ABSTRACT

This meta-analysis evaluates the clinical and angiographic outcomes of the flow re-direction endoluminal device X (FRED^TM X) in treating intracranial aneurysms. A systematic review was performed across Medline, Scopus, and Web of Science databases from inception to March 2025. Eligible studies included those reporting clinical and angiographic results of FRED X treatment. Favorable outcomes were defined as those stated explicitly in the studies or a modified Rankin scale score of 0–2. Pooled estimates were calculated using a random-effects model in R. A total of nine studies encompassing 780 patients with 869 aneurysms were included. The weighted mean age was 56.28 years, with 19.1% of patients being men. Most aneurysms were saccular (85.7%), unruptured (92.52%), and located in the anterior circulation (73.6%), primarily in the internal carotid artery. The average aneurysm size was 13.12 mm. All studies employed dual antiplatelet therapy, with antiplatelet response testing performed in eight studies. The mean clinical follow-up period was 9.27 months. The meta-analysis demonstrated favorable neurological outcomes in 97.71% of cases and complete or near-complete occlusion in 86.9%. Procedure-related complications were reported in 9.28% of cases, while in-stent thrombosis or intimal hyperplasia occurred in 4.29%. Overall mortality was low at 0.60%. Subgroup analysis revealed that unruptured aneurysms had a 100% rate of favorable neurological outcomes and an 84.76% rate of complete or near-complete occlusion. Complication and mortality rates were 7.76% and 0.25%, respectively. In addition, favorable outcomes were seen in 100% of ruptured aneurysm cases; however, complete occlusion was achieved in only 59.65%, and the mortality rate was higher at 9.19%. Therefore, FRED X demonstrated high efficacy and procedural safety in the treatment of intracranial aneurysms, offering improved outcomes compared with earlier-generation flow diverters.

In 2011, the approval of a pipeline embolization device by the United States (US) Food and Drug Administration (FDA) marked a significant milestone in the treatment of intracranial aneurysms. Following the success of the pipeline embolization device, flow diverter (FD) stents have become an increasingly integral part of clinical practice. The flow re-direction endoluminal device (FRED^TM) and its smaller counterpart, FRED junior (FRED Jr), manufactured by MicroVention, now Terumo Neuro (Aliso Viejo, CA, USA), are notable examples of these devices. Designed with a dual-layer construction, they employ a self-expanding braided nitinol mesh to ensure superior wall apposition and facilitate safe delivery to distal aneurysms.^{1, 2}

An important advancement in flow-diversion technology has been the development of antithrombotic coatings, which aim to reduce the risk of thrombus-related complications. Building on this trend and the original FRED system, FRED X represents the latest generation of FDs. While retaining the structural design of its uncoated predecessor, the FRED X incorporates innovative X technology surface coating. This coating consists of an amphiphilic polymer, poly (2-methoxyethyl acrylate), which features a hydrophobic segment facing the device’s surface and a hydrophilic segment oriented toward the vascular lumen.^{3, 4} This unique design creates a boundary layer along the stent struts, minimizing protein denaturation and subsequent platelet adhesion. These attributes suggest a potentially improved safety profile for the device. The FRED X received FDA premarket approval in September 2021, and the first clinical use was reported in February 2022. However, while preliminary studies suggest high procedural safety with the FRED X, the clinical benefits of these surface coatings remain uncertain and warrant further investigation.⁵

To address this gap, this study provides a comprehensive systematic review and meta-analysis of the existing literature on the clinical outcomes of using FRED X in the treatment of intracranial aneurysms. This meta-analysis aims to identify knowledge gaps and offer valuable insights to inform clinical decision-making regarding this novel therapeutic approach by synthesizing the current evidence and critically analyzing the findings.

Methods

This systematic review and meta-analysis followed the recommendations of the Cochrane Collaboration Handbook for Systematic Review of Interventions⁶ and the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) 2020 statement guidelines.⁷ The NeuroComp Meta-Analysis Checklist was adopted to assess the outcomes related to complications.⁸

Eligibility criteria

This meta-analysis included studies that met the following criteria: (1) case series, prospective, or retrospective cohort studies, or randomized controlled trials; (2) studies providing follow-up data on clinical and angiographic outcomes; and (3) studies specifically involving the FRED X. Studies using other FRED stents (e.g., FRED, FRED Jr) were excluded from this analysis. There were no restrictions regarding aneurysm type, location, rupture status, or other related factors.

