MINERVA MEDICA COPYRIGHT

Transcription

1 SPECIAL ARTICLES J CARDIOVASC SURG 2015;56: Physician-initiated prospective Italian Registry of carotid stenting with the C-Guard mesh-stent: the IRON-Guard registry. Rationale and design According to the World Health Organization, every year, 5 million peoples die for stroke and another 5 million are permanently disabled. Although there are many causes of acute stroke, a common treatable cause of acute stroke is atheromatous narrowing at the carotid bifurcation. Carotid endarterectomy is still the standard of car, even if carotid artery stenting (CAS) has become an effective, less invasive alterantive. Unfortunately, CAS procedure is not yet perfect; regardless the use of an embolic protection device (EPD), percutaneous treatment has been correlated with a risk of cerebral ischemic events related to distal embolization. The objective of the IRON- Guard Registry is to evaluate the clinical outcome of treatment by means of stenting with the C-Guard (InspireMD, Boston, MA, USA) in subjects requiring CAS due to significant extracranial carotid artery stenosis with a physician-initiated, Italian, prospective, multicenter, single-arm study. A total of 200 enrolled subjects divided over different centers are planned to be enrolled. CAS will performed by implanting of C- Guard stent. Procedure will be performed according to the physician s standard of care. Standard procedures will be followed based on the Instructions for Use, for the C-Guard device of Inspire. The primary endpoint of this study is the 30-day rate of major adverse events (MAE), defined as the cumulative incidence of any periprocedural ( 30 days postprocedure) death, stroke or myocardial infarction. Secondary endpoints are rate of late ipsilateral stroke (31 through 365 days), system technical success, device malfunctions, major adverse events (MAEs), serious device-related and procedure-related adverse events, target lesion revascularization, and in-stent restenosis rates. Key words: Stroke - Stents - Embolization, therapeutic. Corresponding author: C. Setacci, Vascular and Endovascular Surgery Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Bracci 1, Siena, Italy. setacci@unisi.it C. 1, F. SPEZIALE 2, G. DE DONATO 1, P. SIRIGNANO 2 F. 2, L. CAPOCCIA 2, G. GALZERANO 1, W. MANSOUR 2 On behalf of IRON-Guard Study Group. 1Vascular and Endovascular Surgery Unit, Policlinico Santa Maria alle Scotte, University of Siena, Siena, Italy 2Vascular and Endovascular Surgery Unit, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy According to the World Health Organization, every year, 5 million peoples die for stroke and another 5 million are permanently disabled. For those, stroke is the third-leading cause of death in the United States and the leading cause of serious long-term disability. 1 Although there are many causes of acute stroke including emboli from the heart, blood vessel dissection, and small perforator vessel occlusion, a common treatable cause of acute stroke is atheromatous narrowing at the carotid bifurcation. It is generally believed that in this situation ischemic stroke most commonly occurs from local thrombus formation that develops as a consequence of both ulceration and laminar flow disturbances in and around the stenotic lesion. Less frequently, ischemic stroke may be due to low flow from a critical stenosis resulting in a hemodynamic insufficiency to a region of the brain. 2 In case of significant carotid stenosis, surgical removal of atheromatous material from inside the artery by carotid endarterectomy (CEA) represents the standard of care. With the advent of new technologies and with the more frequent requests of minimally invasive techniques, carotid artery stenting (CAS) has become an alternative to open surgical procedures, especially for subjects with surgical risk factors for CEA. 2-4 The SAPPHIRE Trial 5 has proved the non-inferi- Vol No. 5 THE JOURNAL OF CARDIOVASCULAR SURGERY 787

2 ority of CAS versus carotid endarterectomy in highrisk patients, which led to the US FDA approval of carotid stent for high-risk patients. The CREST Trial, 6 the largest randomized trial comparing stenting versus endarterectomy, showed no significant difference in death, stroke or myocardial infarction. Over the last 15 years, the accumulation of experience, the improvement of stent platforms and embolic protection devices, and the strong demand from patients for a less invasive alternative to CEA has made carotid artery stenting an equally efficient and safe procedure for the prevention of stroke. Unfortunately, CAS procedure is not yet perfect; regardless the use of an embolic protection device (EPD), percutaneous treatment has been correlated with a risk of cerebral ischemic events related to distal embolization. The occurrence of periprocedural ischemic brain lesions on magnetic resonance imaging (MRI) after revascularization of atherosclerotic stenosis of the internal carotid artery, either with CAS or CEA, has been commonly described. 