Carotid Revascularization Endarterectomy Versus Stenting Trial Research Articles

Safety of Stenting and Endarterectomy by Symptomatic Status in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)

Safety of Stenting and Endarterectomy by Symptomatic Status in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)

Myocardial Infarction After Carotid Stenting and Endarterectomy

Background— The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) found a higher risk of stroke after carotid artery stenting and a higher risk of myocardial infarction (MI) after carotid endarterectomy. Methods and Results— Cardiac biomarkers and ECGs were performed before and 6 to 8 hours after either procedure and if there was clinical evidence of ischemia. In CREST, MI was defined as biomarker elevation plus either chest pain or ECG evidence of ischemia. An additional category of biomarker elevation with neither chest pain nor ECG abnormality was prespecified (biomarker+ only). Crude mortality and risk-adjusted mortality for MI and biomarker+ only were assessed during follow-up. Among 2502 patients, 14 MIs occurred in carotid artery stenting and 28 MIs in carotid endarterectomy (hazard ratio, 0.50; 95% confidence interval, 0.26 to 0.94; P =0.032) with a median biomarker ratio of 40 times the upper limit of normal. An additional 8 carotid artery stenting and 12 carotid endarterectomy patients had biomarker+ only (hazard ratio, 0.66; 95% confidence interval, 0.27 to 1.61; P =0.36), and their median biomarker ratio was 14 times the upper limit of normal. Compared with patients without biomarker elevation, mortality was higher over 4 years for those with MI (hazard ratio, 3.40; 95% confidence interval, 1.67 to 6.92) or biomarker+ only (hazard ratio, 3.57; 95% confidence interval, 1.46 to 8.68). After adjustment for baseline risk factors, both MI and biomarker+ only remained independently associated with increased mortality. Conclusions— In patients randomized to carotid endarterectomy versus carotid artery stenting, both MI and biomarker+ only were more common with carotid endarterectomy. Although the levels of biomarker elevation were modest, both events were independently associated with increased future mortality and remain an important consideration in choosing the mode of carotid revascularization or medical therapy. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov . Unique identifier: NCT00004732.

Influence of sex on outcomes of stenting versus endarterectomy: a subgroup analysis of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST)

In the randomised Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), the primary endpoint did not differ between carotid artery stenting and carotid endarterectomy in patients with symptomatic and asymptomatic stenosis. A prespecified secondary aim was to examine differences by sex. Patients who were asymptomatic or had had a stroke or transient ischaemic attack within 180 days before random allocation were enrolled in CREST at 117 clinical centres in the USA and Canada. The primary outcome was the composite of stroke, myocardial infarction, or death during the periprocedural period or ipsilateral stroke within 4 years. We used standard survival methods including Kaplan-Meier survival curves and sex-by-treatment interaction term to assess the relation between patient factors and risk of reaching the primary outcome. Analyses were by intention to treat. CREST is registered with ClinicalTrials.gov, NCT00004732. Between Dec 21, 2000, and July 18, 2008, 2502 patients were randomly assigned to carotid endarterectomy (n=1240) or carotid artery stenting (n=1262), 872 (34.9%) of whom were women. Rates of the primary endpoint for carotid artery stenting compared with carotid endarterectomy were 6.2% versus 6.8% in men (hazard ratio [HR] 0.99, 95% CI 0.66-1.46) and 8.9% versus 6.7% in women (1.35, 0.82-2.23). There was no significant interaction in the primary endpoint between sexes (interaction p=0.34). Periprocedural events occurred in 35 (4.3%) of 807 men assigned to carotid artery stenting compared with 40 (4.9%) of 823 assigned to carotid endarterectomy (HR 0.90, 95% CI 0.57-1.41) and 31 (6.8%) of 455 women assigned to carotid artery stenting compared with 16 (3.8%) of 417 assigned to carotid endarterectomy (1.84, 1.01-3.37; interaction p=0.064). Periprocedural risk of events seems to be higher in women who have carotid artery stenting than those who have carotid endarterectomy whereas there is little difference in men. Additional data are needed to confirm whether this differential risk should be taken into account in decisions for treatment of carotid disease in women. National Institute of Neurological Disorders and Stroke and Abbott Vascular Solutions (formerly Guidant).

