Flow-Diversion Treatment of Unruptured Saccular Anterior Communicating Artery Aneurysms: A Systematic Review and Meta-Analysis

BACKGROUND: Flow diversion for anterior communicating artery aneurysms required further investigation. PURPOSE: Our aim was to analyze outcomes after treatment of anterior communicating artery aneurysms with flow-diverter stents. DATA SOURCES: A systematic search of 3 data bases was performed for studies published from 2008 to 2018. STUDY SELECTION: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we included studies reporting anterior communicating artery aneurysms treated with flow diversion. DATA ANALYSIS: Random-effects meta-analysis was used to pool the following: aneurysm occlusion rate, complications, and factors influencing the studied outcomes. DATA SYNTHESIS: We included 14 studies and 148 unruptured saccular anterior communicating artery aneurysms treated with flow diversion. The long-term complete/near-complete (O'Kelly-Marotta C–D) occlusion rate was 87.4% (91/105; 95% CI, 81.3%–93.6%; I2 = 0%) (mean radiologic follow-up of 11 months). The treatment-related complication rate was 8.6% (14/126; 95% CI, 4%–13.1%; I2 = 0%), with morbidity and mortality rates of 3.5% (5/126; 95% CI, 2%–7%; I2 = 0%) and 2.5% (2/148; 95% CI, 0.3%–5%; I2 = 0%), respectively. Most complications were periprocedural (12/126 = 7%; 95% CI, 3%–11%; I2 = 0%). Thromboembolic events were slightly higher compared with hemorrhagic complications (10/126 = 6%; 95% CI, 2%–10%; I2 = 0% and 4/126 = 3%; 95% CI, 1%–6%; I2 = 0%). Branching arteries (A2 or the recurrent artery of Heubner) covered by the stent were occluded in 16% (7/34; 95% CI, 3.5%–28%; I2 = 25%) of cases. Pre- and posttreatment low-dose and high-dose of antiplatelet therapy was not associated with significantly different complication and occlusion rates. LIMITATIONS: We reviewed small and retrospective series. CONCLUSIONS: Flow diversion for unruptured saccular anterior communicating artery aneurysms appears to be an effective alternative treatment for lesions difficult to treat with coiling or microsurgical clipping. The treatment-related complication rate was relatively low. However, larger studies are needed to confirm these results.

A nterior communicating artery (AcomA) aneurysms are among the most common intracranial aneurysms.Determining the best treatment strategy for such lesions is often diffi-cult because AcomA aneurysms may present a therapeutic challenge for both clipping (deep location, anatomic variability, perforator arteries) 1 and endovascular treatment (wide-neck lesions incorporating branching vessels). 2In addition, AcomA aneurysms may have a risk of rupture higher than those in other locations. 3On the basis of their ability to reconstruct the parent artery, the off-label uses of flow-diverter stents are constantly extended, especially for aneurysms with unfavorable anatomy. 2,4,5low-diversion treatment of complex AcomA aneurysms has been recently reported as an alternative strategy when conventional coiling or stent-assisted coiling is not a feasible option.However, data describing treatment-related outcomes of flow diversion for lesions located at the AcomA region are scanty, and the efficacy and safety of this technique remain unclear.Our metaanalysis examined occlusion rates and procedure-related complications of saccular unruptured AcomA aneurysms treated with flow-diverter stents.

Literature Search
A comprehensive literature search of PubMed, Ovid MEDLINE, and Ovid EMBASE was conducted for studies published from January 2008 to September 2018.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 6 were followed.The key words and the detailed search strategy are reported in On-line Table 1, and the studies included in our review are reported in On-line Table 2.The inclusion criterion was the following: studies reporting series with patients with unruptured AcomA aneurysms treated with flow-diverter stents.Exclusion criteria were the following: 1) case reports, 2) review articles, 3) studies published in languages other than English, 4) in vitro/ animal studies, and 5) series reporting aneurysms located at the A1 or distal to the AcomA region (A2, A3).In cases of overlapping patient populations, only the series with the largest number of patients or most detailed data were included.Two independent readers screened articles in their entirety to determine eligibility for inclusion.A third author solved discrepancies.

