Carotid endarterectomy versus stenting in patients with carotid artery stenosis and type 2 diabetes: a nationwide cohort study from the USA

P rimarily on the basis of data derived from the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial, 1 the US Food and Drug Administration (FDA) has approved the use of carotid stents (CASs) in high-risk patients.The SAPPHIRE trial was published and much heralded as a randomized trial demonstrating that CASs were not inferior to carotid endarterectomy (CEA).Yet, the more recent Endarterectomy Versus Angioplasty in Patients with Symptomatic Carotid Stenosis randomized trial of CASs compared with CEA had to be stopped because the stroke rate with stents was so high that it triggered the safety guidelines of the study design. 2How can we explain the striking difference in outcome between these 2 studies, and how did it happen that the FDA was so convinced of the quality and validity of the SAPPHIRE trial that it granted approval for CASs?An examination of the SAPPHIRE trial-its conduct, data collection and analysis, the circumstances of publication, the presentation to the FDA Advisory Panel, and its consequent approval-is the primary focus of this article.This is a case study of the flaws in our system for the evaluation and approval of medical devices that warrant serious reflection on our ability to properly create and act on accurate information and live up to our commitment to evidence-based decision making. Response by Samuelson et al p 1601As it now stands, existing studies leave us with the unfortunate but not unreasonable conclusion that no scientific basis exists for the use of CASs as approved by the FDA, and in the absence of change, there is every reason to doubt the capability of our current system to protect the public from unnecessary risk in the future.Although this article focuses on just 1 example of how our systems are flawed at multiple levels to provide a reliable assessment of CASs and other technology, readers seeking further examples can find a wealth of related information.

Carotid artery stenting versus carotid endarterectomy in the treatment of symptomatic and asymptomatic carotid stenosis: a systematic review and meta-analysis

Critique of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST): Flaws in CREST and its Interpretation

Short-term outcome after stenting versus endarterectomy for symptomatic carotid stenosis: a preplanned meta-analysis of individual patient data

Regarding “Stroke and death after carotid endarterectomy and carotid artery stenting with and without high risk criteria”

Carotid artery stenting versus endarterectomy for carotid stenosis – Authors' reply

Objective To investigate the clinical efficacy and safety of carotid endarterectomy(CEA)and carotid artery stenting(CAS)for the treatment of carotid artery stenosis in the elderly. Methods Clinical data of 116 elderly patients aged over 65 years with carotid artery stenosis were retrospectively analyzed.Of 116 patients, 73 patients underwent CAS(the CAS group)and 32 received CEA(the CEA group). The success rate, 30-day perioperative complications and follow-up results were compared between the two groups. Results There was no significant difference in the success rate(96.8% vs.100.0%, P>0.05), 30-day perioperative complications, such as bradycardia(6.25% vs.4.5%, χ2=0.228, P=0.663), acute myocardial infarction(0.0 vs.1.4%, χ2=0.432, P=0.511), transient hypotension(6.3% vs.8.1%, χ2=0.114, P=0.735), ischemic stroke(6.3% vs.6.8%, χ2=0.009, P=0.923), and cerebral hyperperfusion syndrome(18.8% vs.10.8%, χ2=0.009, P=0.923), between the CEA and CAS groups.The incidence of persistent hypotension was lower in the CEA group than in the CAS group(3.1% vs.17.6%, χ2=4.398, P=0.036). No significant difference was found in carotid artery restenosis(moderate: 6.3% vs.8.1%, χ2=0.114, P=0.735; severe: 3.1% vs.2.7%, χ2=0.014, P=0.905)and ipsilateral stroke(3.1% vs.5.4%, χ2=0.279, P=0.598)between the CEA and CAS groups at one-year fellow-up. Conclusions Both CEA and CAS have good efficacies in treating carotid artery stenosis in the elderly, while the incidence of persistent hypotension is higher with CAS than with CEA. Key words: Carotid stenosis; Stents; Endarterectomy carotid

Primarily on the basis of data derived from the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial,1 the US Food and Drug Administration (FDA) has approved the use of carotid stents (CASs) in high-risk patients. The SAPPHIRE trial was published and much heralded as a randomized trial demonstrating that CASs were not inferior to carotid endarterectomy (CEA). Yet, the more recent Endarterectomy Versus Angioplasty in Patients with Symptomatic Carotid Stenosis randomized trial of CASs compared with CEA had to be stopped because the stroke rate with stents was so high that it triggered the safety guidelines of the study design.2 How can we explain the striking difference in outcome between these 2 studies, and how did it happen that the FDA was so convinced of the quality and validity of the SAPPHIRE trial that it granted approval for CASs? An examination of the SAPPHIRE trial—its conduct, data collection and analysis, the circumstances of publication, the presentation to the FDA Advisory Panel, and its consequent approval—is the primary focus of this article. This is a case study of the flaws in our system for the evaluation and approval of medical devices that warrant serious reflection on our ability to properly create and act on accurate information and live up to our commitment to evidence-based decision making. Response by Samuelson et al p 1601 As it now stands, existing studies leave us with the unfortunate but not unreasonable conclusion that no scientific basis exists for the use of CASs as approved by the FDA, and in the absence of change, there is every reason to doubt the capability of our current system to protect the public from unnecessary risk in the future. Although this article focuses on just 1 example of how our systems …

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.