7 The randomized ICSS (International Carotid Stenting Study) compared CAS with CEA in patients with symptomatic carotid stenosis. 8 In the MRI sub-study of ICSS (ICSS-MRI), 50% of patients treated with CAS and 17% of those undergoing CEA had periprocedural ischemic brain lesions on diffusion-weighted imaging (DWI) on MRI scans obtained a median of 1 day after treatment. The clinical significance of these lesions remains unclear, even if was postulated that them could lead to a cognitive decline in asymptomatic carotid stenosis after revascularization. 9 Many factors may cause an intraprocedural embolization (including incorrect endoluminal maneuvres, complex aortic arch, use of cerebral protection devices, stent deployment and ballooning), while events occurring in the early postoperative period are contemplated as the consequences of remodelling of the atheroma, which is more or less contained behind the stent struts. There is great interest in the possibility to recognize further details regarding the interaction between carotid plaque and stent, considering that plaque prolapse through the cell stent has been suggested as one of the major causes of postprocedural complications following CAS (off-table events). 10 A new intravascular diagnostic tool, the optical coherence tomography (OCT) with its high-resolution capability of 10 μm and its ability to carotid plaque definition has to be considered the innovative tool to define new indications to treatment, new suggestions in the CAS vs. CEA debate, and above all new criteria for the development of new carotid stent and testing their performance. A recent study 11 focused on the complex interaction between carotid plaques and stents by analyzing OCT findings (stent malapposition, plaque prolapse and cap rupture) according to stent design. The main message from this investigation is that an unexpected high number of microimperfections after CAS are noticeable with all carotid stent designs by OCT images acquisition. On OCT analysis the frequencies of malapposed struts were higher with closed cell (CC) compared to open cell (OC) and hybrid design (Hyb) (34.5% vs. 15% and 16.3%, respectively; P<0.01). Plaque prolapse was more frequent with OC vs. CC (68.6% vs. 23.3%; P<0.01) and vs. hybrid cell stents (30.8%; P<0.01). Significant differences were also noted in the rates of fibrous cap rupture between CC and OC (24.2% vs. 43.8%; P<0.01), and between CC and Hyb (24.2% vs. 39.6%; P<0.01), but not between OC vs. Hyb stents (P=0.4). The main conclusion from this study was that the rate of plaque prolapse was extremely high with open cell design (nearly 70%). Even the best available stent configuration worked rather poorly in term of plaque covering; actually one out of 4 patients treated by closed cell stent had plaque prolapse as revealed by OCT. Moreover these results clearly show that the carotid stent designs available at the time of investigation were tremendously suboptimal with regards to plaque coverage and wall apposition as depicted by OCT (Figure 1). The so called mesh-stents are a new class of carotid stent that promise to offer a higher scaffolding of carotid plaque in comparison to previous carotid stent design, avoiding, or at least limiting plaque prolapse through the cell struts. The objective of the IRON-Guard Registry is to evaluate the clinical outcome of treatment by means of stenting with the C-Guard (InspireMD, Boston, MA, USA) in subjects requiring CAS due to significant extra-cranial carotid artery stenosis. The C-Guard Stent The device under investigation is the C-Guard carotid artery stent, an innovative monorail, selfexpanding, OC, nitinol carotid stent covered by a polyethylene terephthalate (PET) micromesh. This 788 THE JOURNAL OF CARDIOVASCULAR SURGERY October 2015

3 Figure 1. OCT intraoperative findings of plaque prolapse trough the stent. coverage allows the device to prevent the embolization by plaque and thrombus particles during and after the carotid stenting procedure. The stent has a crossing profile of 2 mm and an external diameter of 6F, it s compatible with any 8F catheter and any distal EPD. C-Guard Carotid stent is indicated for carotid stenting procedures on patients with vessel diameter included between 4.8 and 9.0 mm at the level of the lesion (available diameters from 6 to 10mm and lengths from mm). The PET micromesh has a thickness of 20 µ and a porosity of µ. The IRON-Guard Registry The IRON-Guard is a physician-initiated, prospective, multicenter, single-arm study. A total of 200 enrolled subjects divided over different Italian centers (Appendix A) are planned to be enrolled. The principal investigator of each clinical site should be highly experienced in carotid artery stenting. The anticipated duration of this clinical investigation is approximately 24 months, namely 12 months per patient follow-up, with a recruitment period of 12 months. Patients will be selected based on the investigator s assessment and evaluation