Carotid Artery Stenting…How to achieve good results? Recommendation 10: Training, Training, Training!

An important caveat is the recognition of high-risk cases dependent primarily on the knowledge and skill of the interventional vascular specialist

The early outcome results from the International Carotid Stenting Study (ICSS) were recently presented in May at the European Stroke Conference [1]. The results firmly add to the evidence that carotid artery stenting (CAS) is everything but simple and should be undertaken by well-trained operators who have attained a high level of expertise.
The ICSS is a randomized controlled trial (RCT), non-inferiority design, comparing CAS with carotid endarterectomy (CEA) in patients with >50% symptomatic carotid stenosis. Recruitment began in 2002 and the trial enrolled 1713 patients, with 853 patients allocated to CAS. The 30-day rate of stroke or death, intention-to-treat analysis, was 8.5% with CAS and 4.6% with CEA...a clear sense of dèjá vu! The excess of strokes in the stenting arm was driven largely by minor strokes 4.0% vs 1.0% in the CEA arm. In terms of access complications, there were 44 cases of cranial nerve palsy (5.0%) with CEA vs one in the CAS arm, a patient who had crossed over to CEA. There were an excess of haematoma with CEA 5.0% vs CAS 3.0%, defined as requiring surgery, transfusion or prolonged hospital stay.  
Back in 2006, publications of both EVA-3S and SPACE trials shook the arena of carotid intervention like two earthquakes [2,3]. In the SPACE trial, the 30-day rate of ipsilateral ischaemic stroke or death was 6.84% with CAS (N=605) and 6.34% with CEA (N=595). In the EVA-3S trial, the 30-day rate of stroke or death was 9.6% after CAS (N=261) and 3.9% after CEA (N=259). After the dust settled and following much interest and debate, the crucial importance of expertise came to the fore. Of course, there were other issues such as the optional use of embolic protection devices (EPD) and the fact that these non-inferiority designed trials failed to recruit sufficient numbers of patients and hence were underpowered. In the reality they were stopped trials for one or more reasons: concerns over safety, slow recruitment, funding ran out.
Before discussing further critical issues of the above mentioned RCTs, I want to highlight the findings from a study that was presented recently in June at the British Cardiovascular Society Annual Conference, the subject of which will be published in a forthcoming issue of EuroIntervention Journal [4]. The study comes out of the Interventional Cardio-Angiology Unit at Villa Maria Cecilia Hospital, Cotignola, Italy which is one of the world’s foremost centres on CAS and has one of the largest single-centre CAS registries. The study assessed the success, safety and long-term durability of CAS in stroke prevention for “all-comers” managed with mandatory neuroprotection and a “tailored-approach” to intervention. The defining strength of the data reflects treatment for “all-comers” with minimal exclusion criteria and a near universal proceed to endovascular intervention following conventional diagnostic angiography confirming duplex ultrasound findings, meaning, that more than 99% of patients who required revascularization proceeded to the endovascular approach. The Cotignola-registry is a prospective CAS registry and the study analysed 1523 CAS procedures in a population with a very high burden of polyvasculopathy. CAS success was 99.6% and regarding early outcome, the 30-day all-stroke/death rate was 1.5%. This risk was 1.2% for asymptomatic patients and 2.7% for symptomatic patients. Results from this large cohort show that carotid stenting in a “real-world” setting is safe.
Why such good results? Firstly, evidence is accumulating from other experienced high-volume centres that CAS is producing good results. The Cotignola study suggests very good results can be obtained by the following three factors: i/ mandatory neuroprotection, ii/ a tailored-approach to intervention and iii/ a high-level of experience.

Mandatory neuroprotection: Certainly, there is no randomized trial to assess the efficacy of neuroprotection and there is unlikely to ever be one. It would be like randomizing jumping out of an airplane with and without a parachute.
SPACE, EVA-3S (before a change in the study design following an interim report highlighting an increased risk with unprotected CAS) and ICSS did not mandate neuroprotection. In addition to being significantly underpowered, post-hoc analyses comparing outcomes in patients treated with and without EPD are fundamentally flawed because the trials were not designed to evaluate the benefit of EPD and certainly patients were not randomized into a protection and nonprotection group. According to a subanalysis of the SPACE trial [5] the 30-day rate of ipsilateral stroke or death were similar (p=0.40): 8.3% in those treated with EPD (n=145) and 6.5% in those treated without EPD (n=418). The authors concluded that the evidence does not support the need for EPD. It is reasonable to suggest that there may be a selection bias wherein physicians did not use EPD in “low-risk” cases, reserving the use of EPD in “high-risk” cases. Yet, the results achieved in the presumed “low-risk” cases treated without EPD were just as high in the presumed “high-risk” cases treated with EPD. It is not beyond reasonable thinking, that it is probable, if EPD were used in the presumed “low-risk” cases the risk may have been substantially lower, and since this represented the great majority of patients the overall outcome may have been much better. For this reason, such post-hoc analyses are scientifically flawed. 
    In the Cotignola practice, neuroprotection is mandatory and such an approach standardises the procedure which contributes to the effectiveness. The choice of distal filter including subtypes or proximal occlusion devices is highly dependant on many factors such as vascular anatomy and plaque characteristics. Experience is thus maintained at a high-level, an essential element in the safe application of such devices. In addition, this approach allows experience to be gained in the use of multiple devices which are readily available on the shelf, allowing the safe application of the individual treatment approach. 

