Moore, Wesley S.

Objective: To compare the perioperative risk of any stroke, death and MI and the long-term risk of re-stenosis and stroke following CEA with patching (a prosthetic or vein patch sutured to the arterial opening to widen the closure) versus CEA with primary closure in CREST. Methods: We included patients who were randomized and underwent CEA in CREST. We compared peri-procedural and 4-year event rates and 2-year restenosis rates, in addition to rates of reoperation between the two groups. Re-stenosis was defined as elevated peak systolic velocity ≥3.0 m/s on carotid duplex US. Treatment differences were assessed using proportional hazard models adjusting for age, sex, and symptomatic status. Results: There were 1,148 patients who underwent CEA (755 {66%} patch; 328 {29%} primary closure). We excluded 43 patients who underwent eversion CEA and 24 patients missing CEA data (5%). There was no significant difference between the two groups with respect to age, sex, race and comorbidities (Table 1). There were significant reductions in the risk of any periprocedural stroke and death (HR 0.35, 95% CI 0.15-0.82, P<0.02), in re-operation (OR 0.33, 95% CI 0.14-0.80, P<0.01), in the 4-year risk of stroke (HR 0.52, 95% CI 0.28-0.97, P<0.04) and in the 2-year risk of re-stenosis (HR 0.26, 95% CI 0.14-0.45, P<0.0001) in the patch compared to the primary closure group (Table 2). Conclusion: Patch closure should be considered for all CEAs because of the association of patch closure with reductions in risk of periprocedural stroke and death, re-operation, and long-term clinical and anatomic durability.

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: We have previously reported that carotid artery stenting (CAS) carries a higher stroke risk than carotid endarterectomy (CEA) in patients over the age of 70. The question arises if advanced age is a surrogate for other factors? If so, can those factors be separately identified such that advanced chronological age alone would not be considered a contra-indication for CAS? Here we consider whether the CAS/CEA choice could be guided by other factors known in the clinical center at the time of patient evaluation, independent of age, in order to provide optimal 4-year outcomes. Methods: Demographic factors (age, sex and race), symptomatic status, patient risk factors (hypertension, diabetes, dyslipidemia, smoking), and arterial characteristics (percent stenosis) were available on 2,502 patients. Additional detailed arterial characteristics (ulcerated plaque, distal tortuosity, sequential lesions, circumferential calcification) were available on 1141 CAS and 438 CEA patients. Potential differential treatment efficacy was assessed by the addition of factor-by-treatment interaction terms to a proportional hazard model containing established predictors of outcome (treatment, symptomatic status, sex, age and age-by-treatment interaction). Results: No other factor was found to mitigate advanced age with evidence of additional treatment effect modification of 4-year outcome (p > 0.10). Discussion: Beyond the previously described differential treatment efficacy by age, there were no other patient or arterial characteristic detected to identify patient subgroups that would differentially benefit from the choice of CAS versus CEA. Our inability to identify factors to guide treatment choices could be due to the low number of stroke and death events, incomplete information regarding arterial characteristics in the CEA population, or the potential exclusion of “high risk” groups (such as those with severe arterial tortuosity) from the study.

Background The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) enrolled 2502 patients between December of 2000 and mid-July of 2008. We analyzed temporal changes in outcomes for both CEA and CAS over the course of this study. Methods Enrollment was divided into 3 consecutive epochs (5 years, 14 months, and 16 months), each with approximately 834 patients ( Table ). Rates for the primary outcome of death, stroke, and myocardial infarction (DSMI) and for death and stroke (DS) during the periprocedural period were calculated. Poisson regression was used to adjust rates for age, sex, dyslipidemia, and symptomatic status, all of which were found to influence outcomes. Results For CAS, there was a 26% decline in DSMI (6.2% → 4.6%) and a 35% decline in DS (5.5% → 3.6%). For both composite endpoints in CEA there was no consistent pattern ( Table ). As CREST progressed, it enrolled younger patients, more men, patients more likely to be dyslipidemic and enrolled more asymptomatic patients (all p < 0.05). Adjustment for these changes mediated the improvement in event rates for the CAS patients, and had no consistent effect on CEA event rates ( Table ). Conclusion Periprocedural safety for CAS improved over time in CREST. Changes were inconsistent for CEA. Improvements for CAS in part appear to reflect changes in patient selection related to age, sex, and risk factors, as adjustment for those variables attenuated the decline in rates. Linking rates to operator experience was not feasible because of the large number of new interventionalists and surgeons entering CREST over time.

Introduction: Inclusion of asymptomatic patients in randomized trials comparing revascularization to medical therapy has been questioned if they have been previously symptomatic. Hypothesis: Duration of asymptomatic status is not associated with better outcomes following endarterectomy (CEA) or stenting (CAS). Methods: Patients in CREST were classified as asymptomatic if they had not had a TIA or stroke ipsilateral to the study artery within 6 months prior to randomization. We compared those patients who had always been asymptomatic (AA) to those who had been previously symptomatic (PS) ≥ 6 months prior to randomization. Proportional hazards models adjusting for age and treatment were used to assess risk of 30-day stroke or death (S+D), and risk of any 30-day S+D plus ipsilateral stroke at 4 years by asymptomatic status Results: Among the 1056 asymptomatic patients who received the assigned procedure within 30 days of randomization, 977 (93%) were AA and 79 (7%) were PS. There was no difference in the 30-day and 4 year outcomes (Table). Conclusion: In CREST, 93% of the asymptomatic patients were always asymptomatic. Similar outcomes for the previously symptomatic patients (7%) supports the inclusion of such patients in randomized trials comparing CEA and CAS to medical treatment.

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

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