of the underlying disease. Patients should be willing and able to cooperate in this clinical study, and remain available for long term follow-up. Refusal or non-eligibility of patients to participate in this study will in no way affect their care at the institution. To be enrolled in the registry, patient should meet all the Inclusion Criteria: 1) neurological symptoms and 50% stenosis (NASCET criteria), or asymptomatic 70% stenosis (NASCET criteria); 3 2) target lesion located in the distal common carotid artery (CCA), internal carotid artery (ICA), or carotid bifurcation; 3) arterial segment to be stented has a diameter between 4 mm and 9 mm; 4) life expectancy >12 months from the date of the index procedure; 5) willing and able to comply with follow-up requirements. Exclusion criteria, as usual for this kind of study, are: 1) contraindication to percutaneous transluminal angioplasty (PTA); 2) sever vascular tortuosity or anatomy that would preclude the safe introduction of a guide catheter, sheath, embolic protection system or stent system; 3) lesions in the ostium of the common carotid artery (unless treated simultaneously); 4) occlusion of the target vessel; 5) evidence of intraluminal thrombus; 6) known sensitivity to nickel-titanium; 7) known allergy to heparin, aspirin or other anticoagulant/antiplatelet therapies, or is unable or unwilling to tolerate such therapies; 8) uncorrectable bleeding disorders, or will refuse block transfusion; 9) history of prior life-threatening contrast media reaction; 10) previous stent placement in the target vessel; 11) evolving stroke or intracranial hemorrhage; 12) previous intracranial hemorrhage or brain surgery within the past 12 months; 13) clinical condition that makes endovascular therapy impossible or hazardous. Preprocedure All consecutive patients admitted at each participating centers will be recorded (screening form). All information and data concerning patients or their participation in this clinical investigation will be considered confidential. Inclusion/exclusion criteria will be reviewed in this form resulting in a decision about study participation. All patients enrolled into the clinical investigation will undergo a baseline clinical examination, including: demographic characteristics, medical history, physical examination, carotid Duplex ultrasound (CUS), computed Vol No. 5 THE JOURNAL OF CARDIOVASCULAR SURGERY 789

4 tomographic angiography (CTA) or RM (ECG-gated Steady State Free Procession) to evaluate aortic arch morphologies, presence of thrombus, calcifications and vessels tortuosity, RM-DWI and independent neurological assessment. Procedure A patient is considered enrolled in the study if there is full compliance with the study in- and exclusion criteria and after successful guidewire passage through the study target lesion. Procedure will be performed according to the physician s standard of care. Standard procedures will be followed based on the Instructions for Use, for the C-Guard device of Inspire (Figure 2). Postprocedure Postprocedural assessment includes OCT (or intravascular ultrasound, IVUS) immediately postpro- Figure 2. Intraoperative result of a stent procedure performed by deployment of C-Guard stent.minerva cedure (when available) and RM-DWI within 24 hours. Before hospital discharge patient underwent physical examination, independent neurological assessment and CUS. Follow-up Clinical data will be collected at patient enrolment, implant, discharge, planned follow-ups (1-, 6- and 12-months postprocedure), unplanned or interim follow-ups, and patient death. At 30-day follow-up a new RM-DWI will be performed. Regular follow-ups are necessary to monitor the condition of the patient and the stent/procedure. Patients should adhere to a follow-up visit time restriction of ±7 days for the 1-month and ±30 days for the 6- and 12-month follow-up visits. Study endpoints The primary endpoint of this study is the 30-day rate of major adverse events (MAE), defined as the cumulative incidence of any periprocedural ( 30 days post-procedure) death, stroke or myocardial infarction (MI). Secondary endpoints are rate of late ipsilateral stroke ( days), system technical success, device malfunctions, major adverse events (MAEs), serious device-related and procedure-related adverse events as defined per ISO :2011, 12 target lesion revascularization (TLR) and in-stent restenosis (ISR) rates. An adverse event (AE) is defined as any undesirable clinical occurrence in a patient whether it is considered to be device related or not. This definition includes events occurring during the enrolment in the study right up to the last follow-up visit. Underlying disease that was present at the time of enrolment is not reported as an AE, but any increase in the severity of the underlying disease is to be reported as an AE. An adverse device effect (ADE) is a device-related AE. All AEs and ADEs will be monitored from the time of enrolment through the 12-month follow-up visit. Adverse events can be classified as mild, moderate, severe and serious. A serious adverse event (SAE) or serious adverse device effect (SADE) is defined as an AE or ADE, which results in death, is life-threatening, results in persistent or significant disability/incapacity, requires in-patient hospitalization or unduly prolonged hospitalization or necessitates an intervention to prevent a permanent impairment of a body function or permanent damage to a body structure. MEDICA 790 THE JOURNAL OF CARDIOVASCULAR SURGERY October 2015

