Lal, Brajesh K.

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

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

Rationale: Asymptomatic carotid stenosis is commonly seen in medical practice. CREST-2 is a pair of concurrent two-arm multi-site randomized trials of intensive medical management versus intensive medical management in combination with revascularization by endarterectomy or stenting. It is not known how often patients entering the trials have opportunities for further risk factor reduction at study entry and whether these opportunities vary across trial centers. Methods: Baseline data on 683 patients from 109 clinical sites were used for these analyses. We determined the rates of control at baseline for systolic blood pressure (SBP), defined as <140 mmHg (or ≥140 with >15mmHg orthostatic drop), and low density lipoprotein (LDL), defined as <70 mg/dl. We then tested differences in these baseline control rates by site-related characteristics, including site type, StrokeNet site vs. not, specialty of site Principal Investigator (PI), type of hospital, central vs local IRB, type of research team and whether site is enrolling in one or both trials. P-value <0.05 was considered significant. Results: At baseline, the mean SBP was 140.4±20.5 mmHg, but only 62% of participants were in target. The mean LDL at baseline was 83.7±36.9, mg/dl, with 42% in target. None of the site characteristics were associated with a higher level of control for SBP at baseline. The only characteristic associated with having a higher level of LDL control was sites enrolling in only the CAS trial (57%) compared to those enrolling in the CEA only (24%) or in both trials (42%) (p=0.02). Conclusions: Opportunities to improve on risk factors are common among CREST-2 participants, but site characteristics did not predict the likelihood of being at goal for SBP while sites enrolling in only the CAS trial had a higher level of LDL control.

Rationale For patients with asymptomatic high-grade carotid stenosis, clinical investigations have focused on preventing cerebral infarction, yet stenosis that reduces cerebral blood flow may independently impair cognition. Whether revascularization of a hemodynamically significant carotid stenosis can alter the course of cognitive decline has never been investigated in the context of a randomized clinical trial. Hypothesis Among patients randomized in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis (CREST-2) trials, the magnitude of treatment differences (revascularization versus medical management alone) with regard to cognition will differ between those with flow impairment compared to those without flow impairment. Sample size We will enroll approximately 500 patients from CREST-2, of which we anticipate 100 will have hemodynamic impairment. We estimate 93% power to detect a clinically meaningful treatment difference of 0.5 SD. Methods and design We will use perfusion-weighted magnetic resonance imaging to stratify by hemodynamic status. Linear regression will compare treatment differences, controlling for baseline cognitive status, age, depression, prior cerebral infarcts, silent infarction, white matter hyperintensity volume, and cerebral microbleeds. Study outcomes The primary outcome is change in cognition at one year. Secondary outcomes include silent infarction, change in white matter hyperintensity volume, number of cerebral microbleeds, and cortical thickness over one year. Discussion If cognitive impairment can be shown to be reversible by revascularization, then we can redefine “symptomatic carotid stenosis” to include cognitive impairment and identify a new population of patients likely to benefit from revascularization. Trial Registration US National Institutes of Health (NIH) clinicaltrials.gov NCT03121209

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.

Rationale Trials conducted decades ago demonstrated that carotid endarterectomy by skilled surgeons reduced stroke risk in asymptomatic patients. Developments in carotid stenting and improvements in medical prevention of stroke caused by atherothrombotic disease challenge understanding of the benefits of revascularization. Aim Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) will test whether carotid endarterectomy or carotid stenting plus contemporary intensive medical therapy is superior to intensive medical therapy alone in the primary prevention of stroke in patients with high-grade asymptomatic carotid stenosis. Methods and design CREST-2 is two multicenter randomized trials of revascularization plus intensive medical therapy versus intensive medical therapy alone. One trial randomizes patients to carotid endarterectomy plus intensive medical therapy versus intensive medical therapy alone; the other, to carotid stenting plus intensive medical therapy versus intensive medical therapy alone. The risk factor targets of centrally directed intensive medical therapy are LDL cholesterol <70 mg/dl and systolic blood pressure <140 mmHg. Study outcomes The primary outcome is the composite of stroke and death within 44 days following randomization and stroke ipsilateral to the target vessel thereafter, up to four years. Change in cognition and differences in major and minor stroke are secondary outcomes. Sample size Enrollment of 1240 patients in each trial provides 85% power to detect a treatment difference if the event rate in the intensive medical therapy alone arm is 4.8% higher or 2.8% lower than an anticipated 3.6% rate in the revascularization arm. Discussion Management of asymptomatic carotid stenosis requires contemporary randomized trials to address whether carotid endarterectomy or carotid stenting plus intensive medical therapy is superior in preventing stroke beyond intensive medical therapy alone. Whether carotid endarterectomy or carotid stenting has favorable effects on cognition will also be tested. Trial registration United States National Institutes of Health Clinicaltrials.gov NCT02089217

Although rapidly expanding in its use, carotid artery stenting remains a relatively new procedure. Its growth is due, at least in part, to the perceived advantages of a less invasive technique. However, the clinical effectiveness and specific role for stenting in the treatment of carotid occlusive disease are still under evaluation. The primary aim of the randomized clinical trial, Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), was to contrast the relative efficacy of carotid stenting versus carotid endarterectomy in preventing stroke, myocardial infarction, or death during a 30-day periprocedural period or ipsilateral stroke over the follow-up period in patients with symptomatic and asymptomatic extracranial carotid stenosis. The secondary goals were to describe the differential efficacy of the 2 procedures in men and women, contrast periprocedural (30-day) morbidity and postprocedural morbidity and mortality, estimate and contrast the restenosis rates of the 2 procedures, evaluate differences in measures of health-related quality of life and cost-effectiveness, and identify subgroups of participants at differential risk of stenting or surgery. This report summarizes the results obtained from CREST with respect to its primary and secondary aims.