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

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.

Effects of carotid endarterectomy or stenting on blood pressure in the International Carotid Stenting Study (ICSS).

BACKGROUND AND PURPOSE: Arterial hypotension is more frequently observed early after carotid artery stenting (CAS) than after carotid endarterectomy (CEA), but their long-term effects on blood pressure (BP) are unclear. We compared the effects of CAS and CEA on BP up to 1 year after treatment in the International Carotid Stenting Study. METHODS: Patients with symptomatic carotid stenosis were randomly allocated to CAS or CEA. Systolic and diastolic BP were recorded at baseline, at discharge, and at 1, 6, and 12 months. Antihypertensive medication use was recorded. A per-protocol analysis was performed. Patients with missing BP records were excluded. Between-group BP changes were compared and adjusted for baseline covariates with linear regression. Within-group BP changes were compared with the paired t test. RESULTS: CAS (N=587) and CEA (N=637) were both associated with a decrease in BP at discharge, which was greater after CAS (mean difference in systolic BP between groups, 10.3 mm Hg; 95% CI, 7.3-13.3; P<0.0001; in diastolic BP, 4.1 mm Hg; 95% CI, 2.4-5.7; P<0.0001). During follow-up, BP changes were not different between groups. Adjustment for differences in baseline characteristics did not change the results. Fewer patients undergoing CAS used antihypertensive medication during follow-up than patients undergoing CEA (relative risk at 12 months, 0.91; 95% CI, 0.85-0.97; P=0.0073). CONCLUSIONS: CAS leads to a larger early decrease in BP than CEA, but this effect does not persist over time. CAS may lessen the requirement for antihypertensive medication more than CEA. Clinical Trial Registration- URL: www.controlled-trials.com. Unique identifier: ISRCTN25337470.

Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial.

BACKGROUND: Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. METHODS: The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. FINDINGS: The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006). Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). INTERPRETATION: Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery. FUNDING: Medical Research Council, the Stroke Association, Sanofi-Synthélabo, European Union.

Randomized controlled trials comparing endarterectomy and endovascular treatment for carotid artery stenosis: a Cochrane systematic review.

BACKGROUND AND PURPOSE: Endovascular treatment of carotid stenosis may be an alternative to surgical endarterectomy. We conducted a systematic review of the randomized evidence to assess the benefits and risks of endovascular treatment compared to surgery. METHODS: Cochrane registers and online databases were searched and researchers in the field contacted. Outcome events were compared using odds ratios (ORs) calculated using the Peto fixed effect and Mantel-Haenszel random effects models if there was significant heterogeneity. RESULTS: Ten trials involving 3178 patients were included. Not all contributed to each analysis. The primary outcome comparison of any stroke or death within 30 days of treatment favored surgery (fixed-effects OR 1.35), the difference was not statistically significant using the random effects model. Endovascular treatment was significantly better than surgery in avoiding cranial neuropathy (OR 0.15) and myocardial infarction (OR 0.34). There was no significant difference between endovascular treatment and surgery in the following comparisons: 30-day stroke, MI, or death (OR 1.12); 30-day disabling stroke or death (OR 1.19); 30-day death (OR 0.99); 24-month death or stroke (OR 1.26); and 30-day death or stroke in endovascular patients treated with or without protection devices (OR 0.75). CONCLUSIONS: The data are difficult to interpret because the trials are heterogeneous. Five trials were stopped early, perhaps leading to an overestimate of the risks of endovascular treatment. The results do not support a change in clinical practice away from recommending carotid endarterectomy as the treatment of choice for suitable carotid artery stenosis but support continued recruitment in the large ongoing 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.

Long-term outcome after angioplasty and stenting for symptomatic vertebral artery stenosis compared with medical treatment in the Carotid And Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomized trial.