We thank Armstrong and colleagues for acknowledging the importance of the original study, which found a positive association between the tPA -7351 TT genotype and lacunar stroke in an Australian population.As we concluded in the article, this association was made after subgroup analysis and was thus interpreted as hypothesis generating.We agree that confirmation in a larger, well-designed study is critical.It is important to reiterate that the tPA Ϫ7351 C/T polymorphism possesses a plausible biological reason to cause cerebral lacunar infarction,

One of the great achievements of modern medicine is the successful prevention of stroke and other cardiovascular diseases. Although the incidence of stroke has substantially declined over the last 30 years, ≈200 000 preventable stroke deaths still occur annually in the United States. According to a recent study based on the Greater Cincinnati/Northern Kentucky Stroke Study, annually ≈41 000 strokes in the United States are attributed to extracranial internal carotid artery stenosis. Early revascularization for symptomatic carotid stenosis—that is, in patients with recent ipsilateral stroke or TIA—is well established as effective at preventing ipsilateral stroke. Carotid stenosis in the absence of symptoms is extremely common, but the best treatment is unclear. While 2 randomized trials showed a benefit of carotid endarterectomy (CEA) over antiplatelet therapy with aspirin, the number needed to treat approaches 200. Does aggressive risk factor control change that balance? Population screening for carotid stenosis followed by revascularization is considered to cause net harm. Are complication rates from endarterectomy and stenting now low enough to justify expanding their indications in asymptomatic patients? The National Institute of Neurological Disorders and Stroke (NINDS)–funded CREST-2 trial (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) is an ambitious attempt to further refine the treatment of asymptomatic carotid stenosis. As one of the largest randomized stroke prevention trials, the first CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) was designed to compare the safety and efficacy of 2 stroke prevention procedures for carotid artery narrowing—CEA and carotid artery stenting (CAS)—in symptomatic and asymptomatic individuals. Starting in December 2000, this NINDS-funded trial enrolled >2500 patients at 117 sites in the United States and Canada. Because of slow enrollment, the trial took 9 years to complete. In 2010, the results of CREST indicated that the 2 revascularization procedures were equivalent for …

Two articles were published in February 2001 that will have a significant impact on our understanding of human development, the pathogenesis of many human diseases, and the discovery of new therapies for many disorders.1 2 These articles deal with the mapping of the human genome. Two different entities, one a publicly traded company (Celera) and the other the Human Genome Project (HGP, sponsored and funded by NIH), published somewhat different versions of the human genome. The HGP began in 1990 (although extensive sequencing of the human genome began in 1995) and cost approximately $3 billion, while the Celera effort began in 1998.1 2 The HGP involved multiple laboratories in the United States and abroad. The 2 projects produced maps that differ from each other in terms of completeness, order of some genetic markers, and the ability to search the database for specific DNA sequences. A comparison of some features of both projects is in Table 1⇓. The challenge of sequencing the 3 billion base pairs of the human genome required the development of unique tools and approaches. Celera constructed a facility capable of high-throughput sequencing at a rate of 175 000 reads per day and conducted sequencing 24 hours a day, 7 days a week. The HGP divided the sequencing task among several large laboratories with demonstrated expertise in large-scale DNA sequencing. The strategy employed by the HGP focused on subcloning the human genome into bacterial artificial chromosomes (BAC), which were then sequenced and properly arranged.1 Each BAC could hold an insert of 150 000 bases on average. Celera used a shotgun whole genome approach to sequencing, which involved generating many small, random fragments of DNA for sequencing.2 After the sequence was determined, advanced computational algorithms combined with publicly available mapping and sequence information …

A 64-year-old man with a past medical history of diabetes mellitus, hyperlipidemia, and hypertension presented with acute-onset left hemiparesis, hemisensory loss, and dysarthria. He was diagnosed with a right middle cerebral artery stroke and treated with systemic thrombolysis. His poststroke workup included a carotid duplex ultrasound and computed tomographic angiogram of the carotid arteries (Figure 1), which confirmed a severe (70%–99%) stenosis in the right internal carotid artery (ICA) secondary to a 20-mm-long atherosclerotic plaque extending from the carotid bifurcation to the level of C2-C3 disc space. The left ICA showed moderate (50%–69%) stenosis. Should this patient be recommended for carotid artery revascularization, and, if so, by which method? Figure 1. Computed tomographic angiogram of the 64-year-old patient presented in this case, showing severe right internal carotid artery stenosis (arrow) in coronal ( A ) and sagittal ( B ) views. Stroke, defined as acute development of a focal neurological deficit attributable to the disruption of blood flow to the brain, is caused by 1 of 2 main causes: ischemia or hemorrhage. The majority (>80%) of strokes are of ischemic etiology, of which ≈15% to 20% are attributable to atherosclerosis of the extracranial carotid arteries. The risk of death and recurrent stroke increases following an ischemic stroke. Transient ischemic attacks, or strokelike symptoms that last <24 hours, are also associated with an increased risk of early recurrent stroke, particularly in patients with carotid artery atherosclerosis. The bifurcation point of the common carotid artery, or carotid bulb, is predisposed to the development of atherosclerosis owing to low wall shear stress and resulting flow stagnation. Narrowing or stenosis of the carotid bulb and ICA because of atherosclerosis can lead to ischemic stroke secondary to plaque embolization or hypoperfusion. The prevalence of ICA stenosis is estimated to be 2% to 3% in the general population, with increased prevalence noted …

