Thirty-Day Results of the Novel CGuard-Covered Stent in Patients Undergoing Carotid Artery Stenting

Introduction

Extracranial carotid artery stenosis is responsible for 20% of ischemic strokes due to the presence of atheromatous lesions at the carotid bifurcation. ¹ Carotid endarterectomy and carotid artery stenting (CAS) are the mainstay treatment options; however, the latter is more recently developed and considered a less invasive technique, especially in high-risk patients. However, there is an increase number of neurologic events after stent placement where cerebral protection device has already been removed.^2-4 The morphology of the atherosclerotic plaque is changed after stent placement with possible protrusion and dislodgement of debris through the struts of the stents enhancing the risk of embolization to the brain. A new type of carotid stent has been recently developed to address this issue. The “double mesh technology” has been highly evolved and is gaining ground. It has shown promising results in clinical and real-world registries.^5-8 CGuard (InspireMD, Tel Aviv, Israel) is a novel carotid embolic prevention system designed to reduce the risk of periprocedural and late embolization in a CAS procedure. The aim of this study was to report early-term evaluation as well as safety and efficacy of CGuard device in a tertiary vascular center.

Device Characteristics

The CGuard Carotid Embolic Prevention System consists of a self-expanding stent using a rapid exchange delivery system. It is an open cell stent platform made by nickel titanium alloy (Nitinol) covered externally with a Micronet mesh made of polyethylene terephthalate (PET) fibers of 20-μm thickness providing low porosity (150–180 μm) when fully expanded. In this way thrombus is trapped and excluded as well as friable atheromatous debris to prevent acute and late embolic events from the target lesion. Thanks to its “SmartFit Technology” CGuard scaffold provides a conformability in anatomically challenging carotid artery bifurcation eliminating the need for tapered version. The crossing profile of the device is 2.03 mm. It requires a luminal opening of 3 mm to enable retrieval CGuard delivery system. The use of embolic protection devices (EPDs) is recommended, not mandatory, when using CGuard stent according to instructions for use (IFU). It is available in an array of lengths (20160 mm) and diameters (6.0–10 mm). It is CE marked and approved since 2016.

Materials and Methods

Patient Selection

Records of all patients who underwent CAS with CGuard carotid embolic protection system from January 2018 to September 2020 in a referral center were collected in a database and prospectively evaluated. The protocol was approved by the institutional review board of our hospital. An informed consent of all patients was obtained, including surgical operation, record of post procedural events, and publication of our results for scientific purposes. The primary indications for CAS with CGuard stent system is symptomatic carotid artery stenosis >50% [transient ischemic attack (TIA), amaurosis fugax, ipsilateral ischemic stroke without major disability National Institutes of Health Stroke Scale <15, Rankin score >3] and asymptomatic carotid artery stenosis >70%, as an institutional algorithm, according to NASCET method ⁹ with the presence of one or more imaging or clinical criteria that make them “higher risk for stroke” (stenosis progression, high echolucency, intraplaque hemorrhage, contralateral TIA or stroke, silent infarction on computed tomography or magnetic resonance imaging). ¹⁰ Exclusion criteria are known allergy or incapacity to comply with heparin, aspirin, or other anticoagulant/antiplatelet therapies, allergy to nickel/titanium, evolving stroke or intracranial hemorrhage; previous intracranial hemorrhage or brain surgery within the past 12 months, allergy to contrast media, uncorrectable bleeding disorders, and presence of intracerebral aneurysm or arteriovenous dysplasia, life expectancy more than 2 years. Demographic and clinical characteristics of patients are listed in Table 1. Preoperative evaluation and planning includes clinical examination of peripheral arterial system to ensure femoral access patency, a duplex ultrasonography of extracranial carotid artery system, a computed tomography angiography or magnetic resonance imaging of aortic arch and supra-aortic branches. The characteristics of aortic arch (angulation, calcification, and thrombus) and morphology of carotid artery lesions (calcification, diameter, length, tortuosity, and kinking) are analyzed preoperatively.

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Table 1.

Demographics and Clinical Characteristics of Patients Who Underwent Carotid Artery Stenting With CGuard Embolic Protection System.

