Is there any proven value for carotid stenting in asymptomatic patients?
The debate as to whether carotid stenting in asymptomatic patients is justified has continued with Drs Barry Katzen, Miami, FL, arguing that as yet no trials have been completed and powered to answer this question. However, Dr William Gray, Columbia University Medical Center, New York, in presenting the results from two studies claims that carotid stenting can achieve comparable outcomes to carotid surgery in asymptomatic patients. According to Dr Barry Katzen, Miami, FL, the news for carotid artery stenting (CAS) in asymptomatic patients is “not very good”. Speaking at the recent Cardiovascular and Interventional Radiological Europe (CIRSE) meeting in Athens, Greece, Katzen’s presentation focused on whether there was any proven value of CAS in the asymptomatic patient. He began by asking the question: “Is there a benefit to revascularization in asymptomatic patients, and if so, which ones?” Referring to data from two large US trials: the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the Asymptomatic Carotid Atherosclerosis Study (ACAS), Katzen reported that in the NASCET trial, the results showed that stroke risk was higher in symptomatic patients compared to asymptomatic, and in the ACAS trial, some asymptomatic patients benefited from CEA versus medical therapy. Both trials were discontinued early when the beneficial outcomes in the surgical arms crossed the threshold required to invoke the respective trial’s “stop rule.” The National Institutes of Health (NIH) released the preliminary results via “clinical alerts” to physicians, and these alerts suggested that CEA is the preferred treatment for both symptomatic and asymptomatic patients with carotid artery disease if the procedures are performed in centers with low risk of perioperative stroke and death.
NASCET and ACAS
Institutions and surgeons who participated in the NASCET and ACAS trials were carefully selected. According to David E Wennberg et al., 1998, (‘Variation in Carotid Endarterectomy Mortality in the Medicare Population’) the NASCET trial required participating centers to have performed at least 25 CEAs a year with a less than 6% combined perioperative stroke and death rate. The ACAS trial used a 2-step selection process: hospitals had to submit mortality and morbidity data; if the center had acceptable results, individual surgeons within the institutions submitted data showing a combined perioperative event rate of less than 3%. Additionally, ACAS had ongoing evaluations of perioperative events; if more than one perioperative event occurred, an institutional audit was undertaken to evaluate eligibility for further participation in the trial. Wennberg and colleagues further explained that patients were also carefully selected. In the NASCET trial, patients were excluded if they were older than 79 years, had organ failure or cancer likely to cause death in five years, or had a cardiac valvular or rhythm abnormality. Additionally, patients were “temporarily ineligible” if they had uncontrolled hypertension or diabetes or had experienced unstable angina or myocardial infarction in the preceding six months. Only one third of the patients operated on in participating institutions were enrolled in the trial. In the ACAS trial, patients were excluded if they were older than 79 years, had comorbidity that could increase their operative risk, or had a condition that could preclude long-term participation or was likely to cause death or morbidity. To meet these criteria, 25 patients were screened for every one randomized.
Katzen also mentioned the Asymptomatic Carotid Surgery Trial (ACST) trial, a large multi-center (n=3120 patients), European trial that compared patient outcomes after immediate surgery with surgery that is deferred. After five years the trial found that people aged below 75 years of age who had immediate surgery halved their five-year risk of stroke from 12% to 6%. However, changes in health service practice will depend on whether these benefits continue beyond five years. Reciting more studies such as the Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events (CAPTURE) trial, ACCULINK for Revascularization of Carotids in High Risk Patients (ARCHeR), Endarterectomy Versus Angioplasty (EVA-3s) and Stenting and Angioplasty with Protection in Patients at HIgh Risk for Endarterectomy (SAPPHIRE), Katzen explained that the problem may in fact lie with emboli or the type of plaque, not percent stenosis for asymptomatic vs. symptomatic patients. He added that best medical therapy has come along way since the NASCET trial (15 years old) where the best medical therapy at that time was only aspirin. Medical therapies such as ACE inhibitors, anti-platelets, and statins are “doing something to reduce strokes,” explained Katzen, therefore there should be more focus on these treatment options in the future and have randomized controlled trials with a best medical therapy arm in asymptomatic patients and compare with CEA and CAS. In his concluding remarks, Katzen explained, “Data regarding stroke prevention in asymptomatic patients is not supportive of treating patients with revascularization.” He added, “CAS may be equal to or superior to CEA but there have been no trials completed and powered to answer this question. Strong data suggests factors other than stenosis may contribute to cause and risk. ACST data failed to demonstrate stenosis as an independent-free zone.” However, according to the results from two carotid stenting studies examining outcomes in real-world patients, carotid stenting results are comparable to guidelines established by the American Heart Association (AHA) for patients treated with carotid artery surgery. However, the results have been criticized for including too many asymptomatic patients and having target goals from a ten-year old consensus document. In 1998, the American Heart Association published its 30-day outcome guidelines in Circulation for patients treated with carotid artery surgery (Circulation 1998;97;501–509). These guidelines were based on the observed stroke and death rates in patients with carotid artery disease who had undergone surgery, or carotid endarterectomy, to treat their condition. The AHA outcome guidelines are for patients less than 80 years old who undergo carotid endarterectomy and recommend stroke and death rates that are within 3% for asymptomatic patients and 6% for symptomatic patients. The patients who underwent carotid artery surgery were at standard risk for experiencing an adverse event from surgery. Abbott claims its post-marketing CAPTURE 2 and EXACT studies are the