Update on Clinical Management with Neurovascular Stents

Endovascular stenting has continued to evolve given the new trials. Several new stents have recently been developed to address specific purposes. In this focused review, we discuss the concepts of neurointerventional stents and address the clinical implications. Furthermore, each type of stent is discussed with supporting evidence for clinical utility. In the final component, we argue for continued development and utilization.


Introduction
Endovascular stenting is a relatively new, but quickly evolving technique for the neurointerventionalist given the advent of multiple novel devices being introduced every year.
While the current indication of intracranial stenting primarily revolves around the management of intracranial aneurysms, there is ongoing research around the use of stenting for patients with intracranial atherosclerosis. On one end, the VISSIT and SAMPRIS trials demonstrated that aggressive medical management may be associated with better outcomes, suggesting that stenting not be appropriate for this indication [1,2]. There are other studies, however, that demonstrate superiority of stenting in symptomatic middle cerebral artery (MCA) stenosis as compared to aggressive medical therapy [3]. For the purposes of inclusivity, this review will address both the different stents available for the management of intracranial atherosclerosis, and also intracranial aneurysms.
The clinical utility of SAC (stent-assisted coiling) for aneurysms is more widespread -a 2016 survey of physicians performing surgical and/or endovascular treatments for intracranial aneurysms showed that over 40% prefer treating basilar apex aneurysms with SAC [4]. With the large variety of currently available devices, however, the clinical and This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. deployment in challenging anatomical vasculature. One thing that is unique about the Leo stent is a large metal surface area. This allows for an effect like flow-diversion (where blood flow is re-routed away from the aneurysm, allowing for obliteration of the aneurysm as well as restoration of normal anatomy through neo-intimal growth), and thus can provide a favorable adjunctive effect when managing intracranial aneurysms. The device has undergone revision, and a newer generation device (Leo+) is available for use. The device comes in a variety of lengths, extending as far as 75 mm, making it very versatile ( Table 1).
The LVIS device: The Low-profile Visualized Intraluminal Support (LVIS) device is a newer generation device that was FDA approved in 2014 for the indication of stent-assisted embolization to treat intracranial aneurysms. The device itself is a self-expanding stent made of nitinol, however it is created by the tight braiding of a single wire. It features a closed cell design, and thus has the benefit of a strong radial force, and good wall apposition. Into the mesh is woven tantalum wire, a novel radiopaque marker, which serves as the guide for allowing for intraluminal visualization during stent-assisted coiling. The device is available in a multitude of lengths, as well as stent diameters (Table 1) [6]. Like the Leo stent, the high surface coverage of the stent promotes a flow-diversion effect which aids to obliterate the aneurysm as an additive effect on top of coiling.

Solitaire AB (aneurysm bridging) device:
The Solitaire device is a uniquely designed tool that is used for stent-assisted coil embolization of intracranial aneurysms. It is a selfexpanding device that has the unique capability of allowing for complete deployment and retrieval by a single operator, until the device is detached. The device can be re-positioned even after 100% deployment up to two times. The device is then detached from its push wire using an electrolytic system with a separate device [13].

Flow diversion
Flow diverters are "ne-mesh stents that are placed at the neck of intracranial aneurysms in the parent vessel. Their function is to re-direct blood flow away from the aneurysm and back into the parent artery, thus, they reduce aneurysmal blood flow eventually obliterating the aneurysm. Over time, the parent vessel is reconstructed with neo-intimal growth promotion from the stent material, which aids in restoring normal anatomy [14].
Currently, there are four available flow diversion devices for use (although not all the devices are available in every country): the Surpass device, The Pipeline Embolization Device (PED), the Flow Redirection Endoluminal Device (FRED), and the Silk device. As with the nature of flow-diversion, each of these device's function in primarily the same method-they all act as stents that divert blood flow away from the aneurysm, eventually leading to obliteration of the aneurysm, and promotion of neo-intimal growth along the parent vessel. The devices vary in the method of deployment, and the overall design of the stent, which leads to flexibility for the operator given unique variable anatomy across many patients [14].