Number of patients	103
Men, n (%)	90 (87.3)
Symptomatic carotid stenosis, n (%)	40 (38.9)
Asymptomatic carotid stenosis, n (%)	63 (61.1)
Mean carotid lesion length (symptomatic/asymptomatic), mm	14.6
Mean internal carotid artery stenosis, %	79.47 (60–95)
Mean PSV of carotid artery stenosis, cm/s	251.57 (160–350)
Mean EDV of carotid artery stenosis, cm/s	154.62 (75–220)
ASA, n (%)
1	3 (2.9)
2	72 (69.9)
3	28 (27.7)
Diabetes mellitus, n (%)	24 (23.7)
Arterial hypertension, n (%)	75 (72.8)
Dyslipidemia, n (%)	56 (54.3)
Coronary Disease, n (%)	38 (36.8)
Chronic renal failure: ESRD, n (%)	6 (5.9)
Peripheral arterial disease, n (%)	16 (15.8)
Atrial fibrillation, n (%)	7 (6.9)
Valvular heart disease, n (%)	7 (6.9)

Abbreviations: ASA, American Society of Anesthesiologists classification; ESRD, end-stage renal disease; PSV, peak systolic velocity.

Operative Technique

Asymptomatic patients are under single antiplatelet therapy and symptomatic patients under dual antiplatelet regimen before admission at our department. According to our clinic protocol no loading dose with clopidogrel is administered preoperatively. All CAS procedures with this technique have been performed by 5 vascular surgeons who are well trained in CAS at this center. Operations are performed in a fully equipped operation room with a new portable C-arm (Ziehm Vision RFD Hybrid edition, Ziehm Imaging, Germany). Under local anesthesia percutaneous access is gained through puncture of the common femoral artery. The patient is systematically heparinized (75 U/kg). An introducer sheath 8Fr is used. Access to the supra-aortic trunks is obtained through an 8Fr JR4 100 cm guiding catheter which is advanced in the aortic arch through a stiff guidewire 180 cm (Terumo, Terumo Corp, Tokyo, Japan). An angiography is performed to visualize the orifice of innominate or left common carotid artery. Inner catheters with different shapes (Imager II, Boston Scientific Corporation) are used in selected cases where aortic arch anatomy is challenging such as type II aortic branch or tortuous supra aortic branches. After successful catheterization the guiding catheter is advanced to the common carotid artery. An angiogram is performed depicting the carotid bifurcation, the stenosis as well as the distal intracranial internal carotid artery perfusion. A 0.014-inch thick 190-cm long hi-torque balance middleweight guidewire (Abbot Vascular, Santa Clara, CA, USA) with hydrophilic coating is used to cross the lesion and is advanced distally. Embolic protection device is not routinely used in our daily practice with “double-mesh” stent, based on the preferences of each operator. The CGuard self-expanding stent is flushed with heparinized saline solution through the side hole until some drops of the solution exit at the distal end of the catheter. In such way air is removed from the delivery system and eliminate the chance of friction within the sheath. Predilatation of the lesion with an appropriate size balloon dilatation catheter of 2.5 to 3.0 mm is used when stent cannot cross the lesion due to severe stenosis. An attempt to drive a distal EPD through the stenosis is performed due to its complexity and then the stent is advanced at the intended carotid lesion site. Once deployment is initiated the stent cannot be repositioned or recaptured. The hemostatic valve is rotated within the handle slot anticlockwise until it rotates with no resistance. A pull back force is steadily applied by holding the hemostatic valve body with the right hand until it travels to its end and the handle slot with left hand. Postdilation with balloon is followed at 8 to 10 atm, with diameter ranges of 4.5 to 5.5 mm. An angiography confirms the final result (Figure 1). If patient has a bovine aortic arch or type III aortic arch where catheterization is highly challenging, a transcarotid access is used under general anesthesia. A small vertical incision in the lower inner margin of sternocleidomastoid muscle is performed and common carotid artery is dissected. A 6Fr introducer sheath is advanced in the common carotid artery angiography and subsequent steps of procedure are performed as previously described. One hundred and fifty milligrams of clopidogrel are administered in the recovery unit followed by aspirin 100 mg in the ward after 7 to 8 hours or a low-molecular-weight heparin in therapeutic dose if patient has atrial fibrillation (AF) or mechanical valve. The introducer sheath is removed 3 to 4 hours postoperatively and manual compression is applied to the groin area for at least 25 minutes. All patients are discharged under dual antiplatelet therapy for 3 months followed by single lifelong aspirin or clopidogrel. In patients with AF or mechanical heart valve a single antiplatelet drug is added to the antithrombotic regimen (non–vitamin K antagonist oral anticoagulants or coumarin) for at least 1 month.