first real-world carotid artery stenting studies to demonstrate results comparable to these goals. Dr William Gray, Columbia University Medical Center, New York, presented the results in a late-breaking clinical trials session at the Cardiovascular Research Foundation’s 19th annual Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium. Outcomes were given from the CAPTURE 2 (Carotid AccuLink/AccuNet Post Approval Trial to Uncover Rare Events) and EXACT (Emboshield and Xact Post Approval Carotid Stent Trial), both sponsored by Abbott Vascular. Patient enrollment for the CAPTURE 2 trial is ongoing. The EXACT trial is closed and 30-day follow up has been completed. The CAPTURE 2 study included 1,987 patients and utilized Abbott’s AccuLink Carotid Stent System and AccuNet Embolic Protection System. The EXACT study included 2,124 patients and utilized the company’s Xact Rapid Exchange Carotid Stent System and Emboshield BareWire Rapid Exchange Embolic Protection System. The key objective of both trials was to determine whether carotid stenting could be performed safely in real-world clinical setting by physicians with varying levels of experience. The primary endpoints were death, stroke and myocardial infarction (MI) at 30 days. The demographics of patients in both trials were similar. The 30-day composite endpoints of stroke and death for patients in the CAPTURE 2 and EXACT studies were:
- 3.1% and 3.0% combined stroke and death in
CAPTURE 2 and EXACT patients without
symptoms under age 80;
- 6.0% and 7.3% combined stroke and death in
CAPTURE 2 and EXACT patients with
symptoms under age 80; and
- 3.8% and 4.0% stroke and death within 30-days
of treatment for the combined patient
Interestingly, asymptomatic patients faired better than symptomatic patients in both trials. The combined all stroke/death rate was 9.9% in the symptomatic group (CAPTURE 2 8.1%, EXACT 7.4%) and 4.9% in the asymptomatic group (CAPTURE 2 3.4%, EXACT 3.6%). “With these two very large, well-conducted, real-world carotid artery stenting trials, not only has carotid stenting achieved a comparable outcome to guidelines established for patients who undergo carotid surgery, but it also did so in a population of patients who are at high risk for experiencing adverse events from surgery,” said Dr Gray. “This is significant because this is the first time physicians have achieved results in high surgical risk candidates that are comparable to the long-standing guidelines that were established for lower surgical risk candidates, demonstrating that stenting can provide a reliable nonsurgical alternative for patients facing the difficult decision of how to manage their carotid artery disease.”
However, in a critical evaluation Dr John Laird, co-Director of Vascular Care at the Washington Hospital Center in Washington, DC, outlined some limitation of the studies. Whist he acknowledged that the studies had both a large sample size and were collected from a number of sites and clinicians, with diverse experience levels, it is difficult to draw any comparisons as CAPTURE 2 is still recruiting and the small symptomatic cohorts preclude any direct comparisons with other studies/trials. Laird also warned that the scientific rigor of post-market studies is not the same as the original high-risk registries as there were a high percentage of asymptomatic patients involved in the studies (CAPTURE 2 90.1%, EXACT 90.4%). “These are really trials evaluating carotid stenting asymptomatic, so not high-risk patients,” add Laird. He also commented that to compare the outcomes with target goals from a ten-year old consensus document (Circulation 1998;97; 501–509) is not a particularly relevant comparison. What really matters for this asymptomatic group of patients is how outcomes with carotid stenting compare to medical therapy or carotid surgery.
BEACH and CABERNET
Also at TCT, Dr L Nelson Hopkins, Chairman of Neurosurgery, Department of Neurosurgery, State University of New York, Buffalo, NY, presented three-year results from the CABERNET and BEACH carotid artery stenting clinical trials. The Carotid Artery Revascularization Using the Boston Scientific EPI FilterWire EX/EZ and the EndoTex NexStent Trial (CABERNET) clinical trial was designed to evaluate the safety and efficacy of Boston Scientific’s NexStent Carotid Stent and FilterWire EZ Embolic Protection System, while the Boston Scientific EPI-A Carotid Stenting Trial for High Risk Surgical Patients (BEACH) clinical trial was designed to evaluate the safety and efficacy of the company’s carotid Wallstent Monorail Endoprosthesis and FilterWire EZ Embolic Protection System. The NexStent Carotid Stent is a closed cell, nitinol stent with a rolled sheet design that enables one stent size to adapt to multiple diameters in tapered or non-tapered vessel configurations. The Carotid WALLSTENT Endoprosthesis is a self-expanding stent with a braided, closed cell design. Closed-cell configurations are designed to increase lesion coverage and provide a smooth inner lumen to help facilitate delivery and retrieval of ancillary devices. The FilterWire EZ System – an advanced technology designed for simplicity and effectiveness – captures debris efficiently, simplifies filter sizing and is easy to deliver and retrieve. When compared to surgical alternatives, this system provides a less-invasive way to treat patients with carotid artery disease. CABERNET and BEACH were both prospective, non-randomized, single-arm clinical trials enrolling 454 patients and 480 patients, respectively, who were at high risk for endarterectomy. Hopkins reported that the CABERNET major stroke rate was 1.3% at 30 days and 2.8% at three years. The reported BEACH major stroke rate was 1.7% at 30 days and 8.1% at three years. According to the three-year CABERNET data, the ipsilateral stroke rate was 2.9% at 30 days and by three years had only increased to 4.9%. In the BEACH trial, the ipsilateral stroke rate was 3.1% at 30 days and by three years had increased to 7.7%. “The three-year results suggest not only an immediate benefit for patients treated with Boston Scientific’s NexStent Carotid Stent and FilterWire EZ Embolic Protection System, but also a longer-term benefit in reducing the incidence of stroke over time,” said Hopkins, Co- Principal Investigator of the CABERNET and BEACH clinical trials. “In particular, the CABERNET three-year trial results are very encouraging and continue to demonstrate the long-term efficacy and durability associated with Boston Scientific’s NexStent Carotid Stent when used with the company’s FilterWire EZ Embolic Protection System in treating patients at high risk for carotid endarterectomy.”