Management of atherosclerotic extracranial carotid artery stenosis

Atherosclerosis leading to stenosis of the internal carotid artery is the underlying cause of 8–15% of ischaemic strokes (symptomatic carotid stenosis). 1–2% of the adult population have asymptomatic carotid stenosis. Clinical trials in patients with symptomatic carotid stenosis showed a higher procedural risk of non-disabling stroke with stenting versus endarterectomy, but a higher risk of myocardial infarction, cranial nerve palsy, and access site haematoma with endarterectomy. Apart from procedural complications, both treatments are equally effective in preventing stroke and recurrent severe carotid stenosis in the medium-to-long term. Endarterectomy has a modest effect in preventing stroke among patients with asymptomatic carotid stenosis, whereas the role of stenting remains to be established. With advances in medical therapy against atherosclerosis, benefit from invasive therapy has become uncertain. Risk modelling, with the inclusion of brain and carotid plaque imaging, will become increasingly important in selecting patients for interventions

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

BACKGROUND: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. METHODS: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. FINDINGS: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86-1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91-1·32; p=0·21). INTERPRETATION: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. FUNDING: UK Medical Research Council and Health Technology Assessment Programme

Silent brain infarcts on diffusion-weighted imaging after carotid revascularisation: A surrogate outcome measure for procedural stroke? A systematic review and meta-analysis

Aim: To investigate whether lesions on diffusion-weighted imaging (DWI+) after carotid artery stenting (CAS) or endarterectomy (CEA) might provide a surrogate outcome measure for procedural stroke. // Materials and Methods: Systematic MedLine® database search with selection of all studies published up to the end of 2016 in which DWI scans were obtained before and within seven days after CAS or CEA. The correlation between the underlying log odds of stroke and of DWI+ across all treatment groups (i.e. CAS or CEA groups) from included studies was estimated using a bivariate random effects logistic regression model. Relative risks of DWI+ and stroke in studies comparing CAS vs. CEA were estimated using fixed-effect Mantel-Haenszel models. // Results: We included data of 4871 CAS and 2099 CEA procedures (85 studies). Across all treatment groups (CAS and CEA), the log odds for DWI+ was significantly associated with the log odds for clinically manifest stroke (correlation coefficient 0.61 (95% CI 0.27 to 0.87), p = 0.0012). Across all carotid artery stenting groups, the correlation coefficient was 0.19 (p = 0.074). There were too few CEA groups to reliably estimate a correlation coefficient in this subset alone. In 19 studies comparing CAS vs. CEA, the relative risks (95% confidence intervals) of DWI+ and stroke were 3.83 (3.17-4.63, p < 0.00001) and 2.38 (1.44-3.94, p = 0.0007), respectively. // Discussion: This systematic meta-analysis demonstrates a correlation between the occurrence of silent brain infarcts on diffusion-weighted imaging and the risk of clinically manifest stroke in carotid revascularisation procedures. // Conclusion: Our findings strengthen the evidence base for the use of DWI as a surrogate outcome measure for procedural stroke in carotid revascularisation procedures. Further randomised studies comparing treatment effects on DWI lesions and clinical stroke are needed to fully establish surrogacy

Inflammation and In-Stent Restenosis: The Role of Serum Markers and Stent Characteristics in Carotid Artery Stenting

BACKGROUND: Carotid angioplasty and stenting (CAS) may currently be recommended especially in younger patients with a high-grade carotid artery stenosis. However, evidence is accumulating that in-stent restenosis (ISR) could be an important factor endangering the long-term efficacy of CAS. The aim of this study was to investigate the influence of inflammatory serum markers and procedure-related factors on ISR as diagnosed with duplex sonography. METHODS: We analyzed 210 CAS procedures in 194 patients which were done at a single university hospital between May 2003 and June 2010. Periprocedural C-reactive protein (CRP) and leukocyte count as well as stent design and geometry, and other periprocedural factors were analyzed with respect to the occurrence of an ISR as diagnosed with serial carotid duplex ultrasound investigations during clinical long-term follow-up. RESULTS: Over a median of 33.4 months follow-up (IQR: 14.9-53.7) of 210 procedures (mean age of 67.9±9.7 years, 71.9% male, 71.0% symptomatic) an ISR of ≥70% was detected in 5.7% after a median of 8.6 months (IQR: 3.4-17.3). After multiple regression analysis, leukocyte count after CAS-intervention (odds ratio (OR): 1.31, 95% confidence interval (CI): 1.02-1.69; p = 0.036), as well as stent length and width were associated with the development of an ISR during follow-up (OR: 1.25, 95% CI: 1.05-1.65, p = 0.022 and OR: 0.28, 95% CI: 0.09-0.84, p = 0.010). CONCLUSIONS: The majority of ISR during long-term follow-up after CAS occur within the first year. ISR is associated with periinterventional inflammation markers and influenced by certain stent characteristics such as stent length and width. Our findings support the assumption that stent geometry leading to vessel injury as well as periprocedural inflammation during CAS plays a pivotal role in the development of carotid artery ISR