Data Collection
We extracted the following information: 1) technical success rate, 2) occlusion rate, 3) treatment-related complications, and 4) clinical outcome.Occlusion and complication rates were analyzed on the basis of the influence of the following: 1) aneurysm size (saccular aneurysms, small-and medium-sized versus large-giant); 2) patient age (younger versus older than 60 years; 3) type of flowdiverter stents; 4) first treatment versus retreatment; and 5) flow diverter alone versus flow diverter plus coiling.
Complete/near-complete aneurysm occlusion was defined on the basis of the following: O'Kelly-Marotta (OKM) grade 7 C-D, when digital subtraction angiography follow-up was available or when "complete occlusion" and "neck remnant" were used in the study.Treatment-related complications were divided into the following: 1) periprocedural/early events (within 30 days) and delayed events (after 30 days); 2) transient (asymptomatic events or complete neurologic recovery) and permanent complications (symptomatic events with permanent deficits); and 3) ischemic and hemorrhagic complications.The angiographic outcome of covered arteries (A2 or the recurrent artery of Heubner) was evaluated as the following: 1) arterial narrowing, or 2) arterial occlusion.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 the terms "no morbidity," "good recovery," or "no symptoms."

Outcomes
The primary objectives of this study were to define the safety (treatment-related complications, mortality rate, and neurologic outcomes) and the efficacy (technical success rate, angiographic occlusion) of AcomA aneurysms treated with flow diversion.The secondary objectives were to define the influence of aneurysm, patient, and treatment characteristics on the analyzed outcomes.

Quality Scoring
The Newcastle-Ottawa Scale 8 was used for the quality assessment of the included studies (details in On-line Tables 3 and 4).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.Heterogeneity of the data was assessed by the Higgins index (I 2 ), and subsequently, the DerSimonian and Laird random-effects model was applied.The graphic representation was performed with a forest plot.The meta-regression and funnel plot followed by the Egger linear regression test were analyzed, respectively, to evaluate the heterogeneity and bias.To compare the percentages and to calculate the P values, we used a Z-test for 2 proportions.Differences were considered significant at P Ͻ .05.Meta-analysis was performed with ProMeta-2 (Internovi, Cesena, Italy) and Open-Meta[Analyst] (http://www.cebm.brown.edu/openmeta/).

Literature Review
Studies included in our meta-analysis are summarized in On-line Table 2.The search flow diagram is shown in On-line Fig 1.
Fourteen studies and 148 AcomA aneurysms treated with flow-diverter stents were included in our review.

Quality of Studies
Studies included in our review were the following: Eleven studies were retrospective single-center series, whereas 3 studies were prospective multicentric series.The latter studies were rated as "high-quality" studies.Details of the rating of the included studies are reported in On-line Tables 3 and 4.
The overall rate of flow modifications of vessels covered by flow diverters (A2 or artery of Heubner) was 28% (12/34; 95% CI, 1.5%-5%;I 2 ϭ 76%).The rate of occlusion of covered arteries during follow-up was 16% (7/34; 95% CI, 3.5%-28%; I 2 ϭ 22%), whereas the rate of arterial narrowing was 11% (5/34; 95% CI, 0.7%-20%; I 2 ϭ 8%).Symptoms related to flow changes on the covered A2 or the recurrent artery of Heubner were reported in 3 cases: 1 case of transitory hemiparesis due to slow flow on the covered A2 immediately after stent deployment, 1 case of transient facial palsy due to the coverage of the artery of Heubner, and 1 case of an asymptomatic ischemic lesion on the territory of the artery of Heubner that was detected with the MR imaging 4 months after treatment.

Factors Related to Aneurysm Occlusion
Overall, the occlusion rate was comparable among patients younger-versus-older than 60 years (P ϭ .7),type of flow-diverter stent, flow diversion as a first treatment or retreatment of recana- a Symptoms related to flow changes on the covered vessels (A2 or the recurrent artery of Heubner) were reported in 3 cases:1 case of transitory hemiparesis due slow flow on the covered A2; 1 case of transient facial palsy due to the coverage of the artery of Heubner; and 1 case of asymptomatic stroke in the territory of the artery of Heubner 4 months after treatment.

