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Zusammenfassung. Intrakranielle atherosklerotische Stenosen sind die häufigste Ursache von ischämischen Hirnschlägen weltweit. Drei Behandlungsverfahren stehen heutzutage für Patienten mit intrakraniellen atherosklerotischen Stenosen zur Verfügung: Das beste konservative Management (bestehend aus Medikamenten, einer optimalen Einstellung vaskulärer Risikofaktoren und einem gesunden Lebensstil), die endovaskuläre Therapie und die chirurgische Therapie. Bei asymptomatischen intrakraniellen atherosklerotischen Stenosen wird aktuell ein bestes konservatives Management empfohlen, ebenso in der Regel bei Patienten mit symptomatischen intrakraniellen atherosklerotischen Stenosen. Ausgewählte Patienten können aber von einer zusätzlichen endovaskulären Therapie profitieren, bspw. wenn sie trotz bestem konservativen Management wiederholte Hirninfarkte im Gefässterritorium der Stenose zeigen. In seltenen Fällen kann auch ein chirurgisches Vorgehen in Frage kommen. Bei Patienten mit symptomatischer extrakranieller atherosklerotischer Karotisstenose konnte wiederholt gezeigt werden, dass die Behandlung mittels Karotisendarterektomie (CEA) ein tieferes Sterblichkeits- und Hirnschlagrisiko aufweist als die Behandlung mittels endovaskulärer Therapie (CAS). Insbesondere bei Patienten im Alter von über 70 Jahren sollte aktuell in der Regel eine CEA dem CAS vorgezogen werden, da das Risiko innerhalb von 30 Tagen nach Behandlung zu versterben oder einen Hirnschlag zu erleiden bei Patienten, welche mit einem CAS behandelt werden praktisch doppelt so hoch liegt, wie bei Patienten, die mittels CEA behandelt werden. Die Studienergebnisse, welche modernisierte Techniken und Devices verwenden, bleiben abzuwarten. Aktuell bleibt es unklar, ob Patienten mit asymptomatischer extrakranieller atherosklerotischer Karotisstenose unter bester konservativer Therapie überhaupt von einer invasiven Therapie im Sinne einer CEA oder eines CAS profitieren.

Atherosclerosis of the intracranial arteries and of the extracranial carotid artery.

Background During carotid endarterectomy (CEA), significant amplitude decrement of somatosensory evoked potentials (SEPs) is associated with post-operative neurological deficits. Objective To investigate the association between an incomplete circle of Willis and/or contralateral ICA occlusion and subsequent changes in intra-operatively monitored SEPs. Methods We performed a retrospective analysis of a single center, prospective cohort of consecutive patients undergoing CEA over a 42-month period after reviewing the collateral arterial anatomy on pre-operative radiological imaging. The primary endpoint was an intra-operative decline in SEPs > 50% compared to the baseline value during arterial cross-clamping. Univariate and multivariate logistic regression analyses were performed to investigate a potential association between contralateral ICA occlusion, incomplete circle of Willis, and subsequent alteration in SEPs. Results A total of 140 consecutive patients were included, of which 116 patients (82.9%) had symptomatic carotid stenosis of at least 50% according to the classification used in the North American Carotid Surgery Trial (NASCET) (Stroke 22:711–720, 1991). Six patients (4.3%) showed contralateral ICA occlusion, 22 patients (16%) a missing/hypoplastic anterior communicating artery (Acom) or A1 segment, and 79 patients (56%) a missing ipsilateral posterior communicating artery (Pcom) or P1 segment. ICA occlusion and missing segments of the anterior circulation (missing A1 and/or missing Acom) were associated with the primary endpoint (p = 0.003 and p = 0.022, respectively). Conclusion Contralateral ICA occlusion and missing anterior collaterals of the circle of Willis increase the risk of intra-operative SEP changes during CEA. Pre-operative assessment of collateral arterial anatomy might help identifying patients with an increased intra-operative risk.

