Roubin, Gary S.

Introduction: Increasing stenosis has been questioned as a factor increasing risk of carotid endarterectomy (CEA) or carotid stenting (CAS) in patients with severe asymptomatic carotid stenosis. Hypothesis: Greater severity of carotid stenosis is associated with higher rates of periprocedural stroke and death following revascularization for asymptomatic patients. Methods: Asymptomatic patients with carotid stenosis ≥ 70% by ultrasound or ≥ 60% by angiogram were eligible for the Carotid Revascularization Endarterectomy vs Stenting Trial (CREST). Patients who had a catheter-angiogram were divided into tertiles based on the degree of stenosis. Outcomes were the occurrence of any stroke or death at 30 days. Proportional hazards models adjusting for age and treatment were used to assess risk of 30 day stroke or death by tertile of stenosis. Results: Among 1181 asymptomatic patients, qualifying angiograms were done for 662 patients who had assigned procedure performed within 30 days of randomization. Median % stenosis was 62.6, 73.4, and 83.0 for the tertiles that otherwise differed only for female sex (40% female in tertile 1, 36% in tertile 2, 29% in tertile 3, p=0.01). The 30-day stroke and death rates did not differ significantly by severity of stenosis (Table), but the number of stroke and deaths was only 14 across the tertiles (Table). Similarly meaningful comparison of CEA vs CAS was not possible. Conclusion: This is the largest contemporary study of carotid angiograms performed in patients with severe asymptomatic carotid stenosis. No relationship was detected between severity of stenosis and 30-day stroke and death. The safety of CEA and CAS in asymptomatic patients limits detection of other factors that may increase risk because so few events complicate these procedures.

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.

Background Carotid artery stent (CAS) placement may be used as an alternative to carotid endarterectomy in selected patients with symptomatic and asymptomatic carotid artery disease. Perhaps because stroke is an uncommon event after CAS, the angiographic predictors of stroke have been incompletely described. Methods A total of 1070 catheter-based angiograms were centrally reviewed in patients undergoing CAS enrolled in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). Of these patients, 43 (4%) experienced periprocedural stroke. Angiograms were reviewed using qualitative and quantitative methodology before and after CAS. Reviews were done blinded to patient outcomes and strokes were adjudicated by a central committee blinded to results of angiography. The view showing the greatest carotid stenosis severity was selected. Extreme tortuosity was defined as 2 severe bends >90 degrees (maximum angulation/20 mm segment) beyond the target lesion, sequential lesions as lesions separated by ≥10 mm, and narrow mouth ulcer as a discrete area of contrast extension beyond the normal arterial lumen with a narrow inlet into the ulceration. Results The internal carotid artery reference diameter was 4.2 ± 0.8 mm, the minimal lumen diameter was 1.1 ± 0.6 mm, and the baseline % diameter stenosis was 74.1 ± 11.6%. There were no differences in vessel size or severity of the stenosis in patients with and without stroke. Morphologic predictors significantly related to the risk of subsequent stroke are listed in the Table . Calcification, lesion eccentricity, baseline flow, and distance from the bifurcation were not predictive of periprocedural stroke (p > 0.05). Conclusion In CREST, four angiographic variables were found to increase risk for stroke during and within 30 days after CAS: severe distal tortuosity, sequential lesions, lesion length > 20 mm, and narrow mouth ulcer. Angiographic characteristics beyond percent stenosis may help in patient selection in terms of best revascularization option.

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.