BACKGROUND AND PURPOSE: The long-term outcome of endovascular intervention compared with best medical management of patients with symptomatic vertebral artery stenosis is uncertain. We therefore compared these treatments in a randomized trial with long-term follow-up. METHODS: In the international, multicenter Carotid And Vertebral Artery Transluminal Angioplasty Study, 16 patients with symptomatic vertebral artery stenosis were randomized in equal proportions to receive endovascular therapy (balloon angioplasty or stenting) or best medical treatment alone. An independent neurologist followed up the patients for as long as 8 years. RESULTS: Endovascular intervention was technically successful in all 8 patients, but 2 patients experienced transient ischemic attack at the time of endovascular treatment. There were no deaths or strokes in any arterial territory within the first 30 days. During a mean follow-up period of 4.7 years, no patient in either treatment group experienced a vertebrobasilar territory stroke, but 3 patients in each treatment arm died of myocardial infarction or carotid territory stroke, and 1 endovascular patient had a nonfatal carotid territory stroke. CONCLUSIONS: Patients with vertebral artery stenosis were more likely to have carotid territory stroke and myocardial infarction during follow-up than have recurrent vertebrobasilar stroke. The trial failed to show a benefit of endovascular treatment of vertebral artery stenosis, but the numbers of patients included was small. Larger randomized trials are required to determine whether vertebral artery stenting is justified in patients at higher risk of vertebrobasilar stroke. Treatment of patients with vertebral artery stenosis should focus on global reduction of vascular risk, including prevention of carotid territory stroke and myocardial infarction.

Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): a randomised controlled trial with cost-effectiveness analysis.

BACKGROUND: Carotid artery stenting (CAS) is an alternative to carotid endarterectomy (CEA) for the treatment of carotid stenosis, but safety and long-term efficacy were uncertain. OBJECTIVE: To compare the risks, benefits and cost-effectiveness of CAS versus CEA for symptomatic carotid stenosis. DESIGN: International, multicentre, randomised controlled, open, prospective clinical trial. SETTING: Hospitals at 50 centres worldwide. PARTICIPANTS: Patients older than 40 years of age with symptomatic atheromatous carotid artery stenosis. INTERVENTIONS: Patients were randomly allocated stenting or endarterectomy using a computerised service and followed for up to 10 years. MAIN OUTCOME MEASURES: The primary outcome measure was the long-term rate of fatal or disabling stroke, analysed by intention to treat (ITT). Disability was assessed using the modified Rankin Scale (mRS). A cost-utility analysis estimating mean costs and quality-adjusted life-years (QALYs) was calculated over a 5-year time horizon. RESULTS: A total of 1713 patients were randomised but three withdrew consent immediately, leaving 1710 for ITT analysis (853 were assigned to stenting and 857 were assigned to endarterectomy). The incidence of stroke, death or procedural myocardial infarction (MI) within 120 days of treatment was 8.5% in the CAS group versus 5.2% in the CEA group (72 vs. 44 events) [hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.16 to 2.45; p = 0.006]. In the analysis restricted to patients who completed stenting, age independently predicted the risk of stroke, death or MI within 30 days of CAS (relative risk increase 1.17% per 5 years of age, 95% CI 1.01% to 1.37%). Use of an open-cell stent conferred higher risk than a closed-cell stent (relative risk 1.92, 95% CI 1.11 to 3.33), but use of a cerebral protection device did not modify the risk. CAS was associated with a higher risk of stroke in patients with an age-related white-matter changes score of 7 or more (HR 2.98, 95% CI 1.29 to 6.93; p = 0.011). After completion of follow-up with a median of 4.2 years, the number of patients with fatal or disabling stroke in the CAS and CEA groups (52 vs. 49), and the cumulative 5-year risk did not differ significantly (6.4% vs. 6.5%) (HR 1.06, 95% CI 0.72 to 1.57; p = 0.776). Stroke of any severity was more frequent in the CAS group (15.2% vs. 9.4% in the CEA group) (HR 1.712, 95% CI 1.280 to 2.300; p < 0.001). There was no significant difference in long-term rates of severe carotid restenosis or occlusion (10.8% in the CAS group vs. 8.6% in the CEA group) (HR 1.25, 95% CI 0.89 to 1.75; p = 0.20). There was no difference in the distribution of mRS scores at 1-year, 5-year or final follow-up. There were no differences in costs or QALYs between the treatments. LIMITATIONS: Patients and investigators were not blinded to treatment allocation. Interventionists' experience of stenting was less than that of surgeons with endarterectomy. Data on costs of managing strokes were not collected. CONCLUSIONS: The functional outcome after stenting is similar to endarterectomy, but stenting is associated with a small increase in the risk of non-disabling stroke. The choice between stenting and endarterectomy should take into account the procedural risks related to individual patient characteristics. Future studies should include measurement of cognitive function, assessment of carotid plaque morphology and identification of clinical characteristics that determine benefit from revascularisation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN25337470. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 20. See the NIHR Journal Library website for further project information. Further funding was provided by the Medical Research Council, Stroke Association, Sanofi-Synthélabo and the European Union.