ObjectiveTo compare outcomes after endovascular therapy (EVT) and IV thrombolysis (IVT) in patients with stroke with emergent large vessel occlusion (LVO) and mild neurologic deficits.MethodsThis was a retrospective analysis of patients from the Swiss Stroke Registry with admission NIH Stroke Scale score ≤5 and LVO treated by EVT (± IVT) vs IVT alone. The primary endpoint was favorable functional outcome (modified Rankin Scale [mRS] score 0–1) at 3 months. Secondary outcomes were independence (mRS score 0–2), mRS score (ordinal shift analysis), and survival with high disability (mRS score 4–5). Safety endpoints were mortality and symptomatic hemorrhage.ResultsOf 11,356 patients, 312 met the criteria and propensity score method matched 108 in each group. A comparably large proportion of patients with EVT and IVT had favorable outcome (63% vs 65.7% respectively; odds ratio 0.94, 95% confidence interval 0.51–1.72; p = 0.840). Patients with EVT showed a nonsignificant trend toward higher mRS score at 3 months (p = 0.717), while the proportion of surviving patients with high disability was comparably very low in both groups (p = 0.419). Mortality was slightly higher among those with EVT (9.3% vs 2.8%; p = 0.06), and symptomatic intracranial hemorrhage was a rare event in both groups (2.8% vs 0%; p = 0.997).ConclusionsIn acute ischemic stroke, EVT and IVT appear similarly effective in achieving favorable outcome at 3 months for patients with LVO and mild neurologic symptoms. EVT might be marginally inferior to IVT regarding outcome across all levels of disability and mortality. Further studies are required to determine whether certain subgroups of patients with LVO and mild symptoms benefit from EVT.Classification of evidenceThis study provides Class III evidence that patients with LVO and mild symptoms receiving either EVT or IVT had similar favorable functional outcomes at 3 months.

Aims Lipoprotein(a) [Lp(a)] is a recognized causal risk factor for atherosclerotic cardiovascular disease but its role for acute ischaemic stroke (AIS) is controversial. In this study, we evaluated the association of Lp(a) with large artery atherosclerosis (LAA) stroke and risk of recurrent cerebrovascular events in AIS patients. Methods and results For this analysis of the prospective, observational, multicentre BIOSIGNAL cohort study we measured Lp(a) levels in plasma samples of 1733 primarily Caucasian (98.6%) AIS patients, collected within 24 h after symptom onset. Primary outcomes were LAA stroke aetiology and recurrent cerebrovascular events (ischaemic stroke or transient ischaemic attack) within 1 year. We showed that Lp(a) levels are independently associated with LAA stroke aetiology [adjusted odds ratio 1.48, 95% confidence interval (CI) 1.14-1.90, per unit log10Lp(a) increase] and identified age as a potent effect modifier (Pinteraction =0.031) of this association. The adjusted odds ratio for LAA stroke in patients aged Conclusion Elevated Lp(a) was independently associated with LAA stroke aetiology and risk of recurrent cerebrovascular events among primarily Caucasian individuals aged