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Figure 1.

Preoperative and postoperative angiography of a severe eccentric stenosis of left internal carotid artery successfully repaired with CGuard without embolic protection device.

Results

A total of 103 patients underwent CAS procedure with CGuard carotid embolic protection system (EPS). Mean age is 68.9 years (49–85 years). Ninety patients were men (87.3%). Forty patients were symptomatic (38.8%). Mean carotid lesion length was 14.6 mm (range 10–29 mm). Preoperative mean PSV was 251.57 cm/s (range 160-350 cm/s, SD 44.535), mean EDV was 154.62 cm/s (range 75-220 cm/s, SD 34.371). Preoperative median carotid stenosis was 79.47% (range 60%–95%, SD 6.857). Technical success was achieved in all patients (100%). Local anesthesia was used in 95 patients (92.2%). No difficulty was noticed in delivering the stent in lesion zone. Transcarotid access was used under general anesthesia in 8 patients due to the presence of bovine or type III aortic arch. The use of EPDs was not mandatory. Robin filter (Balton, Warsaw, Poland) was used in 6 patients (5.8%), all from 1 operator of the vascular unit. Balloon predilatation was performed in 4 patients (3.9%) when the stent across the device could not be advanced through the lesion as a primary maneuver. Due to the complexity of the stenosis we attempted to advance a distal EPD with no success. Predilatation was not associated with cerebral complications. CGuard was used in 4 patients with restenosis, 1 previous carotid endarterectomy, and 3 CAS procedures. Two patients had pseudoaneurysm of femoral artery postoperatively (1.9%). Both had morbid obesity (body mass index >40 kg/m²) and highly atherosclerotic common femoral arteries. They were operated the 2nd and 3rd POD, respectively with evacuation of hematoma and suturing of the femoral artery. Two asymptomatic patients had an ipsilateral TIA, which totally resolves within 24 hours (1.9%). One patient experienced asystole and hypotension after balloon inflation, which was managed with atropine and 2 overlapping stents were deployed to the second patient due to the presence of long lesion. A female asymptomatic patient experienced a cerebral hyperperfusion syndrome 4 hours post-CAS. Her clinical manifestations included a severe ipsilateral headache followed by tonic-clonic convulsions without neurologic deficit. She was successfully managed with anticonvulsant therapy and diazepam. Contrast-enhanced computed tomography excluded hemorrhagic stroke, cerebral edema, or stent occlusion. No TIA, minor or major stroke were observed in the symptomatic group. Postoperative mean internal carotid artery stenosis was 14.68% (range 10%–25%, SD 4.395) [t(102)=83.72, p<001]. Ipsilateral jaw claudication was observed in 4 patients after CAS (3.9%), which accentuated after 15 days. External carotid artery (ECA) was patent at final angiography; however, duplex ultrasound postoperatively demonstrated increased velocities in ECA due to atherosclerosis and stent deployment. Mean time of operation and hospitalization was 35 minutes (range 20–50 minutes), 3.1 days (range 3–5 days) for symptomatic group, and 2.1 days (range 2–3 days) for asymptomatic group respectively. At 30-day follow-up, MAE rate was 0% in both groups. CGuard was patent in all patients (100%), no restenosis was observed. Postoperative mean PSV was 77.29 cm/s (range 10–25cm/s, SD 4.395) [t(102)=40.37, p<001] and mean EDV was 24.63 cm/s (range 18–32 cm/s, SD 3.378 [t(102)=39.639, p<001].