Absence of Consistent Sex Differences in Outcomes From Symptomatic Carotid Endarterectomy and Stenting Randomized Trials.

BACKGROUND AND PURPOSE: CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) reported a higher periprocedural risk for any stroke, death, or myocardial infarction for women randomized to carotid artery stenting (CAS) compared with women randomized to carotid endarterectomy (CEA). No difference in risk by treatment was detected for women relative to men in the 4-year primary outcome. We aimed to conduct a pooled analysis among symptomatic patients in large randomized trials to provide more precise estimates of sex differences in the CAS-to-CEA risk for any stroke or death during the 120-day periprocedural period and ipsilateral stroke thereafter. METHODS: Data from the Carotid Stenosis Trialists' Collaboration included outcomes from symptomatic patients in EVA-3S (Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis), SPACE (Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients), ICSS (International Carotid Stenting Study), and CREST. The primary outcome was any stroke or death within 120 days after randomization and ipsilateral stroke thereafter. Event rates and relative risks were estimated using Poisson regression; effect modification by sex was assessed with a sex-by-treatment-by-trial interaction term, with significant interaction defined a priori as P≤0.10. RESULTS: Over a median 2.7 years of follow-up, 433 outcomes occurred in 3317 men and 1437 women. The CAS-to-CEA relative risk of the primary outcome was significantly lower for women compared with men in 1 trial, nominally lower in another, and nominally higher in the other two. The sex-by-treatment-by-trial interaction term was significant (P=0.065), indicating heterogeneity among trials. Contributors to this heterogeneity are primarily differences in periprocedural period. When the trials are nevertheless pooled, there were no significant sex differences in risk in any follow-up period. CONCLUSIONS: There were significant differences between trials in the magnitude of sex differences in treatment effect (CAS-to-CEA relative risk), indicating pooling data from these trials to estimate sex differences might not be valid. Whether sex is acting as an effect modifier of the CAS-to-CEA treatment effect in symptomatic patients remains uncertain. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00190398 (EVA-3S) and NCT00004732 (CREST). URL: https://www.isrctn.com; Unique identifier: ISRCTN57874028 (SPACE) and ISRCTN25337470 (ICSS)

Carotid stenting: is there an operator effect? A pooled analysis from the carotid stenting trialists' collaboration.

BACKGROUND AND PURPOSE: Randomized clinical trials show higher 30-day risk of stroke or death after carotid artery stenting compared with surgery. We examined whether operator experience is associated with 30-day risk of stroke or death in the Carotid Stenting Trialists' Collaboration database. METHODS: The Carotid Stenting Trialists' Collaboration is a pooled individual patient database including all patients recruited in 3 randomized trials of stenting versus endarterectomy for symptomatic carotid stenosis (Endarterectomy Versus Angioplasty in patients with Symptomatic Severe Carotid Stenosis trial, Stent-Protected Angioplasty versus Carotid Endarterectomy trial, and International Carotid Stenting Study). Lifetime carotid artery stenting experience, lifetime experience in stenting procedures excluding the carotid, and annual number of procedures performed within the trial (in-trial volume), divided into tertiles, were used to measure operator experience. The outcome event was the occurrence of any stroke or death within 30 days of the procedure. The analysis was done per protocol. RESULTS: Among 1546 patients who underwent carotid artery stenting, 120 (7.8%) had a stroke or death within 30 days of the procedure. The 30-day risk of stroke or death did not differ according to operator lifetime carotid artery stenting experience (P=0.8) or operator lifetime stenting experience excluding the carotid (P=0.7). In contrast, the 30-day risk of stroke or death was significantly higher in patients treated by operators with low (mean ≤3.2 procedures/y; risk 10.1%; adjusted risk ratio=2.30 [1.36-3.87]) and intermediate annual in-trial volumes (3.2-5.6 procedures/y; 8.4%; adjusted risk ratio=1.93 [1.14-3.27]) compared with patients treated by high annual in-trial volume operators (>5.6 procedures/y; 5.1%). CONCLUSIONS: Carotid stenting should only be performed by operators with annual procedure volume ≥6 cases per year