Cost-utility analysis of stenting versus endarterectomy in the International Carotid Stenting Study.

BACKGROUND: The International Carotid Stenting Study was a multicenter randomized trial in which patients with symptomatic carotid artery stenosis were randomly allocated to treatment by carotid stenting or endarterectomy. Economic evidence comparing these treatments is limited and inconsistent. AIMS: We compared the cost-effectiveness of stenting versus endarterectomy using International Carotid Stenting Study data. METHODS: We performed a cost-utility analysis estimating mean costs and quality-adjusted life years per patient for both treatments over a five-year time horizon based on resource use data and utility values collected in the trial. Costs of managing stroke events were estimated using individual patient data from a UK population-based study (Oxford Vascular Study). RESULTS: Mean costs per patient (95% CI) were US$10,477 ($9669 to $11,285) in the stenting group (N = 853) and $9669 ($8835 to $10,504) in the endarterectomy group (N = 857). There were no differences in mean quality-adjusted life years per patient (3.247 (3.160 to 3.333) and 3.228 (3.150 to 3.306), respectively). There were no differences in adjusted costs between groups (mean incremental costs for stenting versus endarterectomy $736 (95% CI -$353 to $1826)) or adjusted outcomes (mean quality-adjusted life years gained -0.010 (95% CI -0.117 to 0.097)). The incremental net monetary benefit for stenting versus endarterectomy was not significantly different from zero at the maximum willingness to pay for a quality-adjusted life year commonly used in the UK. Sensitivity analyses showed little uncertainty in these findings. CONCLUSIONS: Economic considerations should not affect whether patients with symptomatic carotid stenosis undergo stenting or endarterectomy.

Safety and efficacy of endovascular treatment of carotid artery stenosis compared with carotid endarterectomy: a Cochrane systematic review of the randomized evidence.

BACKGROUND AND PURPOSE: Endovascular treatment of atherosclerotic carotid artery stenosis may be an alternative to surgical endarterectomy. To evaluate the safety and efficacy of endovascular techniques, we conducted a systematic review of randomized studies that compared endovascular treatment with surgery for carotid stenosis. METHODS: We searched the Cochrane Stroke Group trials register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Science Citation Index for randomized trials of carotid angioplasty and/or stenting compared with surgery. We also contacted researchers in the field and balloon catheter and stent manufacturers. RESULTS: Five trials involving 1269 patients were included. Analysis of 30-day safety data found no significant difference in the odds of treatment-related death or any stroke (odds ratio [OR], endovascular surgery, 1.33; 95% confidence interval [CI], 0.86 to 2.04), death or disabling stroke (OR, 1.22; CI, 0.61 to 2.41), or death, any stroke, or myocardial infarction (OR, 1.04; CI, 0.69 to 1.57). At 1 year after randomization, there was no significant difference between the 2 treatments in the rate of any stroke or death (OR, 1.01; CI, 0.71 to 1.44). Endovascular treatment significantly reduced the risk of cranial nerve injury (OR, 0.13; CI, 0.06 to 0.25). There was substantial heterogeneity between the trials for 4 of the 5 outcomes. CONCLUSIONS: No significant difference in the major risks of treatment was found but the wide confidence intervals indicate that it is not possible to exclude a difference in favor of one treatment. Minor complication rates favor endovascular treatment. There is currently insufficient evidence to support a widespread change in clinical practice away from recommending carotid endarterectomy as the treatment of choice for suitable carotid artery stenosis. Patients suitable for carotid endarterectomy should only be offered stenting within the ongoing randomized trials of stenting versus surgery.

Ischemic brain lesions after carotid artery stenting increase future cerebrovascular risk.

