Jörg Ederle

Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis : the International Carotid Stenting Study (ICSS) randomised trial

Summary Background Stenting is an alternative to endarterectomy for treatment of carotid artery stenosis, but long-term efficacy is uncertain. We report long-term data from the randomised International Carotid Stenting Study comparison of these treatments. Methods Patients with symptomatic carotid stenosis were randomly assigned 1:1 to open treatment with stenting or endarterectomy at 50 centres worldwide. Randomisation was computer generated centrally and allocated by telephone call or fax. Major outcomes were assessed by an independent endpoint committee unaware of treatment assignment. The primary endpoint was fatal or disabling stroke in any territory after randomisation to the end of follow-up. Analysis was by intention to treat ([ITT] all patients) and per protocol from 31 days after treatment (all patients in whom assigned treatment was completed). Functional ability was rated with the modified Rankin scale. This study is registered, number ISRCTN25337470. Findings 1713 patients were assigned to stenting (n=855) or endarterectomy (n=858) and followed up for a median of 4·2 years (IQR 3·0–5·2, maximum 10·0). Three patients withdrew immediately and, therefore, the ITT population comprised 1710 patients. The number of fatal or disabling strokes (52 vs 49) and cumulative 5-year risk did not differ significantly between the stenting and endarterectomy groups (6·4% vs 6·5%; hazard ratio [HR] 1·06, 95% CI 0·72–1·57, p=0·77). Any stroke was more frequent in the stenting group than in the endarterectomy group (119 vs 72 events; ITT population, 5-year cumulative risk 15·2% vs 9·4%, HR 1·71, 95% CI 1·28–2·30, p<0·001; per-protocol population, 5-year cumulative risk 8·9% vs 5·8%, 1·53, 1·02–2·31, p=0·04), but were mainly non-disabling strokes. The distribution of modified Rankin scale scores at 1 year, 5 years, or final follow-up did not differ significantly between treatment groups. Interpretation Long-term functional outcome and risk of fatal or disabling stroke are similar for stenting and endarterectomy for symptomatic carotid stenosis. Funding Medical Research Council, Stroke Association, Sanofi-Synthélabo, European Union.

Long-term risk of carotid restenosis in patients randomly assigned to endovascular treatment or endarterectomy in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): long-term follow-up of a randomised trial

Summary Background In the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), early recurrent carotid stenosis was more common in patients assigned to endovascular treatment than it was in patients assigned to endarterectomy (CEA), raising concerns about the long-term effectiveness of endovascular treatment. We aimed to investigate the long-term risks of restenosis in patients included in CAVATAS. Methods 413 patients who were randomly assigned in CAVATAS and completed treatment for carotid stenosis (200 patients had endovascular treatment and 213 patients had endarterectomy) had prospective clinical follow-up at a median of 5 years and carotid duplex ultrasound at a median of 4 years. We investigated the cumulative long-term incidence of carotid restenosis after endovascular treatment and endarterectomy, the effect of the use of stents on restenosis after endovascular treatment, risk factors for the development of restenosis, and the effect of carotid restenosis on the risk of recurrent cerebrovascular events. Analysis was by intention to treat. This study is registered, number ISRCTN01425573. Findings Severe carotid restenosis (≥70%) or occlusion occurred significantly more often in patients in the endovascular arm than in patients in the endarterectomy arm (adjusted hazard ratio [HR] 3·17, 95% CI 1·89–5·32; p<0·0001). The estimated 5-year incidence of restenosis was 30·7% in the endovascular arm and 10·5% in the endarterectomy arm. Patients in the endovascular arm who were treated with a stent (n=50) had a significantly lower risk of developing restenosis of 70% or greater compared with those treated with balloon angioplasty alone (n=145; HR 0·43, 0·19–0·97; p=0·04). Current smoking or a history of smoking was a predictor of restenosis of 70% or more (2·32, 1·19–4·54; p=0·01) and the early finding of moderate stenosis (50–69%) up to 60 days after treatment was associated with the risk of progression to restenosis of 70% or more (3·76, 1·88–7·52; p=0·0002). The composite endpoint of ipsilateral non-perioperative stroke or transient ischaemic attack occurred more often in patients in whom restenosis of 70% or more was diagnosed in the first year after treatment compared with patients without restenosis of 70% or more (5-year incidence 23% vs 11%; HR 2·18, 1·04–4·54; p=0·04), but the increase in ipsilateral stroke alone was not significant (10% vs 5%; 1·67, 0·54–5·11). Interpretation Restenosis is about three times more common after endovascular treatment than after endarterectomy and is associated with recurrent ipsilateral cerebrovascular symptoms; however, the risk of recurrent ipsilateral stroke is low. Further data are required from on-going trials of stenting versus endarterectomy to ascertain whether long-term ultrasound follow-up is necessary after carotid revascularisation. Funding British Heart Foundation; UK National Health Service Management Executive; UK Stroke Association.