Silk flow divertor: The Silk device is currently not approved for use in the United States; however, this device deserves mention as it was the first ever flow-diversion device available for the management of intracranial aneurysms, gaining approval in Europe in 2008 for routine clinical use. It functions as a self-expandable stent with a closed cell design made of nitinol. The closed cell design lends itself to being re-deployment friendly-it can be re-sheathed at up to 90% deployment. The porosity of the device is roughly 45-60%, corresponding with a 30-35% arterial wall coverage, which is typical across all the flow-diversion devices [13].
Pipeline embolization device: In the United States, the Pipeline device is an FDA approved flow-diversion device available to use for the management of intracranial aneurysms. It was approved in the United States in 2011 when the Pipeline for Uncoilable and Failed Aneurysms trial (PUFS) demonstrated that flow-diversion with the Pipeline device was both safe (low risk of stroke or death) and effective (high rate of complete aneurysm obliteration without flow-limiting stenosis) in the management of large unruptured intracranial aneurysms that had failed prior endovascular treatment [15]. The device itself features a self-expanding deployment and is composed of a mixture of three-quarters chromium-cobalt, and one-quarter platinum tungsten alloy. As with other flow-diverters, it covers approximately 30-35% of the arterial wall surface, with a porosity of about 65-75% [15]. There is a newer generation of the PED, which is called the Pipeline Flex Embolization Device or PED Flex and was approved by the FDA in 2015. This device has the added benefit of being resheathable [16].

Surpass:
The Surpass flow diverter device has recently been FDA approved for the management of intracranial aneurysms following the results of the Surpass Intracranial Aneurysm Embolization System Pivotal Trial to Treat Large or Giant Wide Neck Aneurysms (SCENT) trial, which demonstrated that the device was both safe and effective when deployed for wide-necked, large fusiform, saccular, and blister aneurysms in the supraclinoid and distal ICA segments [17]. The device itself features a self-expanding design with a braided stent. The porosity of the device is 70% with arterial surface coverage of roughly 30%. A key benefit of the Surpass device is the ability to recapture, re-sheath, and reposition the device while maintaining the position of the distal wire [18].
Flow-redirection endoluminal device (FRED): FRED obtained CE Mark approval in Europe in 2013 and was recently afforded FDA premarket approval in 2020 for the management of intracranial aneurysms. It is currently indicated for use in wide-necked saccular/fusiform aneurysms that arise from parent vessels with diameter between 2 and 5 mm. The device is composed of a self-expanding mechanism made of braided nitinol but is unique for what is known as a "stent-within-a-stent" design. That is, there is an outer high-porosity layer of 16 nitinol wires, as well as an inner lower-porosity layer of 48 nitinol wires. The inner and outer layers of the device are merged by a double helix of tantalum, which allow for visibility of both layers under fluoroscopic visualization. Overall, the device offers a surface coverage of 30%, which is on par with other devices, however it also has the greatest variability in length compared to the other 3 flow-diversion devices ( Table 2) [19].

Clinical Utility of SAC for Intracranial Aneurysms
The utility of stents in the treatment of intracranial aneurysms has undergone considerable evolution since the ISAT trials gave way to the recommendations of endovascular coiling as first-line management [11,20]. However, coiling alone is not suitable for many complex aneurysms. In particular, treatment of wide-neck bifurcating aneurysms have been historically challenging with traditional endovascular coiling due to coil instability and risk of protrusion and migration [21]. Due to limitations, a number of assistive and novel endovascular methods have been developed [11]. Stent-assisted coiling (SAC) is an adjunctive method to coiling which has proven efficacious in treating aneurysms of both complex morphology and location [22]. The use of stents for intracranial aneurysm trapping can generally be divided into two main categories -SAC and stent monotherapy, also known as flow diversion [11]. Although flow diversion is advantageous in many regards -such as in its ability to treat wide-neck side wall aneurysms -its use in bifurcating aneurysms remains controversial due to risk for inadequate neck occlusion [23]. Further, the recent introduction of the Woven EndoBridge (WEB) device has indeed proven effective in treating wide-neck bifurcating aneurysms, however, falls short in its ability to treat aneurysms with extremely unfavorable neck sizes (<4mm) and dome-to-neck ratios (<1) [24]. In this regard, SAC techniques have proven quite effective in treating aneurysms of such complex anatomical morphologies and locations that are not amenable to coiling, flow diversion or WEB alone [22]. Specifically, SAC is an attractive technique for the treatment of wide-neck bifurcating aneurysms, such as those seen in the middle cerebral artery and basilar apex [23,25,26].