Revascularization of Asymptomatic High-Grade Stenosis Is Not Indicated With Contemporary Stroke Prevention Medical Therapy

The American Stroke Association Guidelines for Primary Prevention of Stroke state that for patients with asymptomatic carotid artery stenosis, “the advantage of revascularization over current medical therapy alone is not well established.” So, what is the evidence related to the management of asymptomatic high-grade carotid artery stenosis (AHGCAS), and why should we interpret this evidence to conclude that contemporary medical therapy alone is the preferred treatment to reduce ipsilateral stroke risk? Three studies, the Asymptomatic Carotid Atherosclerosis Study (ACAS), the Medical Research Council (MRC) Asymptomatic Carotid Surgery Trial, and the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), have documented 5-year risks of periprocedural complications and subsequent stroke among patients with AHGCAS treated with revascularization of 5.1%, 6.4%, and 4.6% (estimated), respectively. Conversely, the ACAS and MRC studies documented 5-year risks of stroke for patients with AHGCAS treated with medication alone of 11.0% and 11.8%, resulting in an absolute risk reduction in ipsilateral …

The CREST Results: Another Piece to an Unfinished Puzzle

The results of the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) have been eagerly anticipated for almost a decade. Sponsored by the National Institute of Neurologic Disorders, it is the largest randomized clinical trial comparing percutaneous carotid angioplasty to carotid endarterectomy (CEA) ever conducted, allocating 1321 symptomatic patients with 50-99% carotid stenosis and 1181 asymptomatic patients with 60-99% stenosis to either angioplasty (n=1271) or CEA (n=1251) at 117 centers in the United States and Canada from December 2000 to July 2008.

Advances in Emerging Therapies 2010

In 2010, there were significant advancements in stroke prevention, whereas there were fewer studies that unearthed new ground on treatment of acute stroke and rehabilitation. We first discuss important pivotal studies in stroke prevention followed by acute treatment and rehabilitation. ### Prevention #### Homocysteine, Folic Acid, and B Vitamins Approximately 90% of all strokes are attributable to vascular risk factors.1 Homocysteine has also been identified as another risk factor for stroke. VITAmins TO Prevent Stroke (VITATOPS) aimed to assess whether daily administration of folic acid, vitamin B6, and vitamin B12 in patients with recent stroke or transient ischemic attack lowers homocysteine and reduces major vascular events. The data overall and pooled analysis of individual patient data showed that B vitamins have no or at most a marginal positive effect on reducing vascular events.2 #### Blood Pressure There is a correlation between blood pressure levels and risk of stroke. Data from Rothwell and colleagues now show that not only blood pressure levels, but also blood pressure variability account for stroke risk. A meta-analysis of antihypertensive drug trials found that calcium channel blockers and nonloop diuretic drugs were more effective than other antihypertensive agents to reduce blood pressure variability.3 Drug-class effects on interindividual variation in blood pressure can explain differences in effects of antihypertensive drugs on risk of stroke independently of their effects on mean systolic blood pressure. This means that the ideal antihypertensive agent should lower both blood pressure levels and variation in blood pressure to reduce stroke risk; however, we currently do not have such agents in our pharmacopeia for stroke prevention. #### Antithrombotic Drugs and Cerebrovascular Diseases New data have emerged on some age old questions about carotid dissection and intracranial stenosis. The use of aspirin or anticoagulation in spontaneous carotid artery dissection is a matter of debate with little data to guide decision-making. Data within a nonrandomized study suggest that the frequency …

