons performing more than 12 procedures per year with complication rates less than 3% for asymptomatic patients and less than 5% for symptomatic patients; 224 interventionists were certified after a rigorous training and credentialing process that included a lead-in registry. CREST centers were divided into tertiles based on the number of patients enrolled into the study, with Group 1 composed of 82 sites each enrolling <25 patients, Group 2 with 24 sites enrolling 25-51 patients and Group 3 with 10 sites enrolling >51 patients. Differences in periprocedural event rates for the primary composite endpoint and its components were compared using logistic regression adjusting for age, sex, and symptomatic status within site-volume level. Results The safety of CAS and CEA did not vary by site-volume during the periprocedural period as indicated by occurrence of the primary endpoint (p=0.54) or by stroke and death (p=0.87). Conclusion Complication rates (as indicated by the primary endpoint and its components) were low in CREST and were not associated with center-volume. The data are consistent with the value of rigorous training and credentialing in trials evaluating endovascular devices and surgical procedures; because of ongoing entry of new interventionalists and surgeons into CREST, operator experience independent of center-volume cannot be addressed.

Background In previous carotid revascularization trials, stroke as a qualifying symptom has had the greatest importance as a predictor of subsequent outcomes. However, the importance of stroke, TIA, amaurosis fugax, and asymptomatic status has not been analyzed together and comparatively as predictors of outcome for carotid stenosis in a randomized clinical trial (RCT). Methods Qualifying events were analyzed for the 1321 symptomatic patients in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) and were modeled as predictors of the primary outcome (stroke, myocardial infarction, and death during a 30-day peri-procedural period, or ipsilateral stroke over the follow-up period out to 4 years); the potential predictive value was also tested for the outcome of stroke and death. The model included other potential predictors such as age, sex, and treatment. Results The distribution of pre-randomization qualifying events among symptomatic patients in CREST was 572 strokes, 550 TIA, and 199 amaurosis fugax. Relative to symptomatic patients qualifying for the study with stroke, the risk of subsequent primary endpoint was 15% lower for those qualifying with TIA (HR=0.85; 95% CI = 0.57 - 1.28), 36% lower for those qualifying with amaurosis fugax (HR=0.64; 95% CI = 0.3 - 1.23), and 48% lower for asymptomatic patients (HR=0.52; 95% CI = 0.35 - 0.76). The risk of stroke or death was 11% lower for TIA (HR=0.89; 95% CI = 0.57 - 1.40), 18% lower for amaurosis fugax (HR=0.82; 95% CI = 0.42 - 1.60), and 57% lower for asymptomatic patients (HR=0.43; 95% CI = 0.28 - 0.67) when compared to symptomatic patients qualifying with stroke. The risk for patients with stroke or TIA did not differ significantly, and the risk for asymptomatic patients and patients with amaurosis fugax did not differ significantly. Conclusion Outcomes in patients with carotid disease were predicted in descending order by stroke, TIA, amaurosis fugax, and asymptomatic status in a large RCT. Asymptomatic status and amaurosis fugax have a comparatively benign prognosis. Better understanding of these predictors may help in determining who will benefit from carotid revascularization and how quickly they may benefit given the perioperative risks.

Background Randomized clinical trials often encounter slow enrollment. Failing to meet sample size requirements has scientific, financial, and ethical implications. Aims We report interventions used to accelerate recruitment in a large multicenter clinical trial that was not meeting prespecified enrollment commitments. Methods The Carotid Revascularization Endarterectomy vs. Stenting Trial began randomization in December 2000. To accelerate enrollment, multiple recruitment tactics were initiated, which included expanding the number of sites, hiring a recruitment director (May 2003), broadening eligibility criteria (April 2005), branding with a study logo, Web site, and recruitment materials, increasing site visits by study leadership, sending e-mails to the site teams after every enrollment, distributing electronic newsletters, and implementing investigator and coordinator conferences. Results From December 2000 through May 2003, 14 sites became active (54 patients randomized), from June 2003 through April 2005, 44 sites were added (404 patients randomized), and from May 2005 through July 2008, 54 sites were added (2044 patients randomized). During these time intervals, the number of patients enrolled per site per year was 1.5, 3.6, and 5.6. For the single years 2004 to 2008, the mean monthly randomization rates per year were 19.7, 38.1, 56.4, 53.0, and 54.7 (annualized), respectively. Enrollment was highest after recruitment tactics were implemented: 677 patients in 2006, 636 in 2007, and 657 in 2008 (annualized). The prespecified sample size of 2502 patients, 47% asymptomatic, was accomplished on July 2008. Conclusions Aggressive recruitment tactics and investment in a full-time recruitment director who can lead implementation may be effective in accelerating recruitment in multicenter trials.

Background and Purpose— Several carotid endarterectomy randomized, controlled trials and series have reported higher perioperative stroke and death rates for women compared with men. The potential for this same relationship with carotid artery stenting was examined in the lead-in phase of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). Methods— CREST compares efficacy of carotid endarterectomy and carotid artery stenting in preventing stroke, myocardial infarction, and death in the periprocedural period and ipsilateral stroke over the follow-up period. CREST included a “lead-in” phase of symptomatic (≥50% stenosis) and asymptomatic (≥70% stenosis) patients. Patients were examined by a neurologist preprocedure, at 24 hours, and at 30 days. Review of stroke and death was by an independent events committee. The association of sex with periprocedural stroke and death was examined in 1564 patients undergoing carotid artery stenting (26.5% symptomatic). Results— Women comprised 37% of the lead-in cohort and did not differ from men by age, symptomatic status, or characteristics of the internal carotid artery. The 30-day stroke and death rate for women was 4.5% (26 of 579; 95% CI, 3.0% to 6.5%) compared with 4.2% (41 of 985; 95% CI, 3.0% to 5.6%) for men. The difference in stroke and death rate was not significant nor were there any significant differences by sex after adjustment for age, arterial characteristics, or cardiovascular risk factors. Conclusions— These results do not provide evidence that women have a higher carotid artery stenting stroke and death rate compared with men. The potential differential periprocedural risk by sex will be prospectively addressed in the randomized phase of CREST.