Stent jailing is one form of SAC that is considered especially suitable for wide-necked aneurysms [27]. In stent jailing, a coil delivery microcatheter is fed into the aneurysm followed by a second catheter which deploys a stent across the aneurysm neck [27]. At this point, the microcatheter is nudged securely between the stent and vascular wall. Coils are then deployed while the stent creates a barrier to prevent coil herniation. The microcatheter is then retrieved leaving the coils and stent in place. Stent jailing provides an advantage of imparting greater microcatheter stability within complex aneurysms into which insertion may otherwise be difficult [28]. In addition, Y-stenting is another form of SAC suitable for bifurcating aneurysms and can be used in conjunction with stent jailing methods [25,26]. Y-stenting involves the use of two stents and is associated with very good long-term stability in the treatment of complex bifurcating aneurysms [25,26]. Further, when a bifurcating aneurysm neck incorporates more than one daughter vessel, Y-stenting can more reliably protect daughter vessels from coil embolization as compared to single-stent techniques [25].
Following stent-assisted coiling, it is essential to obtain follow up imaging at multiple intervals [29]. Immediately, angiograms are indicated to evaluate for aneurysm occlusion and obliteration and is recommended by the AHA following treatment of all aneurysms [20]. Early and delayed follow-up is also essential to assess for risk of recanalization and future hemorrhage, as well as for in-stent stenosis [29,30]. Although no established guidelines currently exist for such follow-up, it is generally recommended to obtain early follow up around 3 to 6 months and long term follow up at 12 to 24 months, as well as at 3 to 5 years [29]. Follow-up during the first two years is especially critical as most recurrences reveal during this time [31]. Digital subtraction angiography is considered the gold-standard imaging method due to high sensitivity for recurrent flow detection and lack of device-related imaging artifact [29]. However, magnetic resonance angiography is a less invasive and suitable alternative that, despite lower sensitivity for recurrent flow, can still effectively detect aneurysm recurrence, as well as in-stent stenosis [29,[32][33][34].
Overall, SAC is associated with favorable angiographic outcomes, including both occlusion and recanalization rates [35]. However, occlusion rates do appear to vary across studies when looking at difficult to treat aneurysms [24]. In a meta-analysis of SAC-treated unruptured intracranial aneurysms with wide necks, periprocedural and postprocedural occlusion rates were 50.2% and 68.83%, respectively [36]. However, in the ATLAS IDE trials, wide-neck intracranial aneurysm of the anterior circulation treated with a laser-cut stent, achieved complete and adequate occlusion of 88.2% and 96.1%, respectively, at 12 months follow up [37]. In another study evaluating the use of a braided stent, complete and near complete occlusion at 12 months were 70.6% and 92.1%, respectively [38]. Although it is difficult to compare efficacy between various endovascular approaches due to high study heterogeneity -including variations in aneurysm complexity -slightly reduced, yet comparable, postprocedural occlusion rates are seen in SAC when compared to metaanalyses of alternative endovascular techniques [23,[39][40][41] (Table 3). Finally, recanalization rates appear to be relatively low in SAC-treated aneurysms. Recanalization can be used as a surrogate marker for aneurysm rupture risk [11]. In meta-analyses of unruptured aneurysms, the recanalization rate of SAC-treated aneurysms was 7.07% as compared to 24.4% in coiling alone [36,42].
Despite favorable angiographic outcomes, SAC is associated with non-negligible risk for post-intervention mortality and neurologic-related complications, including thromboembolism, in-stent stenosis and intra-/postoperative aneurysm rupture [36,43,44]. Perioperative thrombosis is reported to be the most common complication and is especially concerning, as the risk of aggressive treatment and postoperative hemorrhage must be carefully balanced [44,45]. In a meta-analysis comparing SAC versus coiling alone in the treatment of ruptured intracranial aneurysms, a higher overall perioperative complication rate was found in the SAC group, although no significant difference in mortality at discharge [46].
