What are the latest developments in carotid stenting trials and research? In July of this year, Kensey Nash Corporation announced a Board of Directors decision to cease all activities involving the marketing and regulatory approval process of the flow occlusion and aspiration TriActiv® System platforms. The system had received CE Mark approval in Europe for use as an embolic protection device (EPD) during coronary saphenous vein bypass graft (SVG) and carotid artery stenting (CAS) procedures and in the United States for SVG percutaneous coronary intervention (PCI). A Phase I clinical trial using the next generation device, TriActiv ProGuard for CAS, had been completed and enrollment was underway for a pivotal Phase II study for the same indication. Results of the pilot study were excellent, with a reported 30-day minor/major stroke and death adverse event rate of 8%. At issue for Kensey Nash was the recent CMS decision to limit reimbursement coverage for carotid artery stenting in the United States and the dominance of filter-based EPDs for CAS. The anticipated cost of commercializing the TriActiv ProGuard in the U.S. carotid market and uncertainty as to when (or if) CAS would become an accepted alternative to carotid endarterectomy (CEA) for patients with asymptomatic carotid disease contributed to this cost-related corporate decision. I was disappointed to learn of this decision; the TriActiv System was very successful during CAS. I believe the ProGuard device would have provided excellent alternative protection during CAS, especially in patients with tortuous anatomy distal to a proximal lesion in the internal carotid artery (ICA) or in symptomatic patients with high grade ICA stenosis that might require predilation to allow a larger profile filter-based EPD to be deployed distally. I hope this decision is not repeated by other companies working on next-generation protection devices, especially the proximal flow-reversal systems, and low-profile filter systems currently under development and testing in Europe as well as the U.S. Several recent brief articles in practice tabloids highlighted misleading data to suggest inappropriate conclusions regarding the overall superiority of carotid endarterectomy (CEA) over CAS for the treatment of extracranial carotid artery disease. CAS, complimented with a distal or proximal embolic protection device, has been demonstrated through properly designed and well-managed evidence-based clinical investigations to be at least equivalent to CEA in terms of safety and efficacy. Ongoing CAS clinical trials (http://www.clinicaltrials.gov/ct) funded through the National Institutes of Health (CREST) and industry (ACT I, CHOICE, PROTECT, SAPPHIRE Worldwide, EXACT, CAPTURE 2) will eventually establish the safety and efficacy of CAS relative to the CEA in patients with symptomatic or asymptomatic carotid artery disease. These trials will take considerable time and financial resources to complete; however, the results, in my opinion, will support the use of CAS as a safe and durable alternative to CEA. Patient demographics and clinical history, proximal and distal arterial anatomy, lesion characteristics, and physician CAS or CEA volume and experience, combined with appropriate pre-, peri-, and post-procedural management are common denominators for the short- and long-term success of either procedure. Results of the EVA 3S trial published late last year in the New England Journal of Medicine1 unfortunately added controversy to the CAS versus CEA debate. The study was conducted in France over a five-year period and was sponsored by the National Ministry of Health. Careful review and analysis of the study design, results and published conclusions generated consensus by all experienced CAS physicians that the study results were extremely flawed. EVA-S3 study investigator experience with CAS was significantly less than their experience with CEA; in fact, physicians having no CAS experience performed procedures under the supervision of a physician proctor. The requirement for non-supervised CAS was 5-12 lifetime CAS procedures with or without the use of an embolic protection device. Five different stent systems and seven different embolic protection systems were represented in the catalog of CAS devices and embolic protection was not included in the study until 2.25 years after study enrollment began. Five percent of the CAS procedures required crossover to CEA, with two strokes occurring within this population assigned to the CAS data set this scenario did not occur in SAPPHIRE or any of the CAS registries. Predilation, routinely performed in the U.S. in preparation for stent deployment, was performed in only 20% of the EVA-S3 CAS procedures. Conversely, surgeons were required to have performed at least 25 CEA procedures within the past year. At the start of the trial, symptomatic patients with a > 70% carotid stenosis were screened for enrollment and randomization to either CEA or CAS. Three years into the trial, the stenosis requirement for enrollment was reduced to 60% because pooled data from other CEA trials indicated that CEA was beneficial to patients with stenosis > 50%. The primary study endpoint was stroke or death within 30 days; myocardial infarction (MI) was excluded. Five hundred twenty-seven patients were enrolled from the start of the study in November 2000 