Background Carotid artery stenting is an alternative to carotid endarterectomy for the treatment of atherosclerotic carotid artery stenosis. This review updates a previous version first published in 1997 and subsequently updated in 2004, 2007, and 2012. Objectives To assess the benefits and risks of stenting compared with endarterectomy in people with symptomatic or asymptomatic carotid stenosis. Search methods We searched the Cochrane Stroke Group Trials Register (last searched August 2018) and the following databases: CENTRAL, MEDLINE, Embase, and Science Citation Index to August 2018. We also searched ongoing trials registers (August 2018) and reference lists, and contacted researchers in the field. Selection criteria Randomised controlled trials (RCTs) comparing stenting with endarterectomy for symptomatic or asymptomatic atherosclerotic carotid stenosis. In addition, we included RCTs comparing carotid artery stenting with medical therapy alone. Data collection and analysis One review author selected trials for inclusion, assessed trial quality and risk of bias, and extracted data. A second review author independently validated trial selection and a third review author independently validated data extraction. We calculated treatment effects as odds ratios (OR) and 95% confidence intervals (CI), with endarterectomy as the reference group. We quantified heterogeneity using the I² statistic and used GRADE to assess the overall certainty of evidence. Main results We included 22 trials involving 9753 participants. In participants with symptomatic carotid stenosis, compared with endarterectomy stenting was associated with a higher risk of periprocedural death or stroke (the primary safety outcome; OR 1.70, 95% CI 1.31 to 2.19; P < 0.0001, I² = 5%; 10 trials, 5396 participants; high‐certainty evidence); and periprocedural death, stroke, or myocardial infarction (OR 1.43, 95% CI 1.14 to 1.80; P = 0.002, I² = 0%; 6 trials, 4861 participants; high‐certainty evidence). The OR for the primary safety outcome was 1.11 (95% CI 0.74 to 1.64) in participants under 70 years old and 2.23 (95% CI 1.61 to 3.08) in participants 70 years old or more (interaction P = 0.007). There was a non‐significant increase in periprocedural death or major or disabling stroke with stenting (OR 1.36, 95% CI 0.97 to 1.91; P = 0.08, I² = 0%; 7 trials, 4983 participants; high‐certainty evidence). Compared with endarterectomy, stenting was associated with lower risks of myocardial infarction (OR 0.47, 95% CI 0.24 to 0.94; P = 0.03, I² = 0%), cranial nerve palsy (OR 0.09, 95% CI 0.06 to 0.16; P < 0.00001, I² = 0%), and access site haematoma (OR 0.32, 95% CI 0.15 to 0.68; P = 0.003, I² = 27%). The combination of periprocedural death or stroke or ipsilateral stroke during follow‐up (the primary combined safety and efficacy outcome) favoured endarterectomy (OR 1.51, 95% CI 1.24 to 1.85; P < 0.0001, I² = 0%; 8 trials, 5080 participants; high‐certainty evidence). The rate of ipsilateral stroke after the periprocedural period did not differ between treatments (OR 1.05, 95% CI 0.75 to 1.47; P = 0.77, I² = 0%). In participants with asymptomatic carotid stenosis, there was a non‐significant increase in periprocedural death or stroke with stenting compared with endarterectomy (OR 1.72, 95% CI 1.00 to 2.97; P = 0.05, I² = 0%; 7 trials, 3378 participants; moderate‐certainty evidence). The risk of periprocedural death or stroke or ipsilateral stroke during follow‐up did not differ significantly between treatments (OR 1.27, 95% CI 0.87 to 1.84; P = 0.22, I² = 0%; 6 trials, 3315 participants; moderate‐certainty evidence). Moderate or higher carotid artery restenosis (50% or greater) or occlusion during follow‐up was more common after stenting (OR 2.00, 95% CI 1.12 to 3.60; P = 0.02, I² = 44%), but the difference in risk of severe restenosis was not significant (70% or greater; OR 1.26, 95% CI 0.79 to 2.00; P = 0.33, I² = 58%; low‐certainty evidence). Authors' conclusions Stenting for symptomatic carotid stenosis is associated with a higher risk of periprocedural stroke or death than endarterectomy. This extra risk is mostly attributed to an increase in minor, non‐disabling strokes occurring in people older than 70 years. Beyond the periprocedural period, carotid stenting is as effective in preventing recurrent stroke as endarterectomy. However, combining procedural safety and long‐term efficacy in preventing recurrent stroke still favours endarterectomy. In people with asymptomatic carotid stenosis, there may be a small increase in the risk of periprocedural stroke or death with stenting compared with endarterectomy. However, CIs of treatment effects were wide and further data from randomised trials in people with asymptomatic stenosis are needed.