Optimal cut-off criteria for duplex ultrasound compared with computed tomography angiography for the diagnosis of restenosis in stented carotid arteries in the international carotid stenting study

INTRODUCTION: Previous studies that reported duplex-ultrasound cut-off criteria, based on blood velocity parameters, for the degree of stenosis in a stented carotid artery were either retrospective, or the reference test was carried out only when a patient was suspected of having restenosis at duplex ultrasound, which is likely to have resulted in verification bias. We performed a prospective study of diagnostic accuracy to find new blood velocity cut-offs in duplex ultrasound for in-stent restenosis. PATIENTS AND METHODS: Stented patients within the international carotid stenting study were eligible. Patients had a carotid computed tomography angiography in addition to routine duplex ultrasound performed at a yearly follow-up. Duplex-ultrasound bloodflow velocity parameters were compared to the degree of stenosis on computed tomography angiography. The results were analysed using receiver-operating-characteristic curves. RESULTS: We included 103 patients in this study. On computed tomography angiography, 30 (29.1%) patients had a 30%–49% in-stent restenosis, 21 (20.4%) patients had 50%–69% in-stent restenosis and 5 (4.9%) patients a ≥70% in-stent restenosis. The cut-off value ≥50% stenosis was a peak systolic velocity of 125 cm/s (sensitivity: 63% (95% CI: 41–79), specificity: 83% (95% CI: 72–90)). DISCUSSION: This study provides a level 2b evidence for new cut-off values for in-stent restenosis. Unfortunately, we could not say anything about severe stenosis because of the low number of severe stenosis after one year. CONCLUSIONS: The 125 cm/s cut-off value on duplex ultrasound is lower than found in previous studies and equal to unstented arteries. Duplex-ultrasound measurements made in stented carotid arteries should not be corrected for the presence of a stent when determining the degree of stenosis

Risk of Stroke before Revascularisation in Patients with Symptomatic Carotid Stenosis: A Pooled Analysis of Randomised Controlled Trials.

OBJECTIVE: Current guidelines recommending rapid revascularisation of symptomatic carotid stenosis are largely based on data from clinical trials performed at a time when best medical therapy was potentially less effective than today. The risk of stroke and its predictors among patients with symptomatic carotid stenosis awaiting revascularisation in recent randomised controlled trials (RCTs) and in medical arms of earlier RCTs was assessed. METHODS: The pooled data of individual patients with symptomatic carotid stenosis randomised to stenting (CAS) or endarterectomy (CEA) in four recent RCTs, and of patients randomised to medical therapy in three earlier RCTs comparing CEA vs. medical therapy, were compared. The primary outcome event was any stroke occurring between randomisation and treatment by CAS or CEA, or within 120 days after randomisation. RESULTS: A total of 4 754 patients from recent trials and 1 227 from earlier trials were included. In recent trials, patients were randomised a median of 18 (IQR 7, 50) days after the qualifying event (QE). Twenty-three suffered a stroke while waiting for revascularisation (cumulative 120 day risk 1.97%, 95% confidence interval [CI] 0.75 - 3.17). Shorter time from QE until randomisation increased stroke risk after randomisation (χ2 = 6.58, p = .011). Sixty-one patients had a stroke within 120 days of randomisation in the medical arms of earlier trials (cumulative risk 5%, 95% CI 3.8 - 6.2). Stroke risk was lower in recent than earlier trials when adjusted for time between QE and randomisation, age, severity of QE, and degree of carotid stenosis (HR 0.47, 95% CI 0.25 - 0.88, p = .019). CONCLUSION: Patients with symptomatic carotid stenosis enrolled in recent large RCTs had a lower risk of stroke after randomisation than historical controls. The added benefit of carotid revascularisation to modern medical care needs to be revisited in future studies. Until then, adhering to current recommendations for early revascularisation of patients with symptomatic carotid stenosis considered to require invasive treatment is advisable