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October 2010
A Summary of the CREST Trial
This trial was designed to meet the need for a sufficient comparison of CAS and CEA for patients with carotid atherosclerosis.
By Rita Coram, MD, and Alex Abou-Chebl, MD
The Carotid Revascularization Endarterectomy Versus Stent Trial (CREST) was designed in the late 1990s and was started in 2000.1,2 At the time, there had been no adequate, randomized comparisons of carotid endarterectomy (CEA) and protected carotid artery stenting (CAS). Endarterectomy had been well established to be superior to medical therapy in stroke prevention in the symptomatic but otherwise medically well patient with a > 50% stenosis of the carotid bulb.3 Asymptomatic stenosis treatment remained controversial despite the results of the Asymptomatic Carotid Atherosclerosis Study (ACAS).4 Until then, the only large trial of carotid endovascular therapy, Carotid and Vertebral Transluminal Angioplasty Study (CAVATAS), had been completed and the results presented in abstract form in 1999.5 That study showed no statistically significant difference in stroke or death rates between balloon angioplasty without embolic protection devices and endarterectomy, even out to 8 years of follow-up; there were, however, numerically more strokes in the angioplasty arm.
Some other trials of CAS were conducted, but they were small, poorly run, or never completed.6,7 Protected stenting (ie, stenting with the use of an embolic protection device) using a dedicated, specially designed stent stent had therefore not been validated outside of registries. 8-11 The Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial, which was designed to compare the safety and efficacy of protected CAS versus CEA in high-surgical-risk patients, had just begun enrolling patients.12 The reason for the CREST trial was self-evident: compare protected CAS versus CEA in low-surgical-risk, symptomatic patients.
STUDY DESIGN
CREST was sponsored by both the National Institutes of
Health (NIH) and Guidant (now Abbott Vascular [Santa Clara, CA]). Guidant supplied the devices for all of the
United States and Canadian centers, comprising a small
portion of the funding (15%) as well as support personnel
until 2003.13 The NIH provided the bulk of the funding for
the study, which was a prospective, randomized, parallel,
two-arm, multicenter trial with blinded endpoint assessment.
It was designed as a 2,500-patient trial to compare
the relative efficacy of CAS versus CEA to determine superiority.
There was equal randomization between CEA and
protected CAS using the RX Accunet embolic protection
device (Abbott Vascular) (“whenever feasible”) and the RX
Acculink carotid stent system (Abbott Vascular) in standard-
surgical-risk, symptomatic patients with a carotid
bifurcation stenosis ≥ 50% on angiography, ≥ 70% on ultrasonography,
or ≥ 70% on computed tomographic angiography
or magnetic resonance angiography if the stenosis
on ultrasonography was 50% to 69%.1
For a number of reasons, in 2005, the study was changed to include asymptomatic patients with a stenosis ≥ 60% by angiography, ≥ 70% on ultrasonography, or ≥ 80% on computed tomographic angiography or magnetic resonance angiography if the stenosis on ultrasonography was 50% to 69%. The study also included a vetting of interventionists with an additional lead-in/credentialing phase averaging roughly 20 patients per interventionist.13,14 In addition to the exclusion of high-surgical-risk patients, the study excluded patients who had contraindications to CAS such as severe tortuosity, extensive or diffuse atherosclerotic disease involving the aortic arch and proximal common carotid artery, an intraluminal filling defect, ipsilateral intracranial or extracranial arterial stenosis greater in severity than the lesion to be treated, and occlusion or “string sign” > 1 cm of the ipsilateral common or internal carotid artery. The use of 325-mg aspirin in the CEA arm and dualantiplatelet therapy (325 mg of aspirin plus 75 mg of clopidogrel, or 250 mg of ticlopidine, 1–2 tablets daily) in the CAS arm were mandated by the protocol for at least 30 days, with aspirin in all patients thereafter.
STUDY ENDPOINTS
The study's primary endpoint consisted of the composite
of any stroke, myocardial infarction (MI), or death during
the periprocedural period (ie, within 30 days of the
procedure) plus ipsilateral stroke within 4 years of randomization.
