Brott, Thomas G.

Introduction: Low rates of enrollment into stroke clinical trials are an ongoing challenge for the stroke research community. We sought to retrospectively describe the association between medical eligibility and recruitment rates for two acute clinical trials. Methods: Within a population of 1.3 million, we screened local hospital admissions in 2010 using ICD-9 discharge codes 430-436, and performed chart review. Within the region are 15 adult acute care hospitals, all of which are covered by the same stroke team for clinical care and trial enrollment. Medical eligibility, the number of eligible patients/total number of patients, was calculated for the IMS-III trial and the CLEAR-ER trials using their inclusion/exclusion criteria. The number of patients enrolled in the trial per month of open enrollment was determined for each hospital. Statistical analysis included paired signed rank test and regression. Results: In 2010, 2035 ischemic strokes (IS) were hospitalized in the region. Regional medical eligibility was 1.7% for IMS III and 4.5% for CLEARER (p=0.001), overall regional hospital enrollment/month was 0.81 for IMS III and 1.84 for CLEAR-ER (p=0.001). Eligibility rates per hospital ranged from 0-9.5%, and recruitment rates per hospital/mo ranged from 0-0.38. Hospital-level eligibility and recruitment rates were significantly correlated (see figure for both trials combined, adjusted r2 = 0.57, p<0.001.) Discussion: Within our population, medical eligibility explained 57% of the variability in hospital-level enrollment rates for two acute IS trials. The use of population-based epidemiology in trial planning may identify optimal trial enrollment criteria, which must be weighed against proper patient selection. Many other factors impact enrollment rates, such as competing trials, which were not considered here. Further evaluation of our population-based eligibility rates in sites outside our region and with additional clinical trials is needed.

Background: Carotid endarterectomy (CEA) is the leading procedure for carotid stenosis, yet national data on trends in rates and outcomes are limited. We determined CEA rates among Medicare beneficiaries and evaluated mortality and readmission over 8 years. Methods: We used Medicare fee-for-service data to identify beneficiaries aged ≥65y who had their first CEA (ICD-9 38.12) from 2003-2010 and calculated annual rates per 100,000 person-years (PY). We fit mixed models to assess trends in patient-level outcomes, adjusting for demographics, comorbidities, and symptomatic status. We also evaluated hospital-level trends by calculating risk-standardized mortality (RSMR) and readmission (RSRR) rates. A spatial mixed model adjusted for age, sex, and race was fit to calculate county-specific risk-standardized CEA rates in 2003-2004. Results: There were 505,966 unique CEA hospitalizations. The annual number of CEA discharges decreased from 81,604 in 2003 to 47,597 in 2010 (42% decrease), though the patient characteristics remained largely similar. The national CEA rate was 283 per 100,000 PY in 2003, and there was considerable geographic variability (Figure A). This rate decreased each year to a low of 172 per 100,000 PY in 2010. The rate of stroke or death within 30 days decreased from 3.2 to 2.7%, with a significant adjusted annual reduction of 3% (Figure B). Annual reductions in other short- and long-term outcomes were similar, ranging from 2-3%. The median hospital-level 30-day RSMR decreased over time from 0.99 to 0.57%, while the variation between hospitals increased (interquartile range of 0.7-1.67 percentage points). The 30-day RSRR decreased from 11.0 to 10.1%, but there was more homogeneity across hospitals and years. Conclusions: CEA use among Medicare patients decreased dramatically from 2003-2010, while mortality and readmission outcomes improved. The relative importance of biological and sociological mechanisms for these trends merits further study.