Background and Purpose Standard operating procedures (SOP) incorporating plasma levels of rivaroxaban might be helpful in selecting patients with acute ischemic stroke taking rivaroxaban suitable for IVthrombolysis (IVT) or endovascular treatment (EVT). Methods This was a single-center explorative analysis using data from the Novel-Oral-Anticoagulants-in-Stroke-Patients-registry (clinicaltrials.gov:NCT02353585) including acute stroke patients taking rivaroxaban (September 2012 to November 2016). The SOP included recommendation, consideration, and avoidance of IVT if rivaroxaban plasma levels were 100 ng/mL, respectively, measured with a calibrated anti-factor Xa assay. Patients with intracranial artery occlusion were recommended IVT+EVT or EVT alone if plasma levels were ≤100 ng/mL or >100 ng/mL, respectively. We evaluated the frequency of IVT/EVT, door-to-needle-time (DNT), and symptomatic intracranial or major extracranial hemorrhage. Results Among 114 acute stroke patients taking rivaroxaban, 68 were otherwise eligible for IVT/EVT of whom 63 had plasma levels measured (median age 81 years, median baseline National Institutes of Health Stroke Scale 6). Median rivaroxaban plasma level was 96 ng/mL (inter quartile range [IQR] 18‒259 ng/mL) and time since last intake 11 hours (IQR 4.5‒18.5 hours). Twenty-two patients (35%) received IVT/EVT (IVT n=15, IVT+EVT n=3, EVT n=4) based on SOP. Median DNT was 37 (IQR 30‒60) minutes. None of the 31 patients with plasma levels >100 ng/mL received IVT. Among 14 patients with plasma levels ≤100 ng/mL, the main reason to withhold IVT was minor stroke (n=10). No symptomatic intracranial or major extracranial bleeding occurred after treatment. Conclusions Determination of rivaroxaban plasma levels enabled IVT or EVT in one-third of patients taking rivaroxaban who would otherwise be ineligible for acute treatment. The absence of major bleeding in our pilot series justifies future studies of this approach.

Background and Purpose— Complex vascular anatomy might increase the risk of procedural stroke during carotid artery stenting (CAS). Randomized controlled trial evidence that vascular anatomy should inform the choice between CAS and carotid endarterectomy (CEA) has been lacking. Methods— One-hundred eighty-four patients with symptomatic internal carotid artery stenosis who were randomly assigned to CAS or CEA in the ICSS (International Carotid Stenting Study) underwent magnetic resonance (n=126) or computed tomographic angiography (n=58) at baseline and brain magnetic resonance imaging before and after treatment. We investigated the association between aortic arch configuration, angles of supra-aortic arteries, degree, length of stenosis, and plaque ulceration with the presence of ≥1 new ischemic brain lesion on diffusion-weighted magnetic resonance imaging (DWI+) after treatment. Results— Forty-nine of 97 patients in the CAS group (51%) and 14 of 87 in the CEA group (16%) were DWI+ (odds ratio [OR], 6.0; 95% confidence interval [CI], 2.9–12.4; P P =0.027) and the degree of the largest internal carotid artery angle (≥60° versus P =0.002) were both associated with DWI+, also after correction for age. No predictors for DWI+ were identified in the CEA group. The DWI+ risk in CAS increased further over CEA if the largest internal carotid artery angle was ≥60° (OR, 11.8; 95% CI, 4.1–34.1) than if it was P =0.035). Conclusions— Complex configuration of the aortic arch and internal carotid artery tortuosity increase the risk of cerebral ischemia during CAS, but not during CEA. Vascular anatomy should be taken into account when selecting patients for stenting. Clinical Trial Registration— URL: http://www.isrctn.com/ISRCTN25337470 . Unique identifier: ISRCTN25337470.