Endovascular treatment with angioplasty or stenting versus endarterectomy in patients with carotid artery stenosis in the Carotid And Vertebral Artery Transluminal Angioplasty Study (CAVATAS): long-term follow-up of a randomised trial

Summary Background Endovascular treatment (angioplasty with or without stenting) is an alternative to carotid endarterectomy for carotid artery stenosis but there are scarce long-term efficacy data showing that it prevents stroke. We therefore report the long-term results of the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS). Methods Between March, 1992, and July, 1997, patients who presented at a participating centre with a confirmed stenosis of the internal carotid artery that was deemed equally suitable for either carotid endarterectomy or endovascular treatment were randomly assigned to either treatment in equal proportions by telephone or fax from the randomisation service at the Oxford Clinical Trials Unit, UK. Patients were seen by an independent neurologist at 1 and 6 months after treatment and then every year after randomisation for as long as possible, up to a maximum of 11 years. Major outcome events were transient ischaemic attack, non-disabling, disabling, and fatal stroke, myocardial infarction, and death from any other cause. Outcomes were adjudicated on by investigators who were masked to treatment. Analysis was by intention to treat. This study is registered, number ISRCTN 01425573. Findings 504 patients with stenosis of the carotid artery (90% symptomatic) were randomly assigned to endovascular treatment (n=251) or surgery (n=253). Within 30 days of treatment, there were more minor strokes that lasted less than 7 days in the endovascular group (8 vs 1) but the number of other strokes in any territory or death was the same (25 vs 25). There were more cranial nerve palsies (22 vs 0) in the endarterectomy group than in the endovascular group. Median length of follow up in both groups was 5 years (IQR 2–6). By comparing endovascular treatment with endarterectomy after the 30-day post-treatment period, the 8-year incidence and hazard ratio (HR) at the end of follow-up for ipsilateral non-perioperative stroke was 11·3% versus 8·6% (HR 1·22, 95% CI 0·59–2·54); for ipsilateral non-perioperative stroke or TIA was 19·3% versus 17·2% (1·29, 0·78–2·14); and for any non-perioperative stroke was 21·1% versus 15·4% (1·66, 0·99–2·80). Interpretation More patients had stroke during follow-up in the endovascular group than in the surgical group, but the rate of ipsilateral non-perioperative stroke was low in both groups and none of the differences in the stroke outcome measures was significant. However, the study was underpowered and the confidence intervals were wide. More long-term data are needed from the on going stenting versus endarterectomy trials. Funding British Heart Foundation; UK National Health Service Management Executive; UK Stroke Association.

Effect of white-matter lesions on the risk of periprocedural stroke after carotid artery stenting versus endarterectomy in the International Carotid Stenting Study (ICSS): a prespecified analysis of data from a randomised trial

