Treatment of Intracranial Aneurysms with Self-Expandable Braided Stents: A Systematic Review and Meta-Analysis

BACKGROUND: The safety and efficacy of treatment with self-expandable braided stents (LEO and LVIS) required further investigation. PURPOSE: Our aim was to analyze the outcomes after treatment with braided stents. DATA SOURCES: A systematic search of 3 databases was performed for studies published from 2006 to 2017. STUDY SELECTION: According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we included studies reporting patients treated with LEO or LVIS stents. DATA ANALYSIS: Random-effects meta-analysis was used to pool the following: aneurysm occlusion rate, complications, and neurologic outcomes. DATA SYNTHESIS: Thirty-five studies evaluating 1426 patients treated with braided stents were included in this meta-analysis. Successful stent delivery and complete aneurysm occlusion were 97% (1041/1095; 95% CI, 95%–98%) (I2 = 44%) and 88.3% (1097/1256; 95% CI, 85%–91%) (I2 = 72%), respectively. Overall, treatment-related complications were 7.4% (107/1317; 95% CI, 5%–9%) (I2 = 44%). Ischemic/thromboembolic events (48/1324 = 2.4%; 95% CI, 1.5%–3.4%) (I2 = 27%) and in-stent thrombosis (35/1324 = 1.5%; 95% CI, 0.6%–1.7%) (I2 = 0%) were the most common complications. Treatment-related morbidity was 1.5% (30/1324; 95% CI, 0.9%–2%) and was comparable between the LEO and LVIS groups. Complication rates between the anterior (29/322 = 8.8%; 95% CI, 3.4%–12%) (I2 = 41%) versus posterior circulation (10/84 = 10.5%; 95% CI, 4%–16%) (I2 = 0%) and distal (30/303 = 8%; 95% CI, 4.5%–12%) (I2 = 48%) versus proximal aneurysms (14/153 = 9%; 95% CI, 3%–13%) (I2 = 46%) were comparable (P > .05). LIMITATIONS: Limitations were selection and publication biases. CONCLUSIONS: In this analysis, treatment with the LEO and LVIS stents was relatively safe and effective. The most common complications were periprocedural thromboembolisms and in-stent thrombosis. The rate of complications was comparable among anterior and posterior circulation aneurysms, as well as for proximal and distally located lesions.

T he development of self-expandable stents has progressively changed the treatment strategy for most intracranial aneurysms, creating a mechanical scaffold that prevents coil protrusion and promoting neoendothelization of the neck. 1 Several selfexpandable stents were introduced in the past years, 2,3 including laser-cut open-cell stents (such as the Neuroform; Stryker Neurovascular, Kalamazoo, Michigan) and laser-cut closed-cell stents (such as the Enterprise; Codman & Shurtleff, Raynham, Massachusetts). 2 The third generation of self-expandable closed stents was produced by braiding individual strands of nitinol onto a mandrel (LVIS, MicroVention, Tustin, California; and LEO, Balt Extrusion, Montmorency, France). 4,5 In addition to providing mechanical support, the braided morphology gives a relatively higher pore density than the laser-cut stents, theoretically improving the flow-diverting hemodynamic effect of these devic-es. [6][7][8] Recently, the low-profile design of the braided stents (LEO Baby and LVIS Jr) allowed delivery through a 0.0165-inch microcatheter and navigation in small vessels, with the possibility of treating distally located aneurysms. 9,10 Improved understanding of treatment-related outcomes of braided stents can help practitioners in the selection of lesions amenable to being effectively treated with these devices. Our meta-analysis examined occlusion rates and procedure-related complications after treatment with braided stents, focusing on the influence of aneurysm features, location, and treatment characteristics on the studied outcomes.

Literature Search
A comprehensive literature search of PubMed, Ovid MEDLINE, and Ovid EMBASE was conducted for studies published from January 2006 to February 2018. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 11 were followed. The key words and the detailed search strategy are reported in On-line Table 1. The inclusion criteria were the following: studies reporting series of intracranial aneurysms treated with LEO and LVIS stents. Exclusion criteria were the following: 1) review articles, 2) studies published in languages other than English, 3) in vitro studies, and 4) animal studies. In cases of overlapping patient populations, only the series with the largest number of patients or the most detailed data was included. Two independent readers screened articles in their entirety to determine eligibility for inclusion. A third author solved discrepancies.

Data Collection
From each study, we extracted the following: 1) treatment-related complications, 2) occlusion rate, and 3) clinical outcome. Occlusion and complication rates were analyzed on the basis of the influence of the following parameters: 1) unruptured-versusacutely ruptured aneurysms, 2) distal-versus-proximal location, 3) anterior-versus-posterior circulation, 4) first treatment versus retreatment, 5) stent alone versus stent-assisted coiling (SAC), and 6) single-versus-multiple stents. A subgroup analysis was performed for aneurysms treated with small low-profile braided stents (LEO Baby and LVIS Jr). Distal location was considered for lesions arising distal to the circle of Willis or located in small vessels: A2-3 segments, middle cerebral artery, posterior cerebral artery, posterior inferior cerebellar artery, anterior inferior cerebellar artery, and superior cerebellar artery. The occlusion rate was defined on the basis of the Raymond-Roy classification. Accordingly, we used the following terms: complete occlusion (class I), residual neck or near complete occlusion (class II), and incomplete occlusion or residual aneurysm (class III). 12 Treatment-related complications were divided into 2 groups: periprocedural/early events (within 30 days after treatment) and delayed events (after 30 days). Finally, good outcome was defined as a modified Rankin Scale score of 0 -2 or a Glasgow Outcome Score of 4 -5, or it was assumed if the study used terms such as "no morbidity," "good recovery," or "no symptoms."