to the time the study was halted in September 2005 for reasons of both safety and futility.1 Taking into account the number of participating centers (30), the mid-trial modification of enrollment criteria, delayed introduction of protection devices, and the duration of the study (5 years), the futility of the study was most likely related to slow patient recruitment (average enrollment of 3-4 cases/year/site). One final significant observation related to EVA 3S is that CAS has never been recognized by the French Ministry of Health as an acceptable treatment for carotid artery disease. The existence of this trial, similar to the current situation in the U.S., allowed physicians to perform CAS under the auspices of a government-sanctioned clinical trial. I believe the bottom line is that EVA-S3 provided physicians an opportunity to learn how to perform CAS and therefore the learning curve phenomenon contributed to a flawed conclusion. The only randomized controlled trial in patients who are at high risk for CEA is SAPPHIRE. The trial demonstrated cumulative major adverse event rate of 9.6% with CEA versus 4.8% with CAS at 30 days. The SAPPHIRE randomized cohort cumulative stroke rates to 3 years post procedure support the non-inferiority of CAS to CEA (7.1% vs. 6.7%). Results of CREST, ACT 1 and other studies investigating the benefit of medical therapy alone as well as CAS vs. CEA will shed more light on how best to treat the increasing number of patients with symptomatic or asymptomatic carotid artery disease. I believe CAS is at least equivalent to the 54-year-old gold standard practice of CEA, based on published results of multiple CAS versus CEA clinical trials, and industry-sponsored registries and post market surveillance studies. A recent pooled analysis of our own cohort of single operator symptomatic and asymptomatic high surgical risk CAS patients in the EXACT Study (Abbott Vascular) at Harrisburg Hospital recorded a less than 2% complication rate at 30 days. What do you find challenging about this procedure? I have performed nearly 1,000 CAS procedures over the last six years, and find the biggest challenge is case selection, based on my understanding of the few but serious limitations of the procedure. A CAS procedure must be properly orchestrated to include a careful and thorough evaluation of patient history and screening studies to assess the severity of the lesion and potential anatomical factors that may complicate or preclude a CAS procedure. I frequently have to assess the risk versus benefit of a CAS procedure in a symptomatic patient this is a challenge. The decision to proceed with a CAS procedure, especially with a high surgical risk patient, must be an informed decision by the patient and the physician. The availability of improved diagnostic techniques such as CTA and MRA facilitate assessments of procedure complexity and risk. The challenge is to present to the patient and patient’s family a realistic procedure and outcome scenario to allow them to understand the risks as well as potential benefit to be derived from the CAS procedure. A recent debate has surfaced as to whether baseline intracranial angiography is required in preparation for a CAS procedure. Despite the added procedure time, I believe this procedure is an important component toward achieving a successful CAS outcome. Arch and cerebral arteriography provides critical information for guide wire placement, sheath placement and in some instances, the choice of an embolic protection device. Knowledge of normal, abnormal, and aberrant cerebral vascular anatomy, both arterial and venous, and variant arch anatomy should always be part of a CAS procedure. The identification of variant cerebrovascular anatomies and congenital or acquired defects are a sizeable challenge, yet also extremely important in proper case and embolic protection device selection. How might a carotid artery stenosis differ from a coronary or peripheral stenosis (in terms of plaque, vessel considerations, etc.)? Carotid artery stenting is predominantly about stroke prevention, either subsequently, in a symptomatic patient, or consequent to an evolving, lipid-rich vulnerable atheroma in an asymptomatic patient. The redundancy of the cerebral circulation with bilateral blood flow into the circle of Willis may result in a compensatory increase in flow through a contralateral internal carotid artery as an evolving atherosclerotic lesion gradually obstructs blood flow through an internal carotid artery. Stenosis within the carotid bifurcation will result in a reduction in net flow through the affected artery and with that reduced flow is an increased risk of thrombus formation at areas of flow restriction or recirculation. The objective of CAS or CEA is to stabilize (CAS) or remove (CEA) the plaque and thereby prevent arterial occlusion or worse case, a distal embolic event with significant morbidity. Coronary PCI, on the other hand, resolves ischemia mediated by a flow restriction of a critical stenosis. The reduction in coronary blood flow results in impaired myocardial function and the restoration of blood flow is the critical net result of a coronary PCI. While the coronary circulation does have some redundancy in the form of collateralization, this occurs gradually with age and in its absence, a significant reduction in coronary blood flow can