Summary Background Findings from randomised trials have shown a higher early risk of stroke after carotid artery stenting than after carotid endarterectomy. We assessed whether white-matter lesions affect the perioperative risk of stroke in patients treated with carotid artery stenting versus carotid endarterectomy. Methods Patients with symptomatic carotid artery stenosis included in the International Carotid Stenting Study (ICSS) were randomly allocated to receive carotid artery stenting or carotid endarterectomy. Copies of baseline brain imaging were analysed by two investigators, who were masked to treatment, for the severity of white-matter lesions using the age-related white-matter changes (ARWMC) score. Randomisation was done with a computer-generated sequence (1:1). Patients were divided into two groups using the median ARWMC. We analysed the risk of stroke within 30 days of revascularisation using a per-protocol analysis. ICSS is registered with controlled-trials.com, number ISRCTN 25337470. Findings 1036 patients (536 randomly allocated to carotid artery stenting, 500 to carotid endarterectomy) had baseline imaging available. Median ARWMC score was 7, and patients were dichotomised into those with a score of 7 or more and those with a score of less than 7. In patients treated with carotid artery stenting, those with an ARWMC score of 7 or more had an increased risk of stroke compared with those with a score of less than 7 (HR for any stroke 2·76, 95% CI 1·17–6·51; p=0·021; HR for non-disabling stroke 3·00, 1·10–8·36; p=0·031), but we did not see a similar association in patients treated with carotid endarterectomy (HR for any stroke 1·18, 0·40–3·55; p=0·76; HR for disabling or fatal stroke 1·41, 0·38–5·26; p=0·607). Carotid artery stenting was associated with a higher risk of stroke compared with carotid endarterectomy in patients with an ARWMC score of 7 or more (HR for any stroke 2·98, 1·29–6·93; p=0·011; HR for non-disabling stroke 6·34, 1·45–27·71; p=0·014), but there was no risk difference in patients with an ARWMC score of less than 7. Interpretation The presence of white-matter lesions on brain imaging should be taken into account when selecting patients for carotid revascularisation. Carotid artery stenting should be avoided in patients with more extensive white-matter lesions, but might be an acceptable alternative to carotid endarterectomy in patients with less extensive lesions. Funding Medical Research Council, the Stroke Association, Sanofi-Synthélabo, the European Union Research Framework Programme 5.

Length of carotid stenosis predicts peri-procedural stroke or death and restenosis in patients randomized to endovascular treatment or endarterectomy

Background The anatomy of carotid stenosis may influence the outcome of endovascular treatment or carotid endarterectomy. Whether anatomy favors one treatment over the other in terms of safety or efficacy has not been investigated in randomized trials. Methods In 414 patients with mostly symptomatic carotid stenosis randomized to endovascular treatment (angioplasty or stenting; n = 213) or carotid endarterectomy (n = 211) in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), the degree and length of stenosis and plaque surface irregularity were assessed on baseline intraarterial angiography. Outcome measures were stroke or death occurring between randomization and 30 days after treatment, and ipsilateral stroke and restenosis ⩾50% during follow-up. Results Carotid stenosis longer than 0·65 times the common carotid artery diameter was associated with increased risk of peri-procedural stroke or death after both endovascular treatment [odds ratio 2·79 (1·17–6·65), P = 0·02] and carotid endarterectomy [2·43 (1·03–5·73), P = 0·04], and with increased long-term risk of restenosis in endovascular treatment [hazard ratio 1·68 (1·12–2·53), P = 0·01]. The excess in restenosis after endovascular treatment compared with carotid endarterectomy was significantly greater in patients with long stenosis than with short stenosis at baseline (interaction P = 0·003). Results remained significant after multivariate adjustment. No associations were found for degree of stenosis and plaque surface. Conclusions Increasing stenosis length is an independent risk factor for peri-procedural stroke or death in endovascular treatment and carotid endarterectomy, without favoring one treatment over the other. However, the excess restenosis rate after endovascular treatment compared with carotid endarterectomy increases with longer stenosis at baseline. Stenosis length merits further investigation in carotid revascularisation trials.

Long-Term Outcome of Endovascular Treatment versus Medical Care for Carotid Artery Stenosis in Patients Not Suitable for Surgery and Randomised in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS)

Background: Optimal treatment of carotid stenosis in patients not suitable for surgery is unclear. The Carotid and Vertebral Artery Transluminal Angioplasty study contained a trial comparing medical and endovascular treatment in patients not suitable for surgery. Methods: Forty patients were randomised to medical or endovascular treatment in equal numbers, and patients were followed up for up to 10 years. The primary outcome measure was defined as stroke or death during follow-up, analysed by intention-to-treat. Secondary analyses included disabling stroke, death, any stroke, any stroke or transient ischemic attack (TIA), all during follow-up. Findings: Baseline characteristics were similar. The risk of stroke, retinal infarction or death within 30 days of endovascular treatment was 5% (95% CI: 0.1–24.9%). By the study end, >50% of patients had suffered a recurrent TIA, stroke or died. One third of events were non-stroke deaths. Overall, there was no significant difference between medical and endovascular treatment in the primary outcome rate of stroke or death after randomisation (hazard ratio: 0.98, 95% CI: 0.39–2.48) or the rate of any stroke or TIA (hazard ratio: 1.43, 95% CI: 0.54–3.75). Interpretation: We failed to show superiority of endovascular treatment above medical care alone for carotid stenosis in a very small group of patients not suitable for surgical treatment. However, the trial randomised only 40 patients, and was therefore severely underpowered to detect clinically relevant treatment differences. Ongoing trials of carotid stenting will need to demonstrate improved safety and efficacy before endovascular treatment should enter routine practice.