Study Heterogeneity
Heterogeneity was low for all except 1 of the analyzed outcomes (the overall rate of flow changes among covered vessels).

DISCUSSION
When we combined data from 14 studies, our meta-analysis underlined several important findings related to the flow-diversion treatment of aneurysms originating from the AcomA region.In general, our results demonstrated that complex unruptured AcomA aneurysms can be successfully treated with flow-diverter stents with a high rate of long-term angiographic occlusion and an acceptable rate of treatment-related complications.

Angiographic Outcomes
Successful stent deployment was achieved in 95.5% of cases, demonstrating that flow diversion is a straightforward technique even in complex anatomic situations such as the AcomA region.Given that aneurysm occlusion with flow-diverter stents is a progressive process, only 14% of aneurysms were occluded immediately after treatment, whereas 87% and 85% of the lesions presented with adequate (OKM C-D) and complete (OKM D) occlusion during 1 year of follow-up, respectively.In a large meta-analysis of nearly 1500 AcomA aneurysms treated endovascularly (excluding flowdiverter stents), Fang et al 9 reported a quite high rate of immediate occlusion (88%).However, although their immediate occlusion rate was higher compared with our results, complete/ near-complete occlusion during 6 months of follow-up was 85%, underlining that long-term angiographic outcomes after flow diversion for AcomA aneurysms are comparable with other endovascular techniques.
Recently, intrasaccular flow disruption with the Woven Endo-Bridge device (WEB; Sequent Medical, Aliso Viejo, California) is increasingly used with promising results.However, series focusing on AcomA aneurysms showed approximately a 60% longterm adequate occlusion after treatment with the WEB. 10 In addition, emerging devices for neck protection, such as pCONus (phenox, Bochum, Germany) stents, have been developed to treat wide-neck bifurcation aneurysms.A recent series of 36 AcomA aneurysms treated with the pCONus showed an 80% complete/ near-complete occlusion rate. 11Finally, Y-stent-assisted coiling of AcomA aneurysms appears to be associated with 85%-88% 12,13 complete/near-complete occlusion, though this technique is, in general, technically more complex.Accordingly, Ko et al 12 reported 9 AcomA aneurysms treated with Y-stent placement.All of them were occluded during follow-up, but 2 patients experienced acute in-stent thrombosis and 1 patient had iatrogenic subarachnoid hemorrhage related to aneurysm perforation.
In our study, flow diversion was also effective for the treatment of recanalized AcomA aneurysms (On-line Table 6).Lin et al 14 reported a small series of 6 AcomA aneurysms with recurrences after clipping; occlusion was achieved in 5 of them without treatment-related complications.This outcome is in accordance with those in larger series analyzing treatment-related outcomes of flow diversion used as a retreatment strategy. 15In addition, we found comparable angiographic results among AcomA aneurysms treated with flow diverters alone or in conjunction with coiling.When we investigated the literature, this result appears contradictory: Szikora et al, 16 in a series of 19 wide-neck aneurysms, reported no differences in occlusion rates among lesions treated with or without coil packing, whereas Lin et al 17 showed higher rates of complete occlusion in the group of aneurysms treated with the PED ϩ coils.However, most aneurysms included in our review were unruptured, small lesions (mean size, 6 mm), and additional coiling was not mandatory in most cases.
The device configuration was rarely reported in the included series, and outcome comparison between ipsilateral A1-A2 and ipsilateral A1 to contralateral A2 stent configuration was not possible.In the largest available series of AcomA aneurysms treated with flowdiverter stents, Colby et al 2 described 41 patients treated with PEDs deployed from the ipsilateral A1 to the ipsilateral A2 in 94% of patients and from the A1 to the contralateral A2 in the remaining 6% of patients.The authors reported 85% complete/near-complete occlusion and a 9% complication rate.