result in ischemia and arrhythmia. Under normal blood flow conditions, a 50% reduction in diameter results in a 75% reduction in cross-sectional area; blood flow and area are proportional. Therefore, a 50% stenosis results in a 75% reduction in net blood flow. For peripheral vascular disease, the reduction in blood flow results in life-style limiting claudication and the potential for non-healing ulceration restoration of blood flow through a surgical or an endovascular procedure is effective treatment of critical limb ischemia without the risk of stroke or myocardial infarction as related to CAS or coronary PCI. Has the COURAGE Trial, although not directly addressing carotid stenting patients, had an impact on your patient selection considerations? Patient selection is extremely important in determining which patient may be best treated by CAS or CEA. The COURAGE Trial brought to light the importance of proper medical management as an integral part of patient care. A very important, but frequently not stressed, component of a planned CAS procedure is patient education as to the importance of compliance with prescribed medications before and after the procedure. All patients should be encouraged to act upon lifestyle change recommendations such as smoking cessation, increased exercise, weight loss, and for diabetic patients, careful control of their glycemic index. Many labs are in the beginning stages of offering a carotid stenting program for their patients. How do you think that increasing volumes will affect patient care? Patient care will only improve provided hospital staffing is not reduced. With continued staff training and awareness of the importance of peri- and immediate post procedure surveillance and patient education, short-term and long-term CAS outcomes will continue to be excellent. The importance of proper medication prescription and compliance, as with coronary drug-eluting stents (DES), is extremely important. Staff and patients must be diligent in instruction and compliance. Clopidogrel and aspirin therapy for at least 2 months post procedure should be the minimum, with aspirin therapy continuous thereafter. Some patients may have clopidogrel resistance or variability in responsiveness to the platelet function inhibitor. The use of platelet function testing may be beneficial in identifying the occasional patient that has a peri- or post- procedure minor (TIA) embolic event due to inadequate platelet inhibition. Patient education will play a very important role in the acceptance of CAS as an alternative treatment for carotid artery disease. In time, I predict CEA will be reserved for patients at high risk of complications from CAS for example, patients with a tortuous proximal common carotid artery, loops within the target internal carotid artery, thrombus burden, and significant arch disease. As long as the diagnostic process and case selection process leading toward a decision to perform CAS is informed through current advanced diagnostic technologies (CTA and MRA), the volume of procedures will increase and patient care should only improve. What characteristics do you anticipate for the next generation of carotid stenting systems and embolic protection devices? Filter-based devices having smaller parking space requirements, pore size refinements, filter devices preloaded in their delivery catheter, and refinement of reverse flow protection devices are areas of device research and development that warrant further effort. No reflow and/or vasospasm in the area of filter deployment is an occasional problem with distal embolic protection devices. When a no reflow situation presents post-stenting, I routinely use an aspiration catheter (e.g. QuickCat by Kensey Nash) as a precautionary measure, not knowing if an occluded filter or spasm has affected blood flow through the distal perfusion holes of the filter device. Perhaps the application of a hydrophilic coating to the filter membrane would increase surface lubricity and reduce any spastic stimulus by the device. The development and refinement of guide wires and guide sheaths specific for carotid application will be welcome; a good example of this technology is the Morph deflectable guide sheath (BioCardia, Inc.) and Strada sheath (St. Jude Medical, in development) which in challenging anatomy facilitates guide/sheath placement into the common carotid artery. Gaining safe guide wire access across a high-grade stenosis or calcified ostium is challenging with increased risk of doing harm prior to the actual CAS deployment. The Venture Catheter (St. Jude Medical) is another device that may be invaluable in gaining guide wire access across calcified or otherwise challenging access scenarios. Also, the Emboshield PRO (Next generation filter system, Abbott Vascular) is currently under trial in U.S. and may possess many of the refined characteristics described earlier. The merits and demerits of open and closed-cell stent designs for CAS are a topic of discussion. I routinely use a laser-cut closed cell design self-expanding (SE) stent for the majority of CAS procedures performed at Harrisburg Hospital. I will use an open cell SE stent for a lesion within or just proximal to a tortuous arterial segment; the open cell stent conforms to the bend and is less apt to result in a pseudospasm distally. Closed cell stents present a higher