Percutaneous transluminal angioplasty and stenting for carotid stenosis: a Cochrane review

Carotid endarterectomy remains the treatment of choice for carotid stenosis. In recent years, endovascular treatment has become more readily available. However, randomised trials have so far failed to show equivalence of endovascular treatment. The aim of this review was therefore to analyse the combined available data from randomised clinical trials. Search of the Cochrane Stroke Group trials register (last searched 14 March 2007), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2007), MEDLINE (1950–March 2007), EMBASE (1980–March 2007) and Science Citation Index (1945–March 2007) identified randomised trials of endovascular treatment (angioplasty and/or stenting) compared with endarterectomy (surgery) or medical therapy for carotid artery stenosis. One review author independently applied the inclusion criteria, extracted the data and assessed trial quality. Search results were validated by a second review author. Outcome events after randomisation …

Vascular Intervention in Stroke Prevention: Endarterectomy and Angioplasty

Carotid stenosis is a major risk factor for stroke and transient ischaemic attack. Asymptomatic and symptomatic carotid stenoses need to be considered separately. Carotid endarterectomy was established as the treatment of choice for recently symptomatic severe carotid stenosis by two landmark trials. The effect of surgery is much less in patients with moderate carotid stenosis and harmful in patients with stenosis of less than 50%. Suitable patients should be operated on within 2 weeks of symptoms because the benefit of endarterectomy declines rapidly with increasing time between symptom onset and treatment. The benefits of endarterectomy for asymptomatic stenosis shown in the randomised trials were much less. Improvements in medical treatment, especially increasing statin use after the trials were started, need to be taken into consideration when interpreting the trials, and most neurologists conclude that routine endarterectomy for asymptomatic stenosis is not justified. Early trials of endovascular treatment of carotid stenosis suggested that endovascular treatment might be a safe and effective alternative to carotid endarterectomy. However, subsequent trials have so far failed to provide enough evidence to justify routine carotid stenting as an alternative to endarterectomy in patients fit for surgery. More data from ongoing randomised trials of stenting versus endarterectomy are needed to determine the role of stenting in the treatment of carotid stenosis.

Restenosis and risk of stroke after stenting or endarterectomy for symptomatic carotid stenosis in the International Carotid Stenting Study (ICSS): secondary analysis of a randomised trial

Summary Background 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). Methods 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. Findings 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; p<0·0001). 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. Interpretation 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. Funding Medical Research Council, the Stroke Association, Sanofi-Synthélabo, and the European Union.