Tailored-approach: The “tailored-approach” is especially relevant to achieving good outcomes in the multi-factorial CAS strategy. Many units use predominantly one access system to engage the carotid artery, one type of EPD and one stent type. Currently, the relevance of closed- vs open-cell stent designs are the subject of much controversy. In the Cotignola practice the choice of stent, EPD, guiding catheters and sheaths is strongly dependant on an in-depth knowledge of neuro-assessment, carotid plaque characteristics, vascular anatomy and technical features of a vast array of endovascular materials. As with neuroprotection, there is no randomized trial assessing these issues. Experience with a wide range of devices and techniques allows the operator the flexibility to choose the most appropriate tools and techniques for the safe application of CAS in the management of each individual patient.

High-level of experience: An important element of the “tailored” concept is the recognition of high-risk cases for CAS dependent primarily on the skill of the interventional vascular specialists. The very good results achieved in the Cotignola experience underscore that with experienced operators – built on a philosophy of dedicated training – CAS is a safe procedure. The question then, is how to define or classify expertise. Obviously, experience is difficult to quantify and is related to number of procedures, quality of experience and the background skill of the interventionists.
In 2006 publication of the First Consensus Document of the Italian Consensus Carotid Stenting-SPREAD Joint Committee addressed the concept of training and competence in the field of CAS [6]. The minimum recommended training to achieve competence is as follows:
1. At least 150 procedures of supra-aortic vessel engagement (during diagnostic as well as interventional procedures) within 2 years, of which at least 100 as the primary operator;
2. At least 75 carotid stenting procedures, of which at least 50 as the primary operator, within a 2-year fellowship.
The learning curve is steep and flattens after about 80 interventions with regard to procedural risk and after about 160 interventions with regard to procedural time, which in itself is an important factor determining outcomes. In addition, an environment of learning/training significantly facilitates performance, not only for the operator but the entire cath lab staff and post-op care staff. Also important, independent of numbers, is the length of time involved in the delivery of CAS as an option and the time and discipline it takes to truly appreciate and deliver the tailored-approach in a meticulous manner to the entire management strategy.  This is all part of the experience represented in the Cotignola study.

      The RCTs have known limitations especially with regard to expertise. In the EVA-3S trial the total experience of the interventionalists required at least 12 CAS or at least 35 supra-aortic trunk interventions of which at least 5 were in the carotid artery. A variation was made wherein an interventionalist who did not fulfill the requirement was allowed to treat patients under supervision until the predefined criteria was attained. Indeed, 85% of interventionists in this trial had ≤50 cases in total. In the SPACE trial, interventionists had to show proof of at least 25 successful consecutive percutaneous transluminal angioplasty or stent procedures. Clearly, these trials were not designed to assess the effect of experience. Again, post-hoc analyses comparing outcomes in patients treated by inexperienced and experienced physicians are flawed based on the arguments discussed above regarding neuroprotection. Regarding the ICSS trial, an expert interventionalist was defined by having performed at least 50 stenting procedures anywhere, of which at least 10 should be in the carotid artery. Centres with no or little experience may join the trial as a probationary centre “supervised centre” wherein patients were enrolled and treated under the supervision of a proctor. Subsequently, after the centre achieved the minimum requirement of 10 CAS it was promoted to an experienced centre. From the evidence, the criteria used for defining an experienced operator are far placed from the recommendation by the ICCS-SPREAD document. The operator experience needed, in the planning of the randomized trials were clearly underestimated.
From the Cotignola study, CAS was highly feasible with minimal exclusion criteria in a population with extensive coexisting disease. Moreover, it showed procedural complication rates, in terms of 30-day risk of stroke or death, which are far below the reference bar. In respect of CEA complications, the widely referenced benchmark for symptomatic patients is 6% (2.7% in the Cotignola study) and for asymptomatic patients is 3% (1.2% in the Cotignola study). On the basis of this study, carotid stenting with neuroprotection undertaken with a “tailored-approach” in the hands of well-trained operators can be considered to be a safe therapy. Indeed, the “tailored-approach” appears to reduce complications to a new threshold, and continued refinement in techniques and materials will move us that much closer to stroke prevention. Indeed, well-conducted valid randomized trials are essential in establishing equivalence or superiority of new therapeutic interventions. Thus, what is absolutely needed is a robust randomized trial with a superiority design ensuring a rigorous standard of practice and technical skills in order to truly evaluate the role of carotid stenting.

1. Brown MM, Ederle J, Bonati LH, et al. Safety results of the International Carotid Stenting Study: Early outcome of patients randomised between carotid stenting and endarterectomy for symptomatic carotid stenosis. European Stroke Conference 2009; May 27, 2009; Stockholm, Sweden.
2. Mas JL, Chatellier G, Beyssen B, et al. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med 2006;355:1660-1671.
3. The SPACE Collaborative Group. 30-day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomized non-inferiority trial. Lancet 2006;368:1239-1247.

1. Cremonesi A, Gieowarsingh S, Spagnolo B, Manetti R, Liso A, Furgieri A, Barattoni M, Ghetti L, Tavazzi L, Castriota F. Safety, efficacy and long-term durability of endovascular therapy for carotid artery disease: The tailored Carotid Artery Stenting Experience of a single high-volume center (tailored-CASE Registry). In press EuroIntervention Journal.

5. Jansen O, Fiehler J, Hartmann M, Bruckmann  H. Protection or nonprotection in carotid stent angioplasty from the SPACE trial. Stroke 2009;40:841-846.
6. Cremonesi A, Setacci C, Bignamini A, Bolognese L, Briganti F, Di Sciascio G, Inzitari D, Lanza G, Lupattelli L, Mangiafico S, Pratesi C, Reimers B, Ricci S, de Donato G, Ugolotti U, Zaninelli A, Gensini GF. Carotid artery stenting: first consensus document of the ICCS-SPREAD Joint Committee. Stroke 2006;37(9):2400-9.