Advances in Vascular Neurosurgery 2010

Surgery continues to play a major role in the treatment of intra- and extracranial cerebrovascular disorders. Refinements in endovascular techniques have resulted in a reappraisal of their role vis-a-vis surgery. ### Carotid Stenosis Carotid endarterectomy (CEA) is the gold standard for the treatment of carotid stenosis in both symptomatic patients and in appropriately selected patients who are asymptomatic. In the past decade, carotid angioplasty and stenting (CAS) has been proposed as a possible alternative to CEA. Landmark studies have addressed this issue in the past year. The International Carotid Stenting Study (ICSS) randomized 1713 symptomatic patients with carotid stenosis of >50% to either CEA or CAS. The end point of stroke and death within 30 days was significantly higher in the CAS group (7.4% versus 4.0%; P =0.003).1 In a subgroup analysis, silent brain infarcts were significantly more common in patients undergoing CAS than in patients treated with CEA.2 The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) study randomized patients with symptomatic and asymptomatic carotid stenosis to either CAS or CEA. Unlike other studies, CREST included myocardial infarction in the aggregate end point analysis. Importantly, serum troponin levels and electrocardiograms were mandated per protocol and myocardial infarction was defined as based on serum troponin elevation and electrocardiographic changes even in the absence of clinical symptoms. The aggregate end points were not statistically different between CAS and CEA (7.2% and 6.8%, respectively; P =0.51). However, perioperative strokes were more common in the CAS group (4.1% versus 2.3%, P =0.01), whereas myocardial infarction was more common in patients undergoing CEA (1.1% versus 2.3%; P =0.03). When only symptomatic patients are considered, the incidence of perioperative stroke was 6.0% in the CAS group and 3.2% in the CEA group.3 A debate continues as to whether the composite outcome of stroke and myocardial infarction, …

Safety of Stenting and Endarterectomy by Symptomatic Status in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)

Safety of Stenting and Endarterectomy by Symptomatic Status in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)

Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST): current and future implications for carotid artery stenting

Current reimbursement guidelines from the Centers for Medicare & Medicaid Services, prior to the publication of the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) results, reserve carotid artery stenting for stenosis in patients who are symptomatic, with severe stenosis, and considered high risk for carotid endarterectomy (CEA). CREST is a prospective, multicenter, randomized controlled trial, which compared surgical endarterectomy to endovascular stenting with primary end points of periprocedural stroke, myocardial infarction, or death or postprocedural ipsilateral stroke up to 4 years in standard-risk patients. CREST results indicate that stenting may be equal to CEA. Overall, the trial demonstrated fewer strokes in the CEA group, with a lower risk of myocardial infarction associated with carotid artery stenting. The study suggests that younger patients may actually have improved outcomes with stenting, whereas CEA may be superior for older patients.

Understanding the CREST results

The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) is the largest randomized prospective study to date to compare carotid artery stenting and carotid endarterectomy in a patient population similar to that seen in everyday practice. CREST showed stenting and surgery to be equivalent in terms of the composite end point of stroke, myocardial infarction (MI), or death within 30 days, as well as for the rate of stroke at up to 4 years (N Engl J Med 2010; 363:11-23). Importantly, the risk of major stroke was low with either intervention. However, the results need to be considered in the context of the impact of each procedure on stroke and MI.

Interpreting the Carotid Revascularization Endarterectomy Versus Stent Trial (CREST): Additional Trials Are Needed