Discussion

Our single-center study has prospectively evaluated safety and efficacy of the novel CGuard carotid stenting with EPS. The principal findings of our study are the following:

“Double mesh” technology is a new pioneered idea in the era of CAS. Carotid artery stenting are emboli-generated procedures. Cerebral embolization is the main etiological factor of postprocedural neurologic events where thrombotic, friable atherosclerotic plaques protrude through stent struts until re-endothelialization begins. The average annual risk for postprocedural ipsilateral stroke is still important (0.4%).^11,12 Large series of CAS using first generation of carotid stents showed that 40% to 80% of adverse neurologic events within the first 30 days occur post- rather than intraprocedurally, and often several days after the procedure. ¹³ Clinical studies and meta-analysis described a higher neurological complication rate in symptomatic patients underwent CAS with open-cell stents compared to those with a closed cell configuration.^2,14,15 However other investigators have not found a difference in CAS outcomes according to stent design. ¹⁶

CARENET trial was the first study evaluating efficacy of CGuard and the number of new silent ischemic lesions postprocedurally assessed by diffusion-weighted magnetic resonance imaging (DW-MRI). ⁷ Technical success was 100%, 30 days MAE was 0%, and new diffusion-weighted imaging (DWI) ipsilateral ischemic lesions at 48 hours occurred in 37.0% of patients. At 30 days, DW-MRI showed complete resolution of all but 1 periprocedural lesion and only 1 new minor lesion in relation to the 48-hour scan. In contrast MRI study of International Carotid Stenting Study (ICSS) revealed at least 1 new DWI new ischemic lesion in 50% of stenting group the first postoperative days. ¹⁷

IRON-guard study was a prospective real word multicenter study. ⁸ CGuard was deployed in 200 patients, with EPDs used in 182. There were 2 TIAs and 5 periprocedural minor strokes (2.5%). No death, acute myocardial infarction (AMI) or major stroke occurred periprocedurally. At 12 months, 199 patients complied with 3-, 6-, and 12-month follow-up evaluation. No major neurological adverse event, stent thrombosis or external carotid occlusion was recorded. ¹⁸

The PARADIGM study evaluated midterm efficacy of CGuard mesh stent, 108 patients were totally enrolled. At 12-month follow-up, no minor/major stroke- and neurologic-related deaths were recorded. Duplex ultrasound revealed no stent thrombosis and one isolated asymptomatic restenosis treated with drug-coated balloon. ¹⁹

Two studies have evaluated safety and efficacy of double mesh stents against open-cell and close-cell stents. Vanzin et al ²⁰ compared close-cell stents with Casper (MicroVention, Inc, Tustin, CA, USA) stents. Primary end points were the incidence number and size of new ischemic lesions in DW-MRI. Secondary endpoints were stroke, TIA, and myocardial infarction (MI). Two TIA occurred postoperatively, one in each group. The Casper stents did not show superiority in the rate of incidence, number, and size of new silent ischemic brain lesions detect by DW-MRI. ²⁰ Bugurov et al ²¹ compared Acculink (open-cell stent) with CGuard stent. Fifty patients were randomly divided 1:1 in 2 groups. Primary end point was detection of acute ischemic foci in DW-MRI at 24 to 48 hours and 30 POD. No significant differences were noticed between 2 groups at 24 to 48 hours with a tendency of smaller ischemic foci in the CGuard group compared with Acculink group. At 30 POD no new ischemic lesions were noticed in CGuard group compared with new silent ischemic foci in 2 patients. ²¹

