SummaryBackgroundStents 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.MethodsThe 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.FindingsThe 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).InterpretationCompletion 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.FundingMedical Research Council, the Stroke Association, Sanofi-Synthélabo, European Union.

SummaryBackgroundStenting 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.MethodsPatients 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.Findings1713 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.InterpretationLong-term functional outcome and risk of fatal or disabling stroke are similar for stenting and endarterectomy for symptomatic carotid stenosis.FundingMedical Research Council, Stroke Association, Sanofi-Synthélabo, European Union.

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Conclusions: In patients with heterozygous familial hypercholesterolemia, Evolocumab administered either 140 mg every 2 weeks or 420 mg monthly is well tolerated and yields similar and rapid 60% reductions in LDL cholesterol.Summary: Familial hypercholesterolemia is the most common dominantly inherited disorder in human beings worldwide (Watts GF, et al Int J Card 2014; 171:309-325). Likely more than 3 million people have the disorder in the United States and Europe alone. Familial hypercholesterolemia results from mutations in genes involving key proteins in LDL cholesterol metabolism leading to reduced cellular uptake of LDL cholesterol and increased LDL cholesterol concentrations with premature development of cardiovascular disease. The LDL receptor gene is the site of most mutations and more than 1700 such mutations have been described (Leigh SE, et al Ann Human Gene 2008; 72:485-498). Mutations in the apolipoprotein B gene account for a further 5% of familial hypercholesterolemia cases. Less than 1% of cases involve proprotein convertase subtilisin/kexin type 9 (PCSK9) mutations (Abifadel M, et al Genetics 2003; 34:154-156). Twenty percent of patients with a clinical diagnosis of heterozygous familial hypercholesterolemia have no identified mutation. Statins have improved the treatment of heterozygous familial hypercholesterolemia but many patients do not achieve desirable LDL cholesterol concentrations despite intensive statin therapy. However, phase 1 and 2 trials have now shown that further LDL reductions of 55-60% can be achieved when PCSK9 inhibitors are added to existing lipid lowering treatments. Actions are similar for LDL cholesterol to those reported in patients without familial hypercholesterolemia. The current study is a phase 3 trial to assess the safety and efficacy of Evolocumab (ANG145) in patients with heterozygous familial hypercholesterolemia who, despite intensive lipid lowering therapy, have LDL concentrations $2.6 mmol/l. This was a multi-center randomized double blind-placebo controlled trial undertaken at 39 sites worldwide utilizing primarily specialized lipid clinics generally attached to academic institutions. The trial was conducted between February 7 and December 19, 2013. 331 eligible patients 18-80 years of age who met clinical criteria for heterozygous familial hypercholesterolemia and who were on stable lipid lowering therapy for at least 4 weeks with a fasting LDL concentration of 2.6 mmol/L or higher were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous Evolucomab 140 mg every 2 weeks, Evolucomab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomization was computer generated and stratified by LDL cholesterol concentration at screening (higher or lower than 4.1 mmol/L) and baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and study staff were masked to treatment assignments within dose and frequency groups. The co-primary end points were percent change from baseline and LDL cholesterol at week 12 and...

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.