E vidence founded on well-designed and wellconducted randomized controlled trials is the ‘‘Holy Grail’’ on which to base medical practice. The recent Carotid Revascularization Endarterectomy versus Stent Trial (CREST) is one such trial that compares the outcomes of carotid artery stenting (CAS; n 5 1,262 patients) and carotid endarterectomy (CEA; n 5 1,240). CREST has attracted a great deal of attention and should contribute to determining medical practice. However, like all trials, CREST has intrinsic limitations and other issues that need to be considered when interpreting the results. The primary end point for CREST included the incidence rates of stroke, myocardial infarction, or death from any cause. It was concluded that ‘‘for 2,502 patients over a median follow-up period of 2.5 years, there was no significant difference in the estimated 4-year rates of the primary end point between the stenting group and the endarterectomy group (7.2% and 6.8%, respectively; hazard ratio [HR] with stenting 1.11; 95% confidence interval [CI] 0.81–1.51; p 5 .51).’’ Further analysis showed that CAS was associated with a more than twofold higher risk for periprocedural death (nine vs four deaths for patients undergoing CAS and CEA, respectively; HR 2.25; 95% CI 0.69–7.30). Owing to the small number of deaths, however, this difference was not significant (p 5 .18), with a big CI. CREST was, therefore, underpowered to show significance with regard to this important parameter. In addition, CAS was associated with an almost twofold increased risk for any periprocedural stroke (52 versus 29 strokes for patients undergoing CAS and CEA, respectively; HR 1.79; 95% CI 1.14–2.82). This difference was significant (p 5 .01). In more detail, CAS was associated with a . 2.5-fold increased risk for major ipsilateral stroke (11 versus 4 events for patients undergoing CAS and CEA, respectively; HR 2.67; 95% CI 0.85– 8.4; p 5 .09). Again, because of small numbers, this difference was not significant. However, there was a highly significant more than twofold increased risk for minor ipsilateral stroke (37 versus 17 episodes for patients undergoing CAS and CEA, respectively; HR 2.16; 95% CI 1.22–3.83; p 5 .009). Finally, the 4-year rate of stroke and death was significantly higher with CAS compared to CEA (6.4% versus 4.7%, respectively; HR 1.50; 95% CI 1.05– 2.15; p 5 .03). In contrast, CREST patients undergoing CAS suffered significantly fewer myocardial infarctions compared to those undergoing CEA (14 versus 28, respectively; HR 0.50; 95% CI 0.26–0.94; p 5 .03). This difference balanced the difference in strokes and produced the apparent equivalence in the overall primary end point. These CREST results may be interpreted differently depending on one’s bias. Those with a bias toward CEA focus on the lower stroke and death rate for CEA and conclude that CEA should be used preferentially to treat patients requiring an invasive procedure for carotid stenosis. On the other hand, many with a bias toward CAS regard the CREST findings as definitive and conclude that the equivalent and low overall adverse event rates for the two procedures justifies the widespread and increased use of CAS to treat patients with symptomatic and asymptomatic carotid stenosis. Some believe that no further trials comparing CAS to CEA are needed. Neither of these extreme views is justified. To place CREST in perspective and use its findings appropriately, its flaws must be considered. Some of these are intrinsic to large randomized trials no matter how well designed and flawlessly conducted. Others are specific for CREST. *Department of Vascular Surgery, Red Cross Hospital, Athens, Greece; Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free Hospital Campus, University College Medical School, University College London, London, UK; Academic Department of Vascular Surgery, Imperial College, London, UK; Divisions of Vascular Surgery, New York University Medical Center, New York, NY, and The Cleveland Clinic, Cleveland, OH.

The International Carotid Stenting Study and the North American Carotid Revascularization Endarterectomy Versus Stenting Trial

Recently, 2 multicenter studies pitting carotid endarterectomy (CEA, the defending champion) against carotid artery stenting (CAS, the challenger) have been reported.1,2 These 2 studies have reported somewhat differing results, raising the question of whether 1 trial has the “right message” or is the “truth” somewhat more nuanced? The International Carotid Stenting Study (ICSS) was the first of the randomized CAS versus CEA trials that completed recruitment and was not stopped prematurely.1 The study enrolled patients with ipsilateral carotid territory symptoms within the previous 12 months and with at least 50% internal carotid artery stenosis. A total of 1713 patients were recruited from 50 academic centers. Surgeons were required to have performed at least 50 CEA operations and interventionalists were required to have done at least 50 stenting procedures with at least 10 in the internal carotid artery. The North American Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) originally included only symptomatic patients with at least 50% stenosis on angiography or 70% by ultrasound.2 In 2005, asymptomatic patients with at least 60% stenosis by angiography or 70% by ultrasound also became eligible. A total of 2502 patients were enrolled (including 1181 asymptomatic subjects) from 108 centers. Both surgeons and interventionalists were required to be certified as meeting performance benchmarks. Less experienced interventionalists were required to participate in a lead-in phase before joining the main study. In ICSS, the risk of stroke, death, and …

Is Endovascular Stent Therapy or Endarterectomy More Effective for the Treatment of Symptomatic and Asymptomatic Carotid Stenosis?