It is important to note that the use of SAC in ruptured aneurysms is known to be associated with a greater risk of complications -often attributed to the use of dual antiplatelet therapyand, according to several authors, should generally be avoided in such populations [47][48][49][50]. In this context, a recent meta-analysis investigating morbidity and mortality in SAC-treated unruptured intracranial aneurysm with wide necks, demonstrated an estimated pooled rate of mortality and overall neurologic complications to be 0.02% and 4.33%, respectively [36]. This is compared to 1.2% and 4.8% for coiling alone and 1.7% and 6.7% for clipping alone in the treatment of unruptured intracranial aneurysms [42,51]. Thus, it is possible that overall morbidity and mortality may achieve more favorable rates when utilized in appropriate settings (Table 3).

Clinical Utility of SAC for Intracranial Atherosclerosis
Stenting for intracranial arteriosclerosis was previously abandoned largely due to a high risk of in-stent thrombosis. However, it is important to note that a select few types of stents were utilized in the studies that have noted these poor outcomes, particularly early self-expanding and balloon expandable stents [7,52]. One study that highlighted the negative outcomes using these types of stents was the Vitesse Intracranial Stent Study for Ischemic Stroke Therapy (VISSIT) randomized controlled trial (RCT) in 2015, which compared patients with symptomatic intracranial stenosis who received balloon-expandable stent plus medical therapy vs. medical therapy alone. This study was terminated early due to increased stroke or transient ischemic attack (TIA) rates in patients that received a balloon-expandable stent at both 1-year post-intervention and 30-day post-intervention, in the same vascular territory or in any vascular territory, respectively [1]. Similarly, the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial in 2016 demonstrated negative results using the Wingspan stent, a metal-based, self-expanding stent [53,54]. In this RCT, a total of 451 patients who recently experienced a stroke or TIA accompanied by a 70-99% stenosis of a major intracranial artery was randomized into receiving medical management only or medical management plus stenting. Results indicated that patients who received stenting with this self-expanding stent had higher rates of subsequent stroke or death (p=0.0252), as well as increased rates of intracranial hemorrhage (p=0.0009), compared to those who received medical management only [54]. Thus, the poor outcomes associated with these types of stents subsequently necessitated exploration into the possibility of using other types of stents in order to improve clinical outcomes. The primary type of stent being studied in this manner are drug-eluting stents.
Success in decreasing restenosis rates in coronary arteries using drug-eluting stents was initially proposed decades ago and has now been purported as superior to many of their previous counterparts, such as bare-metal stents [55][56][57]. The initial proposal of using drugeluting stents in both the intracranial and extracranial circulation began over a decade ago, after some success had been demonstrated with their use in the coronary arteries [58][59][60]61]. In 2010, Ogilvy et al. demonstrated decreased occurrence of vertebral artery restenosis in 2/12 (17%) patients who received drug-eluting stents compared to 9/24 (38%) patients who received non-drug-eluting stents. Further, 7 out of the 9 restenotic patients who received non-drug-eluting stents required angioplasty, whereas neither of the 2 restenotic patients who received drug-eluting stents required angioplasty [62]. Although lacking statistical significance between these outcomes, these results set an important precedent for future studies to build upon. A similar, larger study in 2020 examining vertebral artery ostium stenting outcomes demonstrated a statistically significant reduction in restenosis rates in patients who received drug-eluting stents compared to patients who received bare metal stents (p=0.021) [63]. This success with drug-eluting stents has since been demonstrated in intracranial arteriosclerotic lesions. In 2020, Kim et al. demonstrated successful drug-eluting stent placement in 12 patients with intracranial arteriosclerotic stenosis, none of which experienced restenosis in a follow-up period of approximately 43 months [64]. A 2019 meta-analysis examined restenosis rates in 336 intracranial arteriosclerotic stenosis patients who received drug-eluting stents, reporting a restenosis rate of only 4.1% [65]. Authors further reported that this evidence suggests both relative safety and efficacy when compared to the non-drug-eluting stents used in the SAMMPRIS and VISSIT trials [54,54,65]. Most recently, a RCT published in 2022 randomized 263 patients with intracranial arteriosclerotic stenosis into one group who received a drug-eluting stent and another group who received a bare-metal stent. Results at one-year post-intervention demonstrated significantly reduced restenosis rates in patients who received drug-eluting stents compared to those who received bare-metal stents (p<0.001) [66]. Results also showed reduced rates of ischemic stroke recurrence between one month and one year post-intervention in patients who received drug-eluting stents (p<0.03) [66]. In all, these results show great potential for the efficacy of drug-eluting stents, especially when compared with the relatively poor overall outcomes seen with the advent of several types of early non-drug-eluting stents. However, further evaluation using additional, larger-scale trials are needed in order to increase the confidence in these results and validate a clear recommendation for the use of drug-eluting stents over non-drug-eluting stents for this patient population.
