CREST Data Show Equivalence Between CAS and CEA

 

February 26, 2010—Long-awaited results from the CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) study were presented today for the first time at the American Stroke Association’s Annual International Stroke Conference 2010, which convened on February 24–26 in San Antonio, Texas. The CREST Executive Committee met recently to take a first look at this very large data set and prepared the manuscript of the outcome results that was presented.

CREST is comparing stent-assisted carotid angioplasty (CAS) to carotid endarterectomy (CEA) for the treatment of carotid artery stenosis to prevent recurrent strokes in those patients who have had a transient ischemic attack (TIA) or a mild stroke within the previous 6 months (symptomatic) and in those patients who have not had any symptoms within the previous 6 months (asymptomatic). The study is sponsored by the University of Medicine and Dentistry of New Jersey in collaboration with the US National Institute of Neurological Disorders and Stroke. Thomas G. Brott, MD, is the principal investigator for CREST.

Enrollment in the CREST study commenced in December 2000 with an anticipated total enrollment of 2,500 patients and a completion date of December 2011 for collection of data for primary outcome measure. The investigators now report that the current data encompass 2,502 patients enrolled at more than 100 centers in North America. More than 80% of the participants had an artery blockage > 70%.

"We found that the two procedures were similar with regard to the study’s primary endpoint—overall incidence of stroke, heart attack, and death," said Thomas G. Brott, MD, lead author of the study and professor of neurology and director for research at the Mayo Clinic campus in Jacksonville, Florida. "We also found that the rates of these events were low, and that safety for patients with and without symptoms was as good as any reported in any randomized carotid intervention trial."

The CREST investigators reported that their initial findings came from a median follow-up of approximately 2.5 years and that some patients have been followed for up to a total of 4 years. The investigators found that in the 30-day period following the procedure, the rate for stroke was 2.3% in the surgical patients and 4.1% in the stenting group. However, the heart attack rate was higher in the surgical group (2.3%) compared to the stenting group (1.1%). The difference in heart attack and stroke between the two groups was statistically significant.

The study also found that the age of the patient made a difference in outcome. At approximately age 69 and younger, stenting results were slightly better, with a larger benefit for stenting, the younger the age of the patient. Conversely, for patients > 70 years, surgical results were slightly superior to stenting, with larger benefits for surgery, the older the age of the patient.

"The data from the landmark CREST trial has shown that there was no difference between CAS and CEA in this large group of symptomatic and asymptomatic patients. From a practitioner's point of view, we and our patients now have a choice in terms of what type of revascularization therapy might be best for them," said Barry Katzen, MD, Founder and Medical Director of Baptist Cardiac and Vascular Institute and Clinical Professor of Radiology at the University of South Florida College of Medicine in Florida.

Christopher J. White, MD, Chairman, Department of Cardiovascular Diseases, Ochsner Clinic Foundation in New Orleans, Louisiana said, "I think this is clearly a game changer for carotid stenting. It is going to bring reimbursement. It is going to bring choice for our patients, especially in the seniors (the Medicare population) who are being forced to have surgery. I think many good things are going to come out of this."

L. Nelson Hopkins, MD, Professor and Chairman of Neurosurgery, Professor of Radiology, and Director of the Toshiba Stroke Research Center, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York in Buffalo, New York said, "We now know that CAS is equivalent to CEA. This is really good news for patients because they are now going to have choices. The bottom line of the CREST trial now is that, when taken into context, it is one more very important data set in a long series of trials that have shown over the last 15 years that carotid stenting has gotten better over time. It also shows that the results of carotid endarterectomy are as good or better than any trial that has been reported. We have the best results ever recorded for both CAS and CEA. The absolutely critical thing about CREST is that as we start to parse through all the data and pick apart all the subsets, although they won’t reach statistical significance, we will see more hints about which procedure is better for which individual patient. There is no question that these two procedures are quite complementary to each other."

In CREST, patients eligible for randomization included symptomatic patients with recent neurological events (TIA or nondisabling stroke) with an associated carotid stenosis ≥ 50% by angiography or ≥ 70% by ultrasound or ≥ 70% by computed tomographic angiography or magnetic resonance angiography.

Asymptomatic patients eligible for randomization were those with no recent (in the previous 6 months) neurological events referable to the study with artery and carotid stenosis (patients with symptoms beyond 180 days were considered asymptomatic) ≥ 60% by angiography or ≥ 70% by ultrasound or ≥ 80% by computed tomographic angiography or magnetic resonance angiography.