Several previous trials comparing the efficacy of endovascular stent therapy to endarterectomy for treatment of symptomatic and asymptomatic carotid stenosis have been inconclusive, with a trend toward superiority for endarterectomy. The CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) is the largest randomized controlled trial comparing these modalities. It has an added advantage that it incorporated new developments in stent technology as the trial progressed so that valid comparisons could be made with the most modern techniques available.

The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)

Carotid artery stenosis causes up to 10% of all ischemic strokes. Carotid endarterectomy (CEA) was introduced as a treatment to prevent stroke in the early 1950s. Carotid stenting (CAS) was introduced as a treatment to prevent stroke in 1994. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) is a randomized trial with blinded end point adjudication. Symptomatic and asymptomatic patients were randomized to CAS or CEA. The primary end point was the composite of any stroke, myocardial infarction, or death during the periprocedural period and ipsilateral stroke thereafter, up to 4 years. There was no significant difference in the rates of the primary end point between CAS and CEA (7.2% versus 6.8%; hazard ratio, 1.11; 95% CI, 0.81 to 1.51; P=0.51). Symptomatic status and sex did not modify the treatment effect, but an interaction with age and treatment was detected (P=0.02). Outcomes were slightly better after CAS for patients aged <70 years and better after CEA for patients aged >70 years. The periprocedural end point did not differ for CAS and CEA, but there were differences in the components, CAS versus CEA (stroke 4.1% versus 2.3%, P=0.012; and myocardial infarction 1.1% versus 2.3%, P=0.032). In CREST, CAS and CEA had similar short- and longer-term outcomes. During the periprocedural period, there was higher risk of stroke with CAS and higher risk of myocardial infarction with CEA. Clinical Trial Registration-www.clinicaltrials.gov. Unique identifier: NCT00004732.

Clinical Summaries

Clinical Summaries

Carotid Artery Stenting: Lessons From CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial)

The results of the CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) ([1][1]) were recently published, and they confirmed that there is clinical equipoise for stenting versus surgery for symptomatic carotid artery disease in average risk patients. The CREST is the largest

Stroke prevention: carotid stenting versus carotid endarterectomy

Revascularization of the extracranial carotid arteries is a commonly performed surgical procedure to prevent stroke. Open surgery (i.e., carotid endarterectomy [CEA]) is a well-established stroke prevention procedure but is being ‘challenged' by a less invasive percutaneous procedure (i.e., carotid artery stent [CAS] placement). Clinical trials comparing CAS and CEA for average-surgical-risk patients have demonstrated mixed results, whereas the data for CAS compared with CEA in high-surgical-risk patients have demonstrated non-inferiority. The impending Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) results will have a major impact on the utility of CAS relative to CEA in average-surgical-risk patients.

Safety and efficacy of carotid stenting in the very elderly

Carotid artery stenting (CAS) has emerged as an alternative to carotid endarterectomy (CEA) in patients at high risk for complications from surgery. The very elderly (>or=80-year-old) are one subgroup of patients identified as being at increased risk for carotid surgery. However, there is concern that the very elderly are also at increased risk for complications of CAS. A stroke and death rate of 12% was reported in very elderly patients during the roll-in phase of Carotid Revascularization Endarterectomy versus Stent Trial (CREST). We are reporting on a large clinical series of CAS with independent neurological assessment in the very elderly. Between 1994 and 2008, a consecutive series of 418 CAS patients (>or=80-year-old) were treated at four high-volume centers with extensive CAS experience. Independent neurologic assessment was performed after CAS procedures. Thirty-day follow-up information was available in 389 patients. The average age was 83.2 +/- 2.8 years. Most patients were male (63.2%), and the target lesion carotid stenosis was asymptomatic in two-thirds (68.2%) of patients. The majority of patients treated with CAS had a history of coronary artery disease (74.4%), hypertension (87.8%), and dyslipidemia (71.1%). One third (30.1%) were diabetic and more than half (56.5%) were current or former smokers. Embolic protection devices (EPD) were used in 78.7% of cases with the CAS procedure being performed before EPD availability being the most common reason for not using them. The overall 30-day incidence of stroke and death was 2.8% (11/389). The cumulative incidence of major cardiovascular events (stroke, death, or myocardial infarction) during that time period was 3.3% (13/389). This large series of CAS with independent neurologic assessment is convincing evidence that the very elderly (>or=80 years) can safely undergo CAS with stroke and death rates comparable to younger patients. The key to obtaining these excellent results is that CAS be performed by high volume, experienced operators who exercise restraint regarding patient selection.