Although the drug-eluting stent is currently demonstrating the most promise as a new treatment option for intracranial arteriosclerotic stenosis, it is important to note that investigation into the modification of other, previously used stents is still ongoing. The use of several different models of the Neuroform stent, traditionally used for aneurysm stenting, has recently started to be investigated as a treatment option for intracranial arteriosclerosis. A recent study including 45 medically refractory intracranial arteriosclerosis patients underwent re-stenting with the Neuroform EZ stent model with a technical success rate of 100% and no incidence of restenosis at the average follow-up of 7.3 months [67]. A similar recent study using 71 intracranial arteriosclerosis patients also yielded a 100% technical success rate, with an incidence of restenosis of 16.9% [68]. The Neuroform Atlas model is also being evaluated, with demonstration of some early success in intracranial stenting for arteriosclerotic lesions [69]. In addition, new techniques aimed at reducing morbidity are also being explored, such as deployment of the Neuroform Atlas stent using a balloon microcatheter [70]. However, investigation is still in the early stages for the Neuroform models in either regard or further investigation, particularly using RCTs, is warranted.
Regardless of stent placement, a standard antiplatelet regimen needs to be employed in these patients. Dual antiplatelet therapy in the early symptomatic stages of intracranial arteriosclerosis has generally been recommended, based on the relatively elevated recurrent stroke risk associated with early aspirin monotherapy in these patients [71]. Several different options for dual antiplatelet therapy have been suggested over the years. A 2015 RCT showed that aspirin plus cilostazol was superior to aspirin monotherapy in slowing progression of symptomatic intracranial arterial stenosis [72]. Another study showed no significant difference in the efficacy of aspirin plus cilostazol and aspirin plus clopidogrel in slowing progression of intracranial atherosclerotic stenosis [73]. However, aspirin plus clopidogrel as dual antiplatelet therapy specifically has historically been primarily recommended, largely based on results from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial which demonstrated significant risk reduction of stroke in minor stroke or TIA patients who received clopidogrel and aspirin together compared to those who received aspirin monotherapy (p=0.006) [74].
Thus, as it currently stands, in patients who have sustained either a TIA or stroke attributed to intracranial atherosclerosis of 70-99%, dual antiplatelet therapy with aspirin plus clopidogrel is recommended for up to 90 days, followed by long-term aspirin monotherapy. Recommendations for dual antiplatelet therapy using aspirin plus cilostazol or aspirin plus ticagrelor are not yet made, mainly due to limited generalizability and lack of comparative data.
Although evidence is currently not sufficient to recommend as a first-line treatment option, the drug-eluting stent appears to show much promise in the way of significantly improving clinical outcomes in patients with intracranial arteriosclerosis, particularly when compared to outcomes with previously used non-drug-eluting stents. Further investigation into their utility is warranted. More recently developed non-drug-eluting stent models, along with the addition of innovative new methods of delivery, are also being evaluated in this context. Regardless of stent outcomes, recommendations for antiplatelet therapy must be upheld.

Conclusions
Stent technology has continued to evolve at a rapid pace in the neuroendovascular space. Several new types of stents such as flow diverters have recently emerged. Given the rapid developments, the need for a consolidated and user-friendly guide is indicated. This review offers a snapshot of current situation with emphasis on continued development.