Neurological evaluations were performed by
neurologists, or “neuroscientists/physicians certified in
the use of the” NIH Stroke Scale, at baseline preprocedure,
18 to 54 hours after the procedure, 1 month, and every 6
months thereafter. Stroke was defined as “an acute neurologic
event with focal symptoms and signs, lasting for 24
hours or more, that were consistent with focal cerebral
ischemia.” Stroke was further defined as “major” if the NIH
Stroke Scale score was 9 or higher 90 days after the procedure.
MI was defined by a creatine kinase myocardial
band or troponin level that was ≥ 2 times the upper limit
of normal associated with either chest pain, symptoms
consistent with ischemia, or electrocardiographic evidence
of ischemia (new ST depression or elevation ≥ 1
mm in two or more contiguous leads).
The study included angiographic, carotid duplex ultrasonography, and electrocardiographic core laboratories, and carotid stenosis measurements used the NASCET (North American Symptomatic Carotid Endarterectomy Trial) method (a more specific but less sensitive approach than other methods). CREST had several prespecified secondary endpoints including differential efficacy of both procedures in men and women, comparison of periprocedural morbidity and mortality and > 30-day morbidity and mortality, an assessment of the morphology of the treated segment at 6 months and 1 year for the two procedures, a comparison of measures of healthrelated quality of life and cost effectiveness, and the identification of subgroups at differential risk for CAS and CEA. The study used an intention-to-treat analysis because there was a small amount of crossover after randomization; 5.7% randomized to CAS underwent CEA, and 1% randomized to CEA underwent CAS.
OPERATOR SELECTION
As previously mentioned, CREST rigorously vetted surgeons
and interventionists.13,14 The vetting of the latter
set a new standard; only 225 (52%) of 429 interventionists
who applied to be in the trial were finally approved
for randomization.15 Those who were refused outright
had a median case experience of 12 (range, 1–56). Only
70 operators were judged to have sufficient experience
with the procedure and study devices (range of device
experience, 7–81) to be allowed to randomize patients without lead-in cases. Two hundred and forty two met
the criteria for the lead-in phase; this group submitted a
median of 29 cases (range, 3–63) to be considered. Of
this group, 160 (66%) were approved for randomization
after completing an average of nine (range, 1–35) lead-in
cases.
RESULTS
Randomization was completed in July 2008 after 2,522
patients were enrolled (1,271 CAS and 1,251 CEA) with a
median follow-up of 2.5 years.13 The study results were
presented in February of 2010 at the International Stroke
Conference and published online ahead of print in May
2010 and printed July 1, 2010 in the New England Journal
of Medicine. Approximately 5.4% of the CAS patients and
8.8% of the CEA patients were lost to follow-up or withdrew
consent, and the data from one center (nice CAS
and 11 CEA patients) were excluded due to data fabrication.
The patients were very well matched in terms of
demographics other than a slightly higher preponderance
of patients with dyslipidemia in the CEA group (85.8% vs
82.9%, P = .05) and more patients smoking in the CAS
group during follow-up (21.8% vs 13.8%; P = .03). The
median time to treatment from randomization was similar
(median 6 days for CAS and 7 days for CEA). The
majority of the CEA procedures were performed under
general anesthesia (90%), and most had a patch (62.4%)
or shunt (56.7%). The overwhelming majority of CAS procedures
were performed with embolic protection (96.1%),
and most had predilation before stenting (67.7%). There
was a surprisingly high rate (12.1%) of patients not taking
dual-antiplatelet agents at 4 weeks and a similarly high
rate of no aspirin use among CEA patients (8.9%).