BACKGROUND: Brain lesions on diffusion-weighted imaging (DWI) are frequently found after carotid artery stenting (CAS), but their clinical relevance remains unclear. OBJECTIVES: This study sought to investigate whether periprocedural ischemic DWI lesions after CAS or carotid endarterectomy (CEA) are associated with an increased risk of recurrent cerebrovascular events. METHODS: In the magnetic resonance imaging (MRI) substudy of ICSS (International Carotid Stenting Study), 231 patients with symptomatic carotid stenosis were randomized to undergo CAS (n=124) or CEA (n=107). MRIs were performed 1 to 7 days before and 1 to 3 days after treatment. The primary outcome event was stroke or transient ischemic attack in any territory occurring between the post-treatment MRI and the end of follow-up. Time to occurrence of the primary outcome event was compared between patients with (DWI+) and without (DWI-) new DWI lesions on the post-treatment scan in the CAS and CEA groups separately. RESULTS: Median time of follow-up was 4.1 years (interquartile range: 3.0 to 5.2). In the CAS group, recurrent stroke or transient ischemic attack occurred more often among DWI+ patients (12 of 62) than among DWI- patients (6 of 62), with a cumulative 5-year incidence of 22.8% (standard error [SE]: 7.1%) and 8.8% (SE: 3.8%), respectively (unadjusted hazard ratio: 2.85; 95% confidence interval: 1.05 to 7.72; p=0.04). In DWI+ and DWI- patients, 8 and 2 events, respectively, occurred within 6 months after treatment. In the CEA group, there was no difference in recurrent cerebrovascular events between DWI+ and DWI- patients. CONCLUSIONS: Ischemic brain lesions discovered on DWI after CAS seem to be a marker of increased risk for recurrent cerebrovascular events. Patients with periprocedural DWI lesions might benefit from more aggressive and prolonged antiplatelet therapy after CAS. (A Randomised Comparison of the Risks, Benefits and Cost Effectiveness of Primary Carotid Stenting With Carotid Endarterectomy: International Carotid Stenting Study; ISRCTN25337470).

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.

Effects of carotid endarterectomy or stenting on hemodynamic complications in the International Carotid Stenting Study: a randomized comparison.

BACKGROUND: Carotid endarterectomy and carotid artery stenting are frequently complicated by hemodynamic instability. AIMS: The study aims to compare the incidence of hemodynamic complications between carotid artery stenting and carotid endarterectomy in the International Carotid Stenting Study (ISRCTN25337470). METHODS: Patients with symptomatic carotid stenosis were randomly allocated to carotid artery stenting or carotid endarterectomy. The occurrence of peri-procedural hemodynamic depression (severe bradycardia, asystole, or hypotension requiring treatment) and hypertension requiring treatment was assessed in a per-protocol analysis. We compared the rate of hemodynamic complications, determined independent predictors thereof, and assessed their relation with the composite outcome of all-cause death, stroke, and myocardial infarction within 30 days of treatment. RESULTS: A number of 766 carotid artery stenting and 819 carotid endarterectomy patients had a single completed intervention. Hemodynamic depression occurred in 13.8% after carotid artery stenting and in 7.2% after carotid endarterectomy (relative risk 1.9, 95% confidence interval 1.4-2.6, P < 0.0001). Hypertension requiring treatment occurred less often after carotid artery stenting than after carotid endarterectomy (relative risk 0.2, 95% confidence interval, 0.1-0.4, P < 0.0001). In carotid artery stenting patients, a history of cardiac failure was the trongest independent predictor of hemodynamic depression (relative risk 2.4, 95% confidence interval 1.3-4.8, P = 0.009). There was no statistically significant association between hemodynamic complications and the occurrence of the composite outcome. CONCLUSION: Hemodynamic depression occurs more often after carotid artery stenting and severe hypertension more often after carotid endarterectomy, but these complications are not responsible for the excess of major perioperative events after carotid artery stenting.

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.

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.

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.

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.

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.

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 (>or=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.

Long-term hypothermic lung preservation: does adenosine A1 receptor antagonism have a role in ischemic preconditioning protection?