metal-to-artery ratio and therefore may provide better wall apposition for plaque containment and a higher radial force to resist compressive forces exerted by the muscular arterial wall. There is no argument that closed cell stents straighten the artery and may result in pseudospasm distally, which rarely is a problem once the sheath has been removed from the common carotid artery. The two approved close cell stents in the U.S. are Xact (Abbott Vascular) and NexStent (Boston Scientific). Subacute thrombosis has not been a concern with CAS and there does not seem to be a need for DES technology in the treatment of carotid artery disease. Restenosis and thrombosis are extremely rare subsequent to CAS. Can you describe how your practice has evolved since your first involvement with carotid stenting? I arrived in Harrisburg in 2001 and joined Associated Cardiologists with the intent of bringing a CAS program to the central Pennsylvania community. At that time, CAS was not a FDA-sanctioned procedure and I became an investigator in the Abbott Vascular Devices Xact Carotid Stent pivotal study. Since then, multiple systems have been commercialized through the clinical trial and registry process, and CAS is now available to many patients who qualify based on the current guidelines set forth by FDA and CMS. Recent reversals in the acceptable criteria for a reimbursable CAS procedure have unfortunately made CAS less available to some patients. I remain confident that with time and continued data collection, review and comparison the safety, efficacy and long-term durability of CAS will be demonstrated. CAS is available to many patients due to the support of industry and FDA through the large number of randomized trials and post-market approval registries mentioned earlier. How are you seeing physicians with different backgrounds, such as surgery and radiology, consult or work together for the benefit of carotid stenting patients? My own experience has been excellent in terms of the working relationship with my surgical and neurological colleagues. Harrisburg Hospital and I have also conducted CAS-specific training courses for Abbott Vascular, Boston Scientific, eV3 and Cordis Corporation. What I find most interesting of late is the increase in the number of vascular surgeons attending the CAS training courses. Initially interventional cardiologists predominated course attendance with interventional radiologists and interventional neurologists showing an increased presence after the first year of course availability. Today, I notice an increasing number of vascular surgeons attending and anxious to learn guide wire and catheter skill sets, and technique for cerebrovascular arteriography and CAS with embolic protection. Physicians with formal and practice training in related but different disciplines required for CAS recognize that a gradual transition to CAS as an acceptable and perhaps patient-driven alternative to CEA will occur over the next few years and want to be part of this effective treatment modality. We are all aware that the increasing number of elderly patients and morbidity of stroke warrant the treatment of significant carotid artery disease as a preventative measure. The device industry needs to continue their excellent training programs, which will prove vital in years to come in the success of this procedure for the interventional community. Also, forums like Capital Cardiovascular Conference (C3) (www.ccmcme.com/c32007) provide a great venue to learn technical aspects of this very simple-appearing but very complex procedure to ensure better outcomes for any specialists. Just recently concluded, C32007 had demonstrated technical tips for complex octagenerian CAS procedures and vertebral procedures to ensure success. Looking ahead, do you envision interventionalists one day moving beyond the carotids into the cerebrovascular realm? Interventional neurologists already are very actively treating complex congenital and cerebrovascular disease. Stroke intervention is common with advanced technologies such as the Merci Clot Retriever (Concentric Medical), developed specifically to aggressively help patients with ischemic stroke. Stroke treatment is a logical area for interventional therapy and without involvement of interventional cardiology community, all the patients who need this life-saving procedure will never be treated, as there are just not enough dedicated neurointerventionists. However, many hurdles, including reimbursement, etc., remain. To quote a group of respected vascular surgeons who now also perform CAS: The authors concluded that vascular surgeons who possess advanced catheter-based skills can safely perform CAS with results comparable to CEA. Vascular surgeons essentially have three choices when it comes to CAS. We can either lead, get out of the way, or be trampled by the onslaught of other specialists all chomping at the bit to be the principle negotiator in this very common disease process. 2 Dr. Dave can be contacted at firstname.lastname@example.org
1. Mas J, Chatellier G, Beyssen B, et al, for the EVA-3S Investigators. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med Oct 2006;355:1660-1671.
2. Eskandari MK, Longo M, Matsumura JS, et al. Carotid stenting done exclusively by vascular surgeons: First 175 cases. Vascular Surgery and Endovascular Therapy Outlook 2006; 18:1.