There was no difference in the primary study endpoint of any periprocedural stroke, MI, death, or postprocedural ipsilateral stroke within 30 days (CAS 5.2 ± 0.6 vs CEA 4.5 ± 0.6; hazard ratio [HR], 1.18 [0.82–1.68]; P = .38) plus ipsilateral up to 4 years, mean 2.5 years (CAS 7.2 ± 0.8 vs CEA 6.8 ± 0.8; HR, 1.11 [0.81–1.51]; P = .51). For the individual endpoint of periprocedural death (CAS 0.7 ± 0.2 vs CEA 0.3 ± 0.2; P = .18), there was no difference, but for any periprocedural stroke (CAS 4.1 ± 0.6 vs CEA 2.3 ± 0.4; HR, 1.79 [1.14–2.82]; P = .01) or MI (CAS 1.1 ± 0.3 vs CEA 2.3 ± 0.4; HR, 0.5 [0.26–0.94]; P = .03), there were significant differences. There was no statistical difference in major ipsilateral stroke incidence in the perioperative period (CAS 0.9 ± 0.3 vs CEA 0.3 ± 0.2; P = .09) or during the remainder of the study (CAS 1.4 ± 0.3 vs CEA 0.8 ± 0.3; P = .28). After the periprocedural period, the incidence of ipsilateral stroke was similar (CEA 2.4% vs CAS 2%; P = .85), as was the risk of fatal stroke (CAS, N = 7; CEA, N = 6).
There was no difference in the primary endpoint during the perioperative period among symptomatic patients (CAS 6.7% vs CEA 5.4%; HR, 1.26 [0.81–1.96]) or asymptomatic patients (CAS 3.5% vs CEA 3.6%; HR, 1.02 [0.55–1.86]). There was no interaction between sex and symptomatic status and treatment effect, although there was an interaction between age and efficacy (P = .02). The crossover point for age was at approximately 70 years, with greater efficacy with CAS in younger patients and greater efficacy with CEA for older patients. The risk of cranial nerve injury was significantly higher in the CEA group (0.3% vs 4.7%). In a post hoc analysis, there was an effect of minor or major stroke on physical health as measured by the SF-36 physical component scale, but the effect of perioperative MI was “less certain.”13
DISCUSSION
The CREST trial, the first trial to compare protected
CAS versus CEA in standard-surgical-risk symptomatic
and asymptomatic patients, has shown that both procedures
are equivalent in major perioperative morbidity and
mortality as well as long-term stroke prevention. While
there was a difference in the risk of perioperative stroke
with an increased risk in the endovascular group, most of
these strokes were minor. Conversely, there was a higher
risk of MI in the surgical group.
Beyond the perioperative period, the efficacy of the procedures in stroke prevention is equivalent, however. Importantly, the 30-day outcomes for both procedures met the accepted thresholds for clinical benefit compared to medical therapy, that is < 6% for symptomatic (6% stroke/death with CREST CAS and 3.2% for CREST CEA) and < 3% for asymptomatic patients (in CREST, the rate of 30-day stroke/death with CAS was 2.3% for ACAS-eligible patients). These results contradict the results of the recent randomized European trials that have compared CAS and CEA, all of which showed inferiority or failed to show superiority.16-18 There are many possible reasons for these differences, but technical factors (operator experience, use of a single stent system, and the use of embolic protection devices) may be the most likely contributing factors.19
Unlike the results of previous CEA trials, there was no effect of sex on procedural effectiveness, and there was not any differential benefit based on symptomatic status. There was a significant benefit to CAS in younger patients and vice versa. There are several issues that have not yet been addressed by the published results, including the comparative long-term patency or need for repeat revascularization with each procedure has yet to be determined. Moreover, newer embolic protection devices and stents have become available and could be associated with lower stroke rates, thus indicating the potential to further improve on CREST's CAS outcomes.
CONCLUSION
The CREST trial has shown that protected CAS and CEA
are both good options for patients and their advising physicians
in the treatment of low-surgical-risk patients with
bifurcation carotid atherosclerosis.
Rita Coram, MD, is Assistant Professor of Medicine and Director of Women's Cardiovascular Health Program, Division of Interventional Cardiology at the University of Louisville School of Medicine in Louisville, Kentucky. She has disclosed that she holds no financial interest in any product or manufacturer mentioned herein.
Alex Abou-Chebl, MD, is Director of Neurointerventional Services and Associate Professor of Neurology and Neurosurgery at the University of Louisville School of Medicine in Louisville, Kentucky. He has disclosed that he holds no financial interest in any product or manufacturer mentioned herein. Dr. Abou-Chebl may be reached at (502) 852-7642; a.abouchebl@louisville.edu.
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