Background: Carotid revascularization was addressed by NASCET and ACAS. NASCET showed a 2-year stroke and death of 32.3% in medical patients and a 15.8% incidence in surgical patients (16.5% absolute/51% relative reduction). Similarly, ACAS revealed an 11% 5-year risk in medical patients and 5.1% in surgical patients (5.9% absolute reduction/53% relative reduction). Absolute risk (rather than relative risk) reduction is of prime interest to the patient. However, in these studies, treatment efficacy was assessed on a relative basis, and these procedures were equally efficacious (51% vs. 53% relative risk). The higher event rates in the symptomatic patients resulted in a larger absolute risk reduction in NASCET (16.5% vs. 5.9%). CREST is the only carotid revascularization study to include both symptomatic and asymptomatic patients undergoing CEA or carotid artery stenting (CAS), and we looked at absolute and relative risks associated with both procedures. Methods: Treatment differences in CREST by symptomatic status were reviewed and interaction terms analyzed. Results: Symptomatic periprocedural stroke and death rates were 6% for CAS vs. 3.2% for CEA (2.8% absolute/47% relative difference/p = 0.02), and were 2.5% for CAS vs. 1.4% for CEA (1.2% absolute/53% relative difference/p = 0.15) for asymptomatic. While treatment differences in periprocedural rates were significant for symptomatic but not asymptomatic patients, there was no difference in treatment efficacy as determined by relative risk reduction. Even the most prominent interaction terms were clearly not significant, p > 0.38. Discussion: There is no evidence of a CAS-CEA difference in treatment efficacy by symptomatic status in CREST. There are significant findings in symptomatic patients. This is likely a product of an increased background rate of events in this strata. While symptomatic status can identify a subgroup with an increased background rate, other factors (e.g. age or stenosis) could identify subgroups of asymptomatic patients with high event rates and large absolute treatment differences.

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 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.

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.

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.

Background: CREST, a randomized trial comparing carotid artery stenting (CAS) with endarterectomy (CEA) in symptomatic and asymptomatic patients, reported in 2010 that the two procedures were similar for the composite endpoint of stroke, myocardial infarction, or death. Data on temporal trends in the use of these procedures in the US are limited, particularly by sex, race, and geographic region. We reviewed trends in utilization of CAS and CEA for ischemic stroke patients. Methods: Ischemic stroke hospitalizations (ICD-9 433, 434, 436) were identified for patients aged ≥18 years from the Nationwide Inpatient Sample 2007-2011 (N=480,375). Annual trends of CAS and CEA were estimated using mixed models that adjusted for patient age and comorbidities. Models were stratified by sex, race (white, black, other), and 9 geographic regions. Results: Overall, the proportion of stroke patients who received CAS remained relatively stable over time (2.7% in 2007 to 2.8% in 2011) while the proportion who received CEA decreased (from 21.0% to 16.3%). CAS rates increased in the three Central Regions (East North, East South, and West South) but decreased in New England; CEA declines were similar across regions. In adjusted analyses, CAS rates increased slightly for white men, decreased for men and women of other race, but remained stable for the remaining groups (Figure); CEA rates decreased for all sex-race groups. These patterns by sex and race subgroups were generally consistent across geographic regions. Conclusions: The proportion of hospitalized stroke patients receiving CEA decreased over time while CAS rates remained relatively stable, with slight increases seen in the Central regions of the US. There are sex-race differences in the proportion of patients who receive these procedures, but these patterns are largely similar across regions.

Background: Historical data suggest that patients with recently symptomatic carotid stenosis are at high risk of early recurrent stroke. Guidelines therefore recommend revascularization within 2 weeks of symptoms. We assessed the risk of stroke or death occurring before revascularization in modern trials of symptomatic carotid stenosis. Methods: We pooled data of all individual patients with symptomatic carotid stenosis randomised to stenting (CAS) or endarterectomy (CEA) in the EVA-3S, SPACE, ICSS and CREST trials. The outcome event (OE) was death or any stroke occurring between randomization and treatment by CAS or CEA, or up to 120 days after randomization among patients not undergoing treatment in this period. Results: 4707 patients were included in the analysis. Median time from qualifying event until randomization was 18 (interquartile range 7-50) days. Median time from randomization until treatment was 6 (2-11) days in the CAS group, and 7 (3-12) days in the CEA group (p<0.001). 31% of patients in the CAS group and 27% in the CEA group underwent revascularization within 14 days of the qualifying event. The OE occurred in 21 patients (CAS: 8, CEA: 13), all within 31 days of randomization (Kaplan Meier estimate: 2.4%, standard error 0.7%; fig.), including 18 non-fatal strokes, 1 fatal stroke, and 2 non-stroke related deaths. In 2 of the patients, the date of the qualifying event was unknown, in 8 patients the OE occurred within 14 days of the qualifying event and in 11 patients >14 days after the qualifying event. All patients with the OE had severe (70-99% degree) stenosis. No other baseline variables predicted the OE. Discussion: Despite the fact that less than a third of patients underwent revascularization within 14 days of the qualifying event, only 2.4% of patients had a recurrent stroke or died before treatment. The risk is lower than expected from historical data, which may reflect advances in medical therapy. Patients at risk are those with severe degree of stenosis.

