Hughes, Susan

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: 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 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: Concern for underrepresentation of minorities in clinical trials has focused on enrollment proportions and generalizability. The interplay of trial event-rates with diversity has not been emphasized. Methods: The Carotid Revascularization Endarterectomy vs Stent Trial (CREST) randomized 2502 patients and compared them by race, ethnicity, baseline characteristics, and primary outcome (any peri-procedural stroke, death or MI and subsequent ipsilateral stroke up to 10 years); those with unknown race or ethnicity were excluded. Proportional hazards models adjusting for age, sex, symptomatic status and treatment were used to test for a treatment by race/ethnicity interaction. Results: One-hundred-nine patients (4.4%) were black, 32 (1.3%) Asian, 2332 (93.4%) white, 11 (0.4%) other by self-report, and 18 (0.7%) unknown; 90 (3.6%) were Hispanic, 2377 (95%) non-Hispanic, and 35 (1.4%) unknown. Compared to whites, racial minorities were younger (mean age 67±8.9 vs 69±8.8, p=0.004), more often female (44% vs 34%, p=0.01), symptomatic (63 vs 52%, p=0.01), and diabetic (51% vs 29%, p<0.0001), but less often dyslipidemic (76% vs 85%, p=0.004), current smokers (19% vs 27%, p=0.04), or had a history of cardiovascular disease (34% vs 46%, p=0.007). Hispanics were more often diabetic (48% vs 30%, p=0.0002). The rate of the primary endpoint was 10.9%±0.9% at 10 years, and did not differ by race or ethnicity (p inter >0.24). In the context of this low rate, even if minority recruitment were increased to represent 50% of study participants, and if the treatment difference in one race were a greater hazard of HR = 1.49 (anticipated alternative hypothesis), then the hazard ratio in the other group would need to be <0.73, or >3.31, to have 90% power of detection. Conclusions: The proportion of racial and ethnicity participation in CREST was suboptimal at < 10%. Primary outcomes did not differ by minority or ethnic status. However, in low event-rate trials very high and even unrealistic enrollment goals for diversity, for example ≥50%, may still be insufficient for detection of outcome differences by race or ethnicity.

Introduction: Occurrence of stroke and myocardial infarction (MI) after carotid endarterectomy or stenting have each been associated with increased later mortality. Methods: In the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) 69 strokes, 37 protocol MIs, and 19 biomarker + only events occurred within 30 days among 2272 patients followed up to 10 years. Mortality was determined and compared for patients with stroke, MI, or biomarker + only to those without. Cox proportional hazard models adjusting for age, sex, symptomatic status and treatment were calculated to assess the relationship between mortality and stroke and mortality and MI status. Kaplan-Meier survival curves were plotted. Results: Patients with peri-procedural stroke had a 67% greater likelihood of long-term mortality compared to those without stroke (HR=1.67, 95% CI 1.15,2.43; p<0.007)(Figure A). Patients with a protocol MI had a 249% greater likelihood of mortality, and biomarker+ only patients had a 104% greater likelihood of mortality, compared to those without MI (HR=3.49; 95%CI 2.20,5.53, p<0.0001; and HR=2.04; 95% CI 1.09,3.83, p=0.03)(Figure B). Discussion: Stroke, MI, and biomarker + only events following CEA or CAS are associated with increased long-term mortality. The higher risk for MI may be a marker for patients with serious underlying heart disease, rather than causal, providing an opportunity to decrease long-term mortality through aggressive diagnostic evaluation and preventive treatment.

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.

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.