Outcomes
The primary objectives of this meta-analysis were to define the safety (treatment-related complications, neurologic outcomes, mortality rate) and the efficacy (aneurysm occlusion rate) of the treatment of intracranial aneurysms with self-expanding braided stents (LEO and LVIS). The secondary objectives were to define the influence of aneurysm location, aneurysm characteristics, and factors related to the treatment on the analyzed outcomes.

Quality Scoring
A modified version of the Newcastle-Ottawa Scale 13 was used for quality assessment of the included studies. The details are reported in On-line Tables 2 and 3. The quality assessment was performed by 2 authors independently, and a third author solved discrepancies.

Statistical Analysis
We estimated, from each cohort, the cumulative prevalence (percentage) and 95% confidence interval for each outcome. Percentages were calculated with a random-effects meta-analysis. Heterogeneity across studies was evaluated using the I 2 statistic: An I 2 value of Ͼ50% suggests substantial heterogeneity. To compare the percentages and to calculate the P values, we used the Z-test for 2 proportions. Meta-regression was not used in this study. Statistical analysis was performed using OpenMeta[Analyst] (http://www.cebm. brown.edu/openmeta/).

Literature Review
Studies included in our meta-analysis are summarized in On-line Table 4. The search flow diagram is shown in the On-line Figure. A total of 35 studies and 1426 patients with 1518 intracranial aneurysms treated with LEO or LVIS stents were included in our review.

Quality of Studies
Overall, 14 studies (40%) were rated "high quality" (On-line Tables 2 and 3). Three articles were prospective multicentric series, 5 studies were obtained from a prospectively maintained data base, 3 studies were retrospective multicentric, and 24 articles were single-center retrospective.

Study Heterogeneity
Analysis of the angiographic outcomes and treatment-related complications showed high heterogeneity in 10% of the reported results (4 of 39 studied outcomes) (On-line Table 6). The analysis of the factors related to complications and occlusion (On-line Table 5) showed high heterogeneity in 18% of the studied events (4 of 22 reported outcomes). The rate of high heterogeneity among complications and angiographic outcomes after LEO Baby and LVIS Jr (On-line Table 7) was 9% (3 of 33 reported results).

DISCUSSION
With the advent of the SAC technique, most complex, wide-neck intracranial aneurysms can be efficiently treated endovascularly. 14 Compared with other intracranial stents that are laser-cut from nitinol hypotubes, LEO and LVIS stents are braided from a single nitinol wire with a closed-cell design. 6,8 Because of the increased use of these devices, understanding the safety and efficacy of treatment with braided stents is important in the management of lesions amenable to SAC treatment.

Angiographic Outcomes
In combining aneurysmal occlusion rates from 35 series, our analysis provides more representative data on angiographic outcomes than any single study. We demonstrated high rates of complete/ near-complete occlusion for both LEO (88.6%; 95%, CI 83%-93%) and LVIS devices (87.8%; 95% CI, 83%-92%). Meta-analysis of aneurysms treated with SAC using different devices showed 61% long-term occlusion. 15 The high rates of occlusion after treatment with braided stents can be related to the smaller cell size, higher metal coverage and flow-diversion effect than other conventional self-expandable stents. 6,8,16 Computational fluid dynamics studies showed that LVIS stents allowed more flow reduction than laser-cut devices, and double LVIS stents resulted in a better flow-diverting effect than the Pipeline Embolization Device (PED; Covidien, Irvine, California). 8 Aydin et al, 16 investigating the flow-diversion effect of low-profile braided stents used as stent monotherapy, reported 75% complete occlusion during follow-up. In the subgroup of aneurysms treated with double stents, the authors showed a slightly higher rate of complete occlusion (82%). In our study, braided stents used as stent monotherapy allowed a 63% (95% CI, 40%-90%) complete occlusion rate, which was significantly lower compared with the treatment with stent plus coiling (90%; 95% CI, 86%-93%) (P ϭ .0001). Most interesting, lesions treated with SAC with single or multiple stents had comparable rates of occlusion, showing that in most cases, a single stent is enough to achieve complete aneurysm occlusion, avoiding the ischemic complications related to the higher metal density in the vessel.
Knowledge of the safety of braided stents in relation to the location and characteristics of the aneurysms has important therapeutic implications. Most interesting, we found comparable rates of complications between proximal (ICA and circle of Willis) and distal aneurysms beyond the circle of Willis or in small vessels. The rate of complications for distal aneurysms treated with flow-diverter stents ranges between 15% and 20%. 20 16 reported a high occlusion rate and a low incidence (5%) of complications after flow-diversion treatment of aneurysms at or distal to the circle of Willis, with low-profile braided stents used as stent monotherapy.

Strength and Limitations
Our study has limitations. Most series are retrospective studies and single-institution experiences. Details of the antiplatelet therapy were infrequently specified. The smaller number of cases in some subgroup analyses may not provide sufficient power to demonstrate a statistically significant difference among the studied outcomes. However, although retrospective data are low in quality, our meta-analysis is the best available evidence to guide the treatment management of aneurysms with braided stents.

CONCLUSIONS
In our study, treatment with the LEO and LVIS stents was relatively safe and effective. Most of the complications were related to periprocedural thromboembolic events and in-stent thrombosis. We found comparable rates of treatment-related complications among anterior-versus-posterior circulation aneurysms and for proximal-versus-distally located lesions. These findings can guide practitioners in the treatment, management, and selection of aneurysms amenable to treatment with braided stents.