Background: The CREST trial demonstrated that for patients at standard risk of surgical complications, there was no significant difference in the primary composite outcome of periprocedural death, MI, or stroke, or late ipsilateral stroke between carotid artery stenting (CAS) and carotid endarterectomy (CEA), although CAS had a higher rate of stroke, and CEA had a higher rate of MI. The economic implications of these two strategies are unknown. Methods: We performed a prospective health economic study alongside the CREST trial. Costs were assessed from the perspective of the US health care system in 2008 dollars using a combination of resource-based and event-based methods. Costs for carotid revascularization procedures were based on measured resource use and unit costs derived from a sample of study hospitals. Non-procedural costs for these hospitalizations were estimated using hospital billing data (charges) and cost-center-specific cost-to-charge-ratios. Costs for follow-up events were estimated using national average DRG reimbursements. The primary analysis was based on a modified intention-to-treat population for which the assigned procedure was attempted (n=1212 CAS; 1193 CEA). Results: CAS was associated with higher total procedural costs (Δ=$675, see Table), driven mainly by higher costs for disposable supplies. Length of stay was shorter for CAS, with associated reductions in non-procedural hospital costs (Δ = -$436). Total cost for the index hospitalization remained slightly higher for CAS (Δ=$239) with similar differences at 1 year. Conclusions: For patients at standard risk of surgical complications, total 1-year costs are slightly higher for CAS vs. CEA, driven largely by higher initial procedural costs. Cost-utility analysis will be performed to determine whether differences in quality of life observed in CREST render CAS an economically attractive strategy. CAS (n= 1212) CEA (n=1193) Δ CAS - CEA (95% CI via bootstrap) Index Procedure Costs, $ Excluding MD Fees 6782 ± 1412 5743 ± 1370 1039 (926, 1148) MD Fees 1114 ± 240 1478 ± 108 -364 (-379, -349) Total 7896 ± 1551 7221 ± 1450 675 (555, 800) Index Hospital Stay 7159 ± 5108 7595 ± 7482 -436 (-951, -59) TOTAL Index Hosp Costs 15055 ± 5539 14816 ± 7709 239 (-302, 778) Index Hosp LOS (days) ICU LOS 0.7 ± 1.1 0.8 ± 1.4 -0.1 (-0.24, -0.04) Non-ICU LOS 1.9 ± 3.2 2.2 ± 4.1 -0.2 (-0.55, 0.06) TOTAL LOS 2.6 ± 3.3 3.0 ± 4.5 -0.4 (-0.7, -0.06) 1-year Rehosp Costs: Repeat Revasc - CAS 295 ± 2097 273 ± 2126 -21 (-142, 201) Repeat Revasc - CEA 287 ± 2088 477 ± 2510 -190 (-371, -11) Ipsilateral Stroke 556 ± 3273 384 ± 2580 172 (-75, 402) TIA 48 ± 520 33 ± 487 16 (-25, 56) Death 63 ± 846 45 ± 779 18 (-49, 85) TOTAL Rehosp costs 1321 ± 4827 1293± 4502 28 (-334, 396) TOTAL 1-year costs 16375 ± 7730 16108 ± 9030 267 (-366, 961)