Treatment-Related Complications
Treatment-related morbidity after flow diversion in small or distal vessels is reported to be close to 10%. 4,5,18However, flow diversion for aneurysms arising from the AcomA complex should be considered separately due to the angioarchitecture and flow dynamics of this region that present the following: 1) frequent anatomic variations (such as the asymmetry of the A1 segments); 2) several perforating arteries supplying important structures such as the optic chiasm, the anterior hypothalamus, and the anterior perforated substance; and 3) the recurrent artery of Heubner (in general originating from the A1-A2 junction), which perfuses the striatum and the anterior limb of the internal capsule. 1 Accordingly, injury to these arteries may result in a wide range of serious neurologic sequelae, including memory disorders, changes of personality, electrolyte imbalance, and motor deficits. 1hen we investigated the literature, our meta-analysis found 8.6% of complications related to flow-diversion treatment AcomA aneurysms.Most of them occurred in the periprocedural period after treatment (7%).Permanent deficits and mortality related to the treatment were 3.5% and 2.5%, respectively.Not surprising, ischemic events were the most common complications (6%), together with acute in-stent thrombosis (4%).Gawlitza et al 19 reported 2 cases of transient ischemic complications (1 case of facial palsy and 1 case of lacunar infarct detected at MR imaging) related to the covered artery of Heubner.In a series of 9 AcomA aneurysms, Pierot et al 20 reported 1 case of thromboembolism and 1 case of flow-diverter occlusion 4 days after treatment without permanent neurologic deficits.
Another important concern is the patency of the arteries covered with flow diverters. 21Despite very few studies focused on the angiographic outcome of the covered A2 segment (or main branching vessels such as the artery of Heubner), we found a 16% occlusion rate of jailed arteries during follow-up.Pistocchi et al 22 reported 5 cases of occlusion and 4 cases of slow flow of the covered A2 segment among 14 patients with AcomA aneurysms treated with the Silk stent.In this series, only 1 patient experienced a transitory hemiparesis due to the sluggish flow on the covered A2, which regressed after blood pressure augmentation.Saleme et al, 23 in a series of 9 AcomA aneurysms treated with the PED, described 2 cases of asymptomatic A2 occlusion during follow-up.In a recent meta-analysis of nearly 1200 supraclinoid internal carotid artery vessels covered with flow-diverter stents, the overall rate of occlusion was 7%, with important differences among the ophthalmic artery (6%), anterior choroidal artery (1%), and posterior communicating artery (20%), 21 with approximately 1% symptomatic occlusions.One of the most important mechanisms related to branch preservation is the pressure gradient between the artery and its covered branches.In general, when the occlusion progresses slowly, the collateral circulation can ef-ficiently supply the territory of the jailed artery and the occlusion can be tolerated in most cases.
Finally, meta-regression showed a significant (P ϭ .022)decrease of the complication rate during 7 years (from 2011 to 2018), probably due to improvement of the operator experience, 3D angiographic images, and better case selection and posttreatment patient management.
Our results are in accordance with a recent meta-analysis discussing the AT regimen used before and after using the PED.In this study, there was a lack of relationship between patients who received low-versus high-dose pre-PED ASA in terms of thromboembolic and hemorrhagic complications. 24

Strengths and Limitations
Our study has several limitations.Series were often retrospective studies and small single-institution experiences.Because of the small number of cases, the comparison among subgroups may not provide power to show a statistically significant difference among the studied outcomes.Outcome comparison between ipsilateral A1-A2 and transcommunicating (from the A1 to the contralateral A2) stent configurations was not possible because of the scanty data.For the same reason, the asymmetry of the A1 segment was not evaluated.However, publication bias was reasonably excluded, and our review is the first and the largest study focusing on the flow-diversion treatment of AcomA aneurysms.

CONCLUSIONS
On the basis of our meta-analysis, flow diversion for unruptured saccular AcomA aneurysms appears to be an effective alternative treatment for lesions difficult to treat with coiling or microsurgical clipping.The treatment-related complication rate was relatively low, considering that flow-diverter stents are, in general, used for complex aneurysms of the AcomA region.However, larger studies are needed to confirm the safety and efficacy of this procedure.