Howard, George

Introduction: A 3.4% (95% CI: 2.1% to 4.7%) higher peri-procedural stroke and death risk has been previously documented for those treated with carotid artery stenting (CAS) relative to those treated with carotid endarterectomy (CEA). However, the CAS versus CEA treatment differences in long-term outcomes and the post-procedure durability have not been described. Methods: Data from the 4 largest CAS-versus-CEA randomized trials for treatment of symptomatic carotid atherosclerosis (EVA-3S, SPACE, ICSS, and CREST) were pooled, and treatment differences assessed for the outcome of any stroke or death during a 120-day peri-procedural period, plus ipsilateral stroke afterward. Results: Long-term follow-up was analysed for 4754 patients. Median length of follow-up across the studies ranged from 2.0 to 6.9 years, with 88 peri-procedural and 55 post-procedural events among those CEA-treated, and 169 and 64 for those CAS-treated. After the peri-procedural period, the annual rates of stroke following CAS was 0.6% (95% CI: 0.5 to 0.8) and following CEA 0.6% (95% CI: 0.5 to 0.8), resulting in non-significant durability differences of less than 1% over the period extending up to 9 years (see Table). The previously-documented 3.4% higher peri-procedural event rate in the CAS group contributed to a significant 3.1% (95% CI: 1.6% to 4.7%) treatment difference at 1-year, and the aforementioned similar durability implied that this significant difference remained relatively constant over the period extending up to 9 years (see table). Conclusions: The post-procedure durability of CAS and CEA were similar, both with event rates below 1%. The similarity of post-procedure events rates implies that the previously-documented higher peri-procedural in the CAS group is “carried forward” with a higher risk of outcomes extending to 9-years.

Background and Purpose— We investigated whether procedural stroke or death risk of carotid artery stenting (CAS) compared with carotid endarterectomy (CEA) is different in patients with and without history of coronary heart disease (CHD) and whether the treatment-specific impact of age differs. Methods— We combined individual patient data of 4754 patients with symptomatic carotid stenosis from 4 randomized trials (EVA-3S [Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis], SPACE [Stent-Protected Angioplasty Versus Carotid Endarterectomy], ICSS [International Carotid Stenting Study], and CREST [Carotid Revascularization Endarterectomy Versus Stenting Trial]). Procedural risk was defined as any stroke or death ≤30 days after treatment. We compared procedural risk between both treatments with Cox regression analysis, stratified by history of CHD and age (<70, 70–74, ≥75 years). History of CHD included myocardial infarction, angina, or coronary revascularization. Results— One thousand two hundred ninety-three (28%) patients had history of CHD. Procedural stroke or death risk was higher in patients with history of CHD. Procedural risk in patients treated with CAS compared with CEA was consistent in patients with history of CHD (8.3% versus 4.6%; hazard ratio [HR], 1.96; 95% CI, 0.67–5.73) and in those without (6.9% versus 3.6%; HR, 1.93; 95% CI, 1.40–2.65; P interaction =0.89). In patients with history of CHD, procedural risk was significantly higher after CAS compared with CEA in patients aged ≥75 (CAS-to-CEA HR, 2.78; 95% CI, 1.32–5.85), but not in patients aged <70 (HR, 1.71; 95% CI, 0.79–3.71) and 70 to 74 years (HR, 1.09; 95% CI, 0.45–2.65). In contrast, in patients without history of CHD, procedural risk after CAS was higher in patients aged 70 to 74 (HR, 3.62; 95% CI, 1.80–7.29) and ≥75 years (HR, 2.64; 95% CI, 1.52–4.59), but equal in patients aged <70 years (HR, 1.05; 95% CI, 0.63–1.73; 3-way P interaction =0.09). Conclusions— History of CHD does not modify procedural stroke or death risk of CAS compared with CEA. CAS might be as safe as CEA in patients with history of CHD aged <75 years, whereas for patients without history of CHD, risk after CAS compared with CEA was only equal in those aged <70 years.

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 and Purpose— Stenting for symptomatic carotid stenosis (carotid artery stenting [CAS]) carries a higher risk of procedural stroke or death than carotid endarterectomy (CEA). It is unclear whether this extra risk is present both on the day of procedure and within 1 to 30 days thereafter and whether clinical risk factors differ between these periods. Methods— We analyzed the risk of stroke or death occurring on the day of procedure (immediate procedural events) and within 1 to 30 days thereafter (delayed procedural events) in 4597 individual patients with symptomatic carotid stenosis who underwent CAS (n=2326) or CEA (n=2271) in 4 randomized trials. Results— Compared with CEA, patients treated with CAS were at greater risk for immediate procedural events (110 versus 42; 4.7% versus 1.9%; odds ratio, 2.6; 95% CI, 1.9–3.8) but not for delayed procedural events (59 versus 46; 2.5% versus 2.0%; odds ratio, 1.3; 95% CI, 0.9–1.9; interaction P =0.006). In patients treated with CAS, age increased the risk for both immediate and delayed events while qualifying event severity only increased the risk of delayed events. In patients treated with CEA, we found no risk factors for immediate events while a higher level of disability at baseline and known history of hypertension were associated with delayed procedural events. Conclusions— The increased procedural stroke or death risk associated with CAS compared with CEA was caused by an excess of events occurring on the day of procedure. This finding demonstrates the need to enhance the procedural safety of CAS by technical improvements of the procedure and increased operator skill. Higher age increased the risk for both immediate and delayed procedural events in CAS, mechanisms of which remain to be elucidated. Clinical Trial Registration— URL: https://clinicaltrials.gov . Unique identifier: NCT00190398. URL: http://www.isrctn.com . Unique identifier: ISRCTN57874028. URL: http://www.isrctn.com . Unique identifier: ISRCTN25337470. URL: https://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— Prediction models may help physicians to stratify patients with high and low risk for periprocedural complications or long-term stroke risk after carotid artery stenting or carotid endarterectomy. We aimed to evaluate external performance of previously published prediction models for short- and long-term outcome after carotid revascularization in patients with symptomatic carotid artery stenosis. Methods— From a literature review, we selected all prediction models that used only readily available patient characteristics known before procedure initiation. Follow-up data from 2184 carotid artery stenting and 2261 carotid endarterectomy patients from 4 randomized trials (EVA-3S [Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis], SPACE [Stent-Protected Angioplasty Versus Carotid Endarterectomy], ICSS [International Carotid Stenting Study], and CREST [Carotid Revascularization Endarterectomy Versus Stenting Trial]) were used to validate 23 short-term outcome models to estimate stroke or death risk ≤30 days after the procedure and the original outcome measure for which the model was developed. Additionally, we validated 7 long-term outcome models for the original outcome measure. Predictive performance of the models was assessed with C statistics and calibration plots. Results— Stroke or death ≤30 days after the procedure occurred in 158 (7.2%) patients after carotid artery stenting and in 84 (3.7%) patients after carotid endarterectomy. Most models for short-term outcome after carotid artery stenting (n=4) or carotid endarterectomy (n=19) had poor discriminative performance (C statistics ranging from 0.49–0.64) and poor calibration with small absolute risk differences between the lowest and highest risk groups and overestimation of risk in the highest risk groups. Long-term outcome models (n=7) had a slightly better performance with C statistics ranging from 0.59 to 0.67 and reasonable calibration. Conclusions— Current models did not reliably predict outcome after carotid revascularization in a trial population of patients with symptomatic carotid stenosis. In particular, prediction of short-term outcome seemed to be difficult. Further external validation of existing prediction models or development of new prediction models is needed before such models can be used to support treatment decisions in individual patients.