In our study, 2 patients had a TIA, which totally resolved within 24 hours. No MAE was recorded at 30 days. Our low 1.9% perioperative minor/major stroke rate is comparable to other studies reporting their experience with double mesh stenting.^5,7,17,22 One patient experienced a cerebral hyperperfusion syndrome postoperatively. Her medical history included asymptomatic stenosis >90% of right internal carotid, contralateral stenosis 60%, arterial hypertension poorly medically controlled. Her clinical manifestations included severe ipsilateral headache followed by tonic-clonic seizures without neurologic deficit. Contrast-enhanced computed tomography excluded hemorrhagic stroke, cerebral edema, or stent occlusion. She was managed with diazepam and anticonvulsant therapy. Cerebral hyperperfusion syndrome (CHS) is a rare and severe neurologic complication following carotid endarterectomy or CAS. The main pathophysiological mechanism is impairment of cerebral autoregulation. Autoregulation includes myogenic and neurogenic mechanisms; when both fail CHS occurs. ²³ In a meta-analysis, the overall pooled risk of CHS after CAS was 3.5% (2.6%–4.7%) in 13,492 patients treated with CAS. The average time from procedure to development of CHS was 12 hours. No cases were described after 6 days. ²⁴ In contrary, Moulakakis et al showed that the highest incidence of CHS after carotid endarterectomy was between the 5th and 8th POD. ²⁵

External carotid artery occlusion occurred in 2 patients (1.9%) due to deployment of 2 overlapping stents across a long lesion in common carotid and internal carotid arteries. It was not associated with jaw claudication or unilateral headache. Ipsilateral jaw claudication was observed in 4 patients after CAS (3.9%), which accentuated after 15 days. External carotid artery (ECA) was patent at final angiography; however, postprocedural duplex examination depicted increased velocities in ECA due to atherosclerosis and stent deployment. Jaw claudication has been documented as a result of ECA occlusion or hypoperfusion.^26,27 Willford-Ehringer et al ²⁸ reported significant progression of atherosclerotic disease at the orifice of the ipsilateral ECA after CAS compared with the contralateral ECA.

In our study, EPDs were used in 5.8 %, all by one operator. Routine use of EPDs has shown decreased post-CAS neurological complications and it is now accepted that diminish postprocedural stroke risk. ²⁹ However, EPDs were not mandatory in our study, trying to exhibit the efficacy of double mesh stents without protection device, since there are reports that EPDs do not completely eliminate the risk of cerebral embolization.^30,31 In the ICSS study, 73% of the stenting group with cerebral protection device developed new silent ischemic lesions in DW-MRI compared with 34% of the stenting group without protection device. They concluded that protection devices did not seem to be effective in preventing cerebral ischemia during stenting. ¹⁷ Garriboli et al ³² retrospectively evaluated safety and efficacy of CAS without EPD with different types of stents (double-mesh, open-cell, close-cell) in a group of 77 asymptomatic patients with primary internal carotid stenosis and CEA restenosis. Totally, 1 patient experienced TIA and 1 patient major stroke. The combined rate of stroke, death, or myocardial infarction at 30 days was 1.3%. ³² In the CLEAR-ROAD study, no protection device was used in 42% of patients with acceptable perioperative and 30 days neurologic events. ⁵

Transcarotid stenting with flow reversal system (ENROUTE Transcarotid NPS,Silk Road Medical Inc, Sunnyvale, CA, USA) has emerged as an alternative treatment of carotid artery stenosis using blood flow reversal circuit, creating an arteriovenous shunt with an in-line filter with 200-μm pores captures any debris before the blood is returned to the venous system. The overall stroke rate was 1.4% demonstrating that the use of the ENROUTE Transcarotid NPS is safe and effective at preventing stroke during CAS. ³³ Double mesh technique and transcarotid artery revascularization provide similar rates of perioperative neurological events. However the appropriate treatment depends on the institutional experience, patient preference, operator availability and cost of the procedure. Our center has important experience in CAS, performing approximately 100 procedures annually in the past 15 years. We routinely use distal EPDs with open-cell and closed-cell stent. However, there were several occasions when the distal filter was empty after withdrawal, causing concern and raising doubts about its role in our daily practice. Protection devices are used to trap emboli from friable atherosclerotic lesions but sometimes they promote dissection, vasospasm and plaque emboli during manipulations.

Conclusion

Our study shows that CGuard stent with EPS is an effective and safe device for treatment of carotid artery stenosis with acceptable low perioperative and 30 days neurologic events, even with low EPD usage. However larger multicenter randomized trials are necessary to establish its superiority against other types of stent.