Background Carotid stenosis is one of the common reasons for patients with ischemic stroke, and the two invasive options carotid endarterectomy (CEA) and carotid artery stenting (CAS) are the most popular treatments. But the relative efficacy and safety of the methods are not clear. Methods About 521 articles related to CAS and CEA for carotid stenosis published in 1995-2011 were retrieved from MEDLINE, Cochrane Library (CL), and China National Knowledge Infrastructure (CNKI) China Journal Full-Test database. Of them, eight articles were chosen. Meta-analysis was used to assess the relative risks. Results The eight studies included 3873 patients with symptomatic carotid artery stenosis, including 1941 cases in the carotid stent angioplasty group, and 1932 cases in the carotid endarterectomy group. Fixed effect model analysis showed that within 30 days of incidence of all types of strokes, surgery was significantly highly preferred in CAS patients (CAS group) than the CEA patients (CEA group), and the difference was statistically significant (relative ratio (RR)=1.80, 95% confidence interval (CI): 1.380-2.401, P&lt;0.0001). But the incidence of death in the two groups is not showed and is not statistically significant after 30 days (RR=1.52, 95% CI: 0.82-2.82, P=0.18). The rate of cranial nerve injury in the CAS group is lower than the CEA group (RR=0.14, 95% CI: 0.05-0.43, P=0.0005). The incidence of CAS patients with myocardial infarction is lower than the CEA group after 30 days, but statistically meaningless (RR=0.22, 95% CI: 0.05-1.02, P=0.05). The stroke or death in CAS patients were higher than the CEA group after 1 year of treatment ((RR=2.58, 95% CI: 1.03-6.48, P=0.04). Conclusions Compared to CAS, carotid endarterectomy is still the preferred treatment methodology of symptomatic carotid artery stenosis. Future meta-analyses should then be performed in long-term follow-up to support this treatment recommendation.

Objectives The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) showed no difference in the composite endpoint of stroke, myocardial infarction, or death between carotid artery stenting (CAS) and carotid endarterectomy (CEA) in patients with symptomatic or asymptomatic carotid stenosis (CS). We compared restenosis or occlusion, and repeat revascularization, between CAS and CEA over 2 years of follow-up. Methods Restenosis, occlusion, and repeat revascularization were assessed at 1, 6, 12 and 24 months post-randomization. Hemodynamically significant restenosis (≥70% diameter reduction) was defined by a peak systolic velocity (PSV) ≥300 cm/second on standardized duplex ultrasonography (DUS), occlusion by an absence of flow within the target artery on DUS, and repeat revascularization by any additional procedure (CEA, angioplasty or CAS) performed on the index artery. Studies were performed in CREST-certified laboratories and interpreted in the CREST Ultrasound Core Lab. Patients included in this report were those who received their assigned treatment within 30 days of randomization and had an ultrasound reviewed at the Core Lab (n=2191). Treatment differences were assessed using proportional hazards models adjusting for age, sex, and symptomatic status. Results In the analytic cohort, 1086 patients received CAS and 1105 received CEA. Over 2 years 113 patients developed restenosis, 56 (rate 5.8%) in the CAS group and 57 (rate 5.8%) in the CEA group; and 8 developed an occlusion, 3 (rate 0.3 %) in the CAS group and 5 (rate 0.5%) in the CEA group. The combined restenosis-occlusion rate was 6.0% (n=58) for CAS and 6.3% (n=62) for CEA (HR=0.90, 95% CI=0.63-1.29, p=0.58). Forty-three patients of the 2191 underwent repeat revascularization (20 CAS, 23 CEA, p=0.69) of which 28 had restenosis by our criteria and so were included ( Figure ). Stroke occurred in 13 (4 CAS; 9 CEA) of the 120 patients with restenosis or occlusion; 1 of the 4 CAS strokes occurred after restenosis was detected, and 5 of 9 CEA strokes occurred after restenosis was detected. Conclusions This analysis of carotid restenosis is the largest reported to date from any randomized clinical trial. Restenosis and occlusion were infrequent and similar up to 2 years following CAS or CEA among 2191 patients. The rates of revascularization likewise did not differ between CAS and CEA. Follow-up out to 10 years is ongoing. Figure. Kaplan-Meier curves of restenosis and occlusion over 2 years.