The Carotid Revascularization Endarterectomy versus Stenting Trial: Credentialing of Interventionalists and Final Results of Lead-in Phase

The success of carotid artery stenting in preventing stroke requires a low risk of periprocedural stroke and death. A comprehensive training and credentialing process was prerequisite to the randomized Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) to assemble a competent team of interventionalists with low periprocedural event rates. Interventionalists submitted cases to a multidisciplinary Interventional Management Committee. This committee evaluated 427 applicants. Of these, 238 (56%) were selected to participate in the training program and the lead-in phase, 73 (17%) who had clinical registry experience and satisfactory results with the devices used in CREST were exempt from training and were approved for the randomized phase, and 116 (27%) did not qualify for training. At 30 days in the lead-in study, stroke, myocardial infarction, or death occurred in 6.1% of symptomatic subjects and 4.8% of asymptomatic subjects. Stroke or death occurred in 5.8% of symptomatic subjects and 3.8% of asymptomatic subjects. Outcomes were better for younger subjects and varied by operator training. Based on experience, training, and lead-in results, the Interventional Management Committee selected 224 interventionalists to participate in the randomized phase of CREST. We believe that the credentialing and training of interventionalists participating in CREST have been the most rigorous reported to date for any randomized trial evaluating endovascular treatments. The study identified competent operators, which ensured that the randomized trial results fairly contrasted outcomes between endarterectomy and stenting.

Abstract 5033: Safety and Efficacy of Carotid Stenting in the Very Elderly

Background: Carotid artery stenting (CAS) has emerged as an alternative to carotid endarterectomy (CEA) in patients at high-risk for complications from surgery. The very elderly (&gt; 79 years old) are one subgroup of patients identified as being at increased risk for carotid surgery. However, there is concern that the very elderly are also at increased risk for complications of CAS. A stroke and death rate of 12% was reported in very elderly patients during the roll-in phase of Carotid Revascularization Endarterectomy versus Stent Trial (CREST). We are reporting on a large clinical series of CAS with independent neurological assessment in the very elderly. Methods: Between 1994 and 2008, a consecutive series of 418 CAS patients (&gt; 79 years old) were treated at four high-volume centers with extensive CAS experience. Independent neurologic assessment was performed after CAS procedures. Thirty-day follow-up information was available in 389 patients. Results: The average age was 83.2±2.8 years. Most patients were male (63.2%) and the target lesion carotid stenosis was asymptomatic in two-thirds (68.2%) of patients. The majority of patients treated with CAS had a history of coronary artery disease (74.4%), hypertension (87.8%) and dyslipidemia (71.1%). One third (30.1%) were diabetic and more than half (56.5%) were current or former smokers. Embolic protection devices (EPD) were used in 78.7% of cases with the CAS procedure being performed prior to EPD availability being the most common reason for not using them. The 30-day incidence of stroke and death was 2.8% (11/389). The cumulative incidence of major cardiovascular events (stroke, death or myocardial infarction) during that time period was 3.3% (13/389). Conclusion: This large series of CAS with independent neurologic assessment is convincing evidence that the very elderly (&gt; 79 years old) can safely undergo CAS with stroke and death rates comparable to younger patients. The key to obtaining these excellent results is that CAS be performed by high-volume, experienced operators who exercise restraint regarding patient selection.