Background: Over the past decades, stroke risk associated with carotid disease has decreased, reflecting improvements in medical therapy and a more rigorous control of vascular risk factors. It is less clear whether the procedural risk of carotid revascularization has declined over time. Methods: We analyzed temporal changes in procedural risks among 4597 patients with symptomatic carotid stenosis treated with carotid artery stenting (n=2326) or carotid endarterectomy (n=2271) in 4 randomized trials between 2000 and 2008, using generalized linear mixed-effects models with a random intercept for each source trial. Models were additionally adjusted for age and other baseline characteristics predicting treatment risk. The primary outcome event was any procedural stroke or death, occurring during or within 30 days after revascularization. Results: The procedural stroke or death risk decreased significantly over time in all patients (unadjusted odds ratio per year, 0.91; 95% CI, 0.85–0.97; P =0.006). This effect was driven by a decrease in the carotid endarterectomy group (unadjusted odds ratio per year, 0.82; 95% CI, 0.73–0.92; P =0.003), whereas no significant decrease was found after carotid artery stenting (unadjusted odds ratio, 0.96; 95% CI, 0.88–1.04; P =0.33). Carotid endarterectomy patients had a lower procedural stroke or death risk compared with carotid artery stenting patients, and the difference significantly increased over time (interaction P =0.031). After adjustment for baseline characteristics, the results remained essentially the same. Conclusions: The risk of stroke or death associated with carotid endarterectomy for symptomatic carotid stenosis decreased over an 8-year period, independent of clinical predictors of procedural risk. No corresponding reduction in procedural risk was seen in patients treated with stenting. Clinical Trial Registration: URL: https://www.clinicaltrials.gov ; http://www.isrctn.com . Unique identifier: NCT00190398 (EVA-3S), NCT00004732 (CREST), ISRCTN57874028 (SPACE), and ISRCTN25337470 (ICSS).

Background and Purpose— Open-cell carotid artery stents are associated with a higher peri-procedural stroke risk than closed-cell stents. However, the effect of stent design on long-term durability of carotid artery stenting (CAS) is unknown. We compared the medium- to long-term risk of restenosis and ipsilateral stroke between patients treated with open-cell stents versus closed-cell stents in the ICSS (International Carotid Stenting Study). Methods— Patients with symptomatic carotid stenosis were randomized to CAS or endarterectomy and followed with duplex ultrasound for a median of 4.0 years. We analyzed data from patients with completed CAS procedures, known stent design, and available ultrasound follow-up. The primary outcome, moderate or higher restenosis (≥50%) was defined as a peak systolic velocity of >1.3 m/s on ultrasound or occlusion of the treated internal carotid artery and analyzed with interval-censored models. Results— Eight hundred fifty-five patients were allocated to CAS. Seven hundred fourteen patients with completed CAS and known stent design were included in the current analysis. Of these, 352 were treated with open-cell and 362 with closed-cell stents. Moderate or higher restenosis occurred significantly less frequently in patients treated with open-cell (n=113) than closed-cell stents (n=154; 5-year risks were 35.5% versus 46.0%; unadjusted hazard ratio, 0.68; 95% CI, 0.53–0.88). There was no significant difference in the risk of severe restenosis (≥70%) after open-cell stenting (n=27) versus closed-cell stenting (n=43; 5-year risks, 8.6% versus 12.7%; unadjusted hazard ratio, 0.63; 95% CI, 0.37–1.05). The risk of ipsilateral stroke beyond 30 days after treatment was similar with open-cell and closed-cell stents (hazard ratio, 0.78; 95% CI, 0.35–1.75). Conclusions— Moderate or higher restenosis after CAS occurred less frequently in patients treated with open-cell stents than closed-cell stents. However, both stent designs were equally effective at preventing recurrent stroke during follow-up. Clinical Trial Registration— URL: http://www.isrctn.com/ . Unique identifier: ISRCTN25337470.