Ischemic preconditioning or phosphodiesterase inhibition improves lung protection during prolonged hypothermic storage. In ischemic preconditioning of cat lungs, adenosine A1 receptor antagonism was suggested as a possible mechanism. Some phosphodiesterase inhibitors (such as theophylline) are also adenosine antagonists; we showed theophylline to be particularly effective in protecting lungs. In isolated, perfused and ventilated rat lungs, we examined (1) whether synergy exists between phosphodiesterase inhibition and ischemic preconditioning and (2) whether theophylline acts both to inhibit phosphodiesterase and block adenosine receptors, by comparing its effects with enprofylline (selective phosphodiesterase inhibition) or xanthine amine congener (selective adenosine A1 receptor antagonism). In Study 1, rolipram (added to St Thomas' cardioplegia) or ischemic preconditioning before hypothermic storage (8 h) did not improve lung function during reperfusion (40 min); a combination of these treatments was also ineffective. In Study 2, lungs stored in St Thomas' cardioplegia containing enprofylline or theophylline had improved recovery of function compared to control lungs; however, xanthine amine congener was without effect. Thus, no interaction exists between phosphodiesterase inhibition and ischemic preconditioning. Adenosine A1 receptor antagonism plays no role in protecting rat lungs from the effects of prolonged hypothermic storage by either preconditioning or addition of theophylline to the storage solution.

International carotid stenting study: protocol for a randomised clinical trial comparing carotid stenting with endarterectomy in symptomatic carotid artery stenosis.

BACKGROUND: Carotid stenting avoids general anaesthesia, cranial nerve injury and the discomforts of surgical treatment of carotid stenosis. A systematic review of the randomised trials showed no overall difference in the major risks of endovascular treatment for carotid stenosis compared with surgery, but the confidence intervals were wide and both methods carried a significant risk of stroke. The use of protection devices appears to improve the safety of endovascular treatment, but there are little randomised data available about long-term outcomes. We have therefore set up an international, multicentre, randomised, controlled, open, prospective clinical trial, namely the International Carotid Stenting Study (ICSS), also known as CAVATAS-2. The objectives of the ICSS are to compare the risks, benefits and cost-effectiveness of a treatment policy of referral for carotid stenting compared with referral for carotid endarterectomy. METHODS: Centres are required to have a team with audited expertise in carotid endarterectomy and stenting procedures, including at least one neurologist or stroke physician, a surgeon and an interventionalist. Attendance at a carotid stenting training course is required. Centres with more limited experience can join the trial as probationary centres, but stenting must then be proctored by an experienced interventionalist. Symptomatic patients are included over the age of 40 years with atherosclerotic carotid stenosis, suitable for both stenting and surgery, and are randomised in equal proportions between carotid endarterectomy and stenting. Stents and other devices are chosen for use at the discretion of the interventionalists but must be approved by the devices committee. The protocol recommends that a cerebral protection system should be used whenever the operator thinks one can be safely deployed. The combination of aspirin and clopidogrel is recommended to cover stenting procedures. Standard or eversion endarterectomy is allowed using local or general anaesthesia, shunts or patches. All patients will receive best medical care. Patients will be followed up by neurologists at 30 days after treatment, 6 months after randomisation and then annually up to 5 years after randomisation. The primary outcome measure is the difference in the long-term rate of fatal or disabling stroke in any territory between patients randomised to stenting or surgery. Secondary outcome measures include any stroke, myocardial infarction or death within 30 days of treatment, treatment- related cranial nerve palsy or haematoma. Restenosis (>70%) on ultrasound follow-up, economic measures and quality of life will also be analysed. The sample size is estimated at 1,500 patients, which will provide 95% confidence intervals of +/- 3.0 percentage points for the outcome measure of 30-day disabling stroke and death rate and +/- 3.3 percentage points for the outcome measure of death or stroke during follow-up. The trial office monitors outcome events at individual centres and a rate of events above a given threshold triggers a blinded assessment of the events, submitted to the chairman of the data-monitoring committee. CONCLUSIONS: The ICSS protocol incorporates a number of novel features to ensure patient safety, including the concept of probationary centres, proctoring of inexperienced investigators and monitoring of individual centre results on an ongoing basis. The protocol is also designed to mirror routine clinical practice as far as possible, so that the results will be widely applicable and relevant to determining the place of carotid stenting in clinical practice in the future.