Exclusion criteria were conditions that interfere with the evaluation of endpoints, are known to interfere with the completion of CEA or CAS, or affect the likelihood of survival for the study period (4 years). Other exclusion factors were chronic atrial fibrillation and/or anticoagulation or episodic atrial fibrillation within the previous 6 months of proposed enrollment.

The devices used in the trial were the Acculink carotid stent system in conjunction with the RX Accunet embolic protection system (Abbott Vascular, Santa Clara, CA; acquired from Guidant Corporation in 2006).

Participants were randomly assigned to undergo either CAS or CEA. All patients also received best medical management, including treatment with aspirin, treatment of high blood pressure, and treatment of other stroke risk factors. Participants were followed for up to 4 years.

The primary outcome measures were the contrast in relative efficacy of CAS from CEA in preventing stroke, myocardial infarction, and death during a 30-day periprocedural period, or ipsilateral stroke over the follow-up period in patients with symptomatic/asymptomatic extracranial carotid stenosis.

In an interview published in the July 2008 issue of Endovascular Today, Dr. Brott recounted three major challenges early in the CREST trial that affected patient enrollment. Briefly, these challenges were: first, CREST leadership placed very high priority upon including only highly qualified surgeons and interventionists and undertook a careful and time-consuming process of surgeon credentialing at the multiple CREST centers. Second, the Centers for Medicare & Medicaid Services did not initially reimburse CAS within CREST, and even today, some private carriers will not reimburse CAS within CREST. Third, CREST enrollment was slowed by the introduction of embolic protection devices to CAS as data arose supporting their use. This required a suspension of enrollment as the study protocol was amended, endorsements were obtained at the US Food and Drug Administration and the National Institutes of Health, and institutional review board approvals were accomplished at the multiple CREST centers.

In the November 2009 issue of Endovascular Today, CREST investigator Gary S. Roubin, MD, PhD, provided a historical perspective of the trial and its potential impact (2009;8:46–52). The article outlined the following strengths and limitations of CREST.

STRENGTHS OF CREST

  • Largest prospective, randomized carotid revascularization trial ever conducted
  • Most rigorous prospective data on neurological and cardiovascular complications from CEA and stenting ever collected
  • Most rigorous operator training and credentialing ever undertaken in such a trial
  • Large number of operators and study sites will make results applicable to the community
  • Quality-of-life and cost data will facilitate state-of-the-art cost-efficiency analysis
  • All patients were subjected to a protocol-driven best medical therapy regimen

LIMITATIONS OF CREST

  • Indications and exclusions for stenting were based on early experience (1994–1999)
  • Utilized a single, first-generation stent and embolic protection device
  • Most operators proceeded stenting patients during variable points on their learning curve of experience
  • Stenting results may better represent 2000 to 2008 outcomes than 2010 to 2018 outcomes

Dr. Roubin noted that the study’s protocol was formulated based on experience during the 1990s, when the prevailing view was that the main issue was an "either/or" question concerning CEA versus CAS. By 2009, it was generally acknowledged that patient selection for either of these revascularization methods is critical to safety and efficacy. Also, in 2000, there was only a single first-generation stent and embolic protection device, and the CREST investigators opted to go with the tools available at the time. On many occasions, the possibility of expanding this toolbox was discussed, but the myriad of FDA and industry administrative issues seemed daunting. Finally, because the CREST recruitment timeline encompassed an 8-year period, there was a steep collective learning curve, with respect to indications for stenting, a fact that cannot be overemphasized, Dr. Roubin stated.

According to Dr. Roubin, CREST outcome data will differ from other related studies. First, both CEA and stenting cohorts were subjected to the best contemporary medical management. For the first time, the primary endpoint, in addition to 30-day stroke/death and ipsilateral stroke over follow-up, will include perioperative myocardial infarction. In addition, CEA will be subjected to critical neurological monitoring at 24 hours after the procedure, including completion of the National Institutes of Health Stroke Scale by an independent neurologist. These two factors will allow CREST to judge stenting and CEA using identical comparators and will be a major contribution of the trial. In contrast to previous CEA trials, there was no upper age limit in CREST. The combined primary endpoint will include amaurosis fugax as a comparable stroke event. Alternatively, serious cranial injuries (even those with permanent consequences) will not be considered in the primary analysis. Hopefully, these events have been captured by the Clinical Events Committee and should be examined in a secondary analysis.

Related News:
1. CREST Investigators Present Data on Credentialing and Training for the Trial’s Stent Operators
2. Investigators Present Findings From the Lead-in, Credentialing Phase of CREST

 

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