Stroke Prevention@@@Schlaganfallprävention

Stroke is one of the leading causes of death and disability in the Western world and efforts should be made to prevent the occurrence of stroke. Primary preventive measures are influenced by the patients risk factor profile. A healthy lifestyle should be encouraged. Hypertension as a major risk factor for stroke should be controlled either by lifestyle measures or, if that is unsuccessful, through pharmacological means. The risk of stroke in diabetic patients with hypertension is increased and blood pressure and blood sugar levels should be controlled. Atrial fibrillation increases the risk of stroke and in high-risk patients oral anticoagulation is recommended. Patients suffering from coronary artery disease and high-risk hypertensive patients should be treated with statins. Asymptomatic carotid artery disease increases the risk of stroke. Before surgery is considered, it is important to optimize medical treatment of vascular risk factors. In addition to these measures, secondary prevention of stroke includes the prescription of antiplatelet therapy. Oral anticoagulation should be reserved for cardioembolic strokes. Symptomatic carotid stenosis should be treated by carotid endarterectomy. Stenting should be reserved for patients with contraindications to surgery or in the setting of clinical randomized trials.ZusammenfassungDer Schlaganfall ist die Erkrankung mit der höchsten Mortalität in der westlichen Welt und die häufigste Ursache für körperliche Behinderung beim Erwachsenen. Es sollten mehr Anstrengungen unternommen werden, Schlaganfälle zu verhindern.Primärprävention zielt darauf ab, bei bisher gesunden Menschen Schlaganfälle zu verhindern. Präventive Maßnahmen sollten sich am zugrundeliegenden kardiovaskulären Risikoprofil orientieren. Je höher das Risiko, umso deutlicher ist die Evidenz für primärpräventive Maßnahmen. Zunächst muss daher das individuelle kardiovaskuläre Risiko ermittelt werden. Die Verbesserung des Lebensstils stellt eine der Säulen präventiver Maßnahmen dar.Bluthochdruck ist ein wichtiger Risikofaktor für zerebrale Ischämie. Patienten mit konstanten Blutdruckwerten > 160/100 mmHg sollten medikamentös behandelt werden. Das Ziel sollte eine dauerhafte Senkung der Blutdruckwerte auf < 140/90 mmHg bei Nichtdiabetikern und < 130/85 mmHg bei Diabetikern sein. Es gilt zu berücksichtigen, dass der präventive Effekt blutdrucksenkender Medikamente umso größer ist, je stärker der Blutdruck gesenkt wird. Diabetiker neigen zu Arteriosklerose und Bluthochdruck, und die Blutdruckbehandlung ist hier von besonderer Bedeutung. Die besten Ergebnisse wurden in Studien mit ACE-Hemmern oder Angiotensinrezeptorblockern erzielt. Interessanterweise führte eine strenge Blutdruckeinstellung bei Diabetikern zu einer Senkung des Schlaganfallrisikos mit nur geringem Einfluss auf das Herzinfarktrisiko, während die strenge Blutzuckerkontrolle einen umgekehrten Effekt hatte.Bei Patienten mit Vorhofflimmern resultierte die orale Antikoagulation in einer deutlichen Verringerung des Schlaganfallrisikos, während Rhythmuskontrolle nur wenig Einfluss auf das Schlaganfallrisiko zu haben schien. Daher sollten Patienten mit Vorhofflimmern, deren Risiko > 4%/Jahr beträgt, mit einer Ziel-INR (International Normalized Ratio) von 2,0–3,0 antikoaguliert werden.Studien konnten zeigen, dass Patienten mit asymptomatischer Karotisstenose unter bestimmten Umständen von einem operativen Eingriff profitieren. Die Kontrolle anderer kardiovaskulärer Risikofaktoren ist jedoch bei diesen Patienten von herausragender Bedeutung.In der Sekundärprävention von Schlaganfällen hat die Blutdrucksenkung zu einer signifikanten Reduktion des Schlaganfallrisikos geführt, unabhängig davon, ob der Patient als hypertensiv eingestuft worden war oder nicht. Daten zu spezifischen blutdrucksenkenden Medikamenten fehlen weitgehend, in Metaanalysen wurde eine signifikante Reduktion von Reinfarkten unter Diuretika allein oder in Kombination mit ACE-Hemmern nachgewiesen.Der Nutzen von Statinen zur Senkung des Schlaganfallrisikos wurde in mehreren Studien belegt. Hierbei gilt, dass die Wirkung weitgehend unabhängig vom Cholesterinausgangswert im Blut ist.Die Behandlung mit Thrombozytenfunktionshemmern ist ein wichtiger Bestandteil der Sekundärprävention von Schlaganfällen. Leitlinien der Fachgesellschaften empfehlen hier eine Kombination von Aspirin und Dipyridamol bei Hochrisikopatienten. Bei Patienten mit peripherer arterieller Verschlusskrankheit sollte die Gabe von Clopidogrel vorgezogen werden. Die Sekundärprävention mit oralen Antikoagulanzien bei Vorhofflimmern ist hochwirksam, bei nichtkardioembolischen Schlaganfällen bietet die orale Antikoagulation gegenüber Aspirin jedoch keinen Vorteil.Bei symptomatischer Karotisstenose ist die Karotisendarteriektomie die Therapie der Wahl. Stents sollten derzeit nur bei Patienten mit operativen Kontraindikationen und im Rahmen klinischer Studien eingesetzt werden.