Background: Carotid artery stenosis is an important cause for stroke. Carotid endarterectomy (CEA) reduces the risk of stroke in patients with symptomatic carotid stenosis and to some extent in patients with asymptomatic carotid stenosis. More than 20 years ago, carotid artery stenting (CAS) emerged as an endovascular treatment alternative to CEA. Objective and Methods: This review summarises the available evidence from randomised clinical trials in patients with symptomatic as well as in patients with asymptomatic carotid stenosis. Results: CAS is associated with a higher risk of death or any stroke between randomisation and 30 days after treatment than CEA (odds ratio (OR) = 1.74, 95% CI 1.3 to 2.33, p < 0.0001). In a pre-defined subgroup analysis, the OR for stroke or death within 30 days after treatment was 1.11 (95% CI 0.74 to 1.64) in patients Discussion and Conclusion: In symptomatic patients, randomised evidence has consistently shown CAS to be associated with a higher risk of stroke or death within 30 days of treatment than CEA. This extra risk is mostly attributed to an increase in strokes occurring on the day of the procedure in patients ≥70 years. In asymptomatic patients, there may be a small increase in the risk of stroke or death within 30 days of treatment with CAS compared to CEA, but the currently available evidence is insufficient and further data from ongoing randomised trials are needed.

The risk of stroke associated with carotid artery restenosis after stenting or endarterectomy is unclear. We aimed to compare the long-term risk of restenosis after these treatments and to investigate if restenosis causes stroke in a secondary analysis of the International Carotid Stenting Study (ICSS).ICSS is a parallel-group randomised trial at 50 tertiary care centres in Europe, Australia, New Zealand, and Canada. Patients aged 40 years or older with symptomatic carotid stenosis measuring 50% or more were randomly assigned either stenting or endarterectomy in a 1:1 ratio. Randomisation was computer-generated and done centrally, with allocation by telephone or fax, stratified by centre, and with minimisation for sex, age, side of stenosis, and occlusion of the contralateral carotid artery. Patients were followed up both clinically and with carotid duplex ultrasound at baseline, 30 days after treatment, 6 months after randomisation, then annually for up to 10 years. We included patients whose assigned treatment was completed and who had at least one ultrasound examination after treatment. Restenosis was defined as any narrowing of the treated artery measuring 50% or more (at least moderate) or 70% or more (severe), or occlusion of the artery. The degree of restenosis based on ultrasound velocities and clinical outcome events were adjudicated centrally; assessors were masked to treatment assignment. Restenosis was analysed using interval-censored models and its association with later ipsilateral stroke using Cox regression. This trial is registered with the ISRCTN registry, number ISRCTN25337470. This report presents a secondary analysis, and follow-up is complete.Between May, 2001, and October, 2008, 1713 patients were enrolled and randomly allocated treatment (855 were assigned stenting and 858 endarterectomy), of whom 1530 individuals were followed up with ultrasound (737 assigned stenting and 793 endarterectomy) for a median of 4·0 years (IQR 2·3-5·0). At least moderate restenosis (≥50%) occurred in 274 patients after stenting (cumulative 5-year risk 40·7%) and in 217 after endarterectomy (29·6%; unadjusted hazard ratio [HR] 1·43, 95% CI 1·21-1·72; p0·0001). Patients with at least moderate restenosis (≥50%) had a higher risk of ipsilateral stroke than did individuals without restenosis in the overall patient population (HR 3·18, 95% CI 1·52-6·67; p=0·002) and in the endarterectomy group alone (5·75, 1·80-18·33; p=0·003), but no significant increase in stroke risk after restenosis was recorded in the stenting group (2·03, 0·77-5·37; p=0·154; p=0·10 for interaction with treatment). No difference was noted in the risk of severe restenosis (≥70%) or subsequent stroke between the two treatment groups.At least moderate (≥50%) restenosis occurred more frequently after stenting than after endarterectomy and increased the risk for ipsilateral stroke in the overall population. Whether the restenosis-mediated risk of stroke differs between stenting and endarterectomy requires further research.Medical Research Council, the Stroke Association, Sanofi-Synthélabo, and the European Union.

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.