5 Clinical events to be considered and reported as SAEs include (but are not limited to): major adverse clinical events (MACE), death, myocardial infarction, stroke, emergent surgical revascularization of the target vessel, repeat vascularization of the target vessel, and bleeding complication requiring transfusion or reintervention. Data analysis Patient data will be captured using a paper case report form. Descriptive data summaries will be used to present and summarize the collected data. For categorical variables (e.g. gender) frequency distributions and cross tabulations will be given. For numeric variables (e.g. patient age) minimum, maximum, mean, median and standard deviation will be calculated. For all variables a 95% confidence interval for the relevant parameters of the underlying distribution will be calculated. For all time-dependent events, life-tables will be calculated using the Kaplan-Meier estimate method, for a period starting on the date of the procedure up to and including the 12-month follow-up visit. Stratification to pre-procedural risk factors, Rutherford Classification and lesion criteria will be performed and a Cox regression will be used to compare between the different outcomes, associated P-values <0.05 are defined as significant. Additionally all peri- and post-procedural complications (<24 hours) will be evaluated and documented. References 1. World Health Report , from the World Health Organization. Accesses October 31, CO-Principal Investigators Carlo Setacci, Siena Francesco Speziale, Rome Investigators Guido Bellandi, Arezzo Piergiorgio Cao, Rome Renato Casana, Milan Patrizio Castelli, Varese Roberto Chiesa, Milan 2. Setacci C, Argenteri A, Cremonesi A, de Donato G, Galzerano G, Lanza G et al. Guidelines on the diagnosis and treatment of extracranial carotid artery stenosis from the Italian Society for Vascular and Endovascular Surgery. J Cardiovasc Surg (Torino) 2014;55: North American Symptomatic Carotid Endarterectomy Trial Collaboration. Beneficial effect of carotid endarterectomy in symptomatic patients with high grade carotid stenosis. N Engl J Med 1991;325: Rothwell PW, Slattery J, Warlow CP. A systematic review of the risks of stroke and deathe due to endarterectomy for symptomatic carotid stenosis. Stroke 1996;27: SAPPHIRE Investigators (Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy). Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004;351: Brott TG, Hobson RW 2nd, Howard G, Roubin GS, Clark WM, Brooks W et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010;363: Schnaudigel S, Groschel K, Pilgram SM, Kastrup A. New brain lesions after carotid stenting versus carotid endarterectomy: a systematic review of the literature. Stroke 2008;39: Bonati LH, Jongen LM, Haller S, Flach HZ, Dobson J, Nederkoorn PJ et al. New ischaemic brain lesions on MRI after stenting or endarterectomy for symptomatic carotid stenosis: a substudy of the International Carotid Stenting Study (ICSS). Lancet Neurol 2010;9: Capoccia L, Sbarigia E, Rizzo A, Mansour W, Speziale F. Silent stroke and cognitive decline in asymptomatic carotid stenosis revascularization. Vascular 2012;20: Bosiers M, de Donato G, Deloose K, Verbist J, Peeters P, Castriota F et al. Does free cell area influence the outcome in carotid artery stenting? Eur J Vasc Endovasc Surg 2007;33:135-41; discussion de Donato G, Setacci F, Sirignano P, Galzerano G, Cappelli A, Setacci C. Optical coherence tomography after carotid stenting: rate of stent malappostion, plaque prolapse and fibrous cap rupture according to stent design. Eur J Vasc Endovasc Surg 2013;45: ISO 14155: Clinical investigation of medical devices for human subjects. Good clinical practice [Internet]. Available from [cited 2015, May 22]. Received on May 18, Accepted for publication on May 27, Epub ahead of print on May 21, Appendix A - IRON-Guard Study Group Gioachino Coppi, Modena Alberto Cremonesi, Cotignola Gianfranco Fadda, Nuoro Augusto Farina, Crema Paolo Frigatti, Udine Andrea Gaggiano, Asti Franco Grego, Padova Massimo Lenti, Perugia Nicola Mangialardi, Rome Giustino Marcucci, Civitavecchia Stefano Michelagnoli, Florence Giovanni Nano, Milan Franco Nessi, Turin Claudio Novali, Cuneo Giancarlo Palasciano, Tricase Domenico Palombo, Genoa Giovanni Paroni, San Giovanni Rotondo Francesco Pompeo, Pozzilli Claudio Rabbia, Turin Massimo Sponza, Udine Andrea Stella, Bologna Enrico Vecchiati, Reggio Emilia Vol No. 5 THE JOURNAL OF CARDIOVASCULAR SURGERY 791