CREST Trial Shows CAS and CEA To Be Comparable Therapies for Stroke Prevention

Q: What do you anticipate the CREST results will show?

Rosenfield: CREST (Carotid Revascularization Endarterectomy versus Stent Trial) is a landmark trial which shows that endarterectomy and stenting for carotid artery stenosis appear to be comparable based on the primary endpoint of the trial: death, stroke and myocardial infarction. Both carotid artery stenting (CAS) and carotid endarterectomy (CEA) had remarkably low event rates and were shown to be very safe and effective stroke prevention therapies. It should be noted that this is the largest (2,522 subjects, 225 operators, 122 sites in the U.S. and Canada), most rigorous prospective, randomized trial to be carried out for these therapies and represents level-A evidence. The fact that the results are comparable for both of these therapies and that the safety and efficacy for both are very high is great news for patients. Moving forward, patients will have a choice in modalities to reduce stroke, and physicians and patients will be able to decide which therapy is best at an individual level. It is very reassuring to know that these therapies, which have been discussed and applied for years, are just as effective as we thought they were — perhaps even more so. The CREST results demonstrate the best outcomes of any trial to date for this type of broad-based application involving such a large number of patients and investigators. The fact that the trial was able to show such favorable results across this broad spectrum is quite remarkable. Thus, CAS will be better for some patients and CEA for others. We still need to analyze the data and the various factors that would determine which therapy is better for patients at both ends of the spectrum. CREST shows us that the largest group of patients — those in the middle of the spectrum — will be suitable candidates for either therapy, and it will be up to them and their physicians to decide which to undergo. Keep in mind that this study involved a whole new cadre of patients: those in the standard-risk category (symptomatic and asymptomatic), and not surgical high-risk patients, who have been evaluated in previous studies. CREST showed some minor differences in results based on age, with the very elderly patients (> 80 years of age) having better outcomes with endarterectomy, while younger patients

Q: How long will these patients be followed?

Rosenfield: The primary endpoint was a composite of periprocedural death, stroke, and myocardial infarction out to several weeks, and the incidence of ipsilateral stroke out to as long as 4 years (median of 2.5 years). The lead investigator, Dr. Thomas Brott, has recently obtained tentative approval for his center to follow these patients out to as long as 10 years, which will be an important addition to this trial and will provide valuable long-term information about these patients. The Kaplan-Meier curve shows that for both CAS and CEA, a large majority of the events occurred early on.

Q: What about CMS coverage for these procedures? Will the CREST results change their decision about carotid stenting?

Rosenfield: These standard-risk patients are not currently covered by the CMS (Centers for Medicare and Medicaid Services). I think that the CREST trial provides the impetus for the CMS to move forward with approval of stenting for standard-risk patients. The outcomes speak for themselves in terms of both acute and long-term benefits for patients and should result in the CMS looking favorably upon CAS so that patients can have the choice. It should also be noted that both CAS and CEA fall very well within the AHA (American Heart Association) guidelines for appropriate, effective and safe therapies. This is important because it demonstrates that in a broad-based trial involving such a large number of patients, sites and investigators, the results should be generalizable to the population as a whole. In my view, it would only be appropriate for the CMS to act on this information.

Q: Were proximal and/or distal protection devices used in the stenting arm of this trial?

Rosenfield: The stent and distal protection devices were identified at the outset of the CREST trial: the RX Acculink™ carotid stent (Abbott Vascular, Abbott Park, Illinois) and the RX Accunet™ embolic distal protection device (Abbott Vascular) were utilized throughout the trial. The first 4–5% of CAS patients in CREST, however, did not have distal protection devices used, and the trial was temporarily put on hold while this device was entering the market. Of course, over time, techniques and devices have evolved, and the new devices have been introduced to the market. What is exciting about this trial is that it provides the impetus to see how we can even further improve upon these results, given the newer technologies now available.

Q: Has CEA evolved in terms of technique since the launch of CREST?

Rosenfield: There have been some “tweaks” to the procedure over the years. Endarterectomy is a superb, tried-and-true operation that has been done for over 50 years now. Thus, CEA techniques are very well-refined at this point, and most of the refinements had already occurred before CREST was launched. Carotid stenting is a much newer therapy — only about 15 years old — and over the 8+ years of this trial, it has undergone some significant changes. Some of those changes involved technique and technology, while others involved identifying which patients should undergo stenting and which should have surgery. CREST has shown that CSA and CEA are comparable therapies, giving the patient and the physician greater choice and the ability to better determine which therapy is best for a given patient.

Q: What types of imaging modalities were used in the CREST trial to evaluate patients?

Rosenfield: The CREST trial employed a combination of angiography, duplex ultrasound, computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) modalities. Noninvasive imaging was predominantly used to define the patients who would be enrolled in the trial, and this was confirmed by angiographic evaluation in those cases that were randomized to CAS. Thus, the majority of randomized patients underwent noninvasive imaging. There will be much discussion of the CREST results, and I am sure that some will try to perform subgroup analyses for which this trial was not adequately powered. The main message is that CAS and CEA are comparable therapies and are both excellent in terms of their ability to prevent stroke and offer patients greater choice. The results showed some subtle differences based on factors such as age, as mentioned earlier, and stroke and myocardial infarction in the different groups. But when it comes to what really matters: major stroke and death, there was no difference between these two therapies.

For more information and details about the CREST Trial, go to: https://clinicaltrials.gov/ct2/show/NCT00004732

CREST Trial Background Information Launch Date: December 2000 Study Design: Prospective, randomized, parallel, two-arm, multicenter clinical trial with blinded endpoint evaluation. Primary Outcome Measures: If the efficacy of carotid artery stenting (CAS) differs from carotid endarterectomy (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. Patients and Locations: With 2,522 total patient randomizations (1,326 symptomatic and 1,196 asymptomatic) at 118 U.S. and Canadian sites, CREST is the largest trial to address the efficacy of carotid artery stenting (CAS) versus carotid endarterectomy (CEA). Follow-up is ongoing. Inclusion Criteria: Patients who had experienced a transient ischemic attack (TIA), amaurosis fugax (AF), or non-disabling stroke within the past 180 days, and who had an ipsilateral carotid stenosis ≥ 50% by angiography or ≥ 70% by ultrasound or ≥ 70% by CTA or MRA were deemed eligible for this study. Asymptomatic subjects: Patients who had carotid stenosis ≥ 60% by angiography or ≥ 70% by ultrasound or ≥ 80% by CTA or MRA were eligible for this study. (Subjects with symptoms beyond 180 days were considered asymptomatic.) Exclusion Criteria: Patients with comorbid conditions that interfere with the evaluation of endpoints, that are known to interfere with the completion of CEA or CAS, or that affect the likelihood of survival for the 4-year study period, were excluded from this study. Patient Involvement: Eligible patients were randomized to undergo either CAS or CEA. All received aspirin antiplatelet therapy, treatment for hypertension, and management of other stroke risk factors. Follow-up: 4 years, including clinic visits at 1, 6, 12, 18, 24, 30, 36, 42, and 48 months.