Search strategy, data extraction, and quality assessment

A comprehensive literature search was conducted in the Medline, Scopus, and Web of Science databases from inception to March 8, 2025. The search strategy employed keywords such as “FRED X,” “FREDX,” and “FRED^TM” in various combinations using “AND” and “OR” to ensure a broad capture of relevant studies.

Two independent researchers performed the data extraction and quality assessment; any discrepancies were resolved through consensus with two of the study’s researchers. The risk of bias was evaluated using a modified Newcastle–Ottawa Scale.^9-11 Studies were classified as having a “low risk of bias” if they provided satisfactory angiographic and clinical follow-up data together with clear outcome reporting. Studies with unsatisfactory follow-up were categorized as “medium risk of bias,” while those lacking satisfactory follow-up and clear outcome reporting were deemed to have a “high risk of bias” (Supplementary Table 1).

Endpoints, subanalysis, and definitions

Clinical and angiographic outcomes assessed included the following: (1) favorable neurological outcomes; (2) minor and major complications; (3) occlusion rate; (4) adjunctive coiling; (5) aneurysm presentation (ruptured or unruptured); (6) technical success; and (7) mortality. Additional subanalyses examined outcomes specifically for ruptured and unruptured aneurysms. Favorable neurological outcomes were defined as either those reported directly or as a modified Rankin scale score of 0–2 for aneurysms. Complete occlusion was directly reported or, if not, classified as Raymond–Roy class 1 (indicating complete obliteration) or O’Kelly–Morata grade D. Near-complete occlusions were defined as Raymond–Roy class 2 or O’Kelly–Morata grade C, with other outcomes classified as incomplete occlusions.

Statistical Analysis

Analyses were conducted using pooled estimates with a 95% confidence interval (CI) under a random-effects model. Heterogeneity was assessed using the I² statistic, with values above 50% indicating substantial heterogeneity. To explore the robustness of the pooled estimates and identify potential sources of heterogeneity, leave-one-out sensitivity analyses were performed. Assessment of publication bias was not performed using funnel plots or Egger’s regression tests because the meta-analysis comprised fewer than 10 studies, as these methods are considered unreliable with a small sample size. Pearson’s χ² test examined the relationship between aneurysm localizations. A P value <0.05 was considered statistically significant. All statistical analyses were performed using R (version 4.2.3, R Foundation for Statistical Computing, Vienna, Austria), applying inverse variance and restricted maximum likelihood methods.

Results

Literature review

Nine studies were included in the final analysis.^1-5,12-15 The search process is illustrated in Figure 1. Two studies employed a prospective design,^{2, 12} whereas the remaining seven were conducted retrospectively. Additionally, two studies were conducted at a single center,^{12, 13} while the other seven were multicenter studies.

Patient population and study characteristics

The nine studies included in the final analysis represented 780 patients with a weighted mean age of 56.28 years and encompassed 869 aneurysms. Among the 780 patients with reported sex information, 149 (19.1%) were men.

Morphologically, saccular aneurysms were the most common type, comprising 680 of 793 aneurysms (85.7%). The mean aneurysm size across the studies was 13.12 mm. Analysis of the rupture status of the 869 aneurysms evaluated determined that 65 (7.4%) were ruptured and 804 (92.5%) were unruptured. The mean clinical follow-up duration of the nine studies included was 9.27 months (Table 1). Detailed information for each study is provided in Table 2.

Aneurysms were predominantly located in the anterior circulation (n = 640, P < 0.001), with the internal carotid artery (n = 542) being the most common site. Among posterior circulation aneurysms (n = 103), the vertebral (n = 42) and basilar (n = 26) arteries were the primary locations. Additionally, 126 aneurysms lacked specific location information (Table 3).

Antiplatelet regiment

Dual antiplatelet therapy was utilized in all nine studies. The antiplatelet response was assessed in eight studies, with five using the VerifyNow^TM system (Werfen, Bedford, MA, USA), while the method of assessment was not specified in three studies (Supplementary Table 2).

Angiographic, clinical outcomes, and complications

The meta-analysis of the nine studies demonstrated favorable neurological outcomes in 97.7% of cases (95% CI 95.42–100). Complete or near-complete occlusion was achieved in 86.9% of aneurysms (95% CI 79.84–93.60), based on the data reported in eight studies. Complications occurred in 9.2% of cases (95% CI 4.94–13.61), based on the data derived from nine studies. In-stent thrombosis or intimal hyperplasia was observed in 4.2% of cases (95% CI 1.16–7.42) in eight of the studies. Mortality was low, at 0.60% (95% CI 0.00–1.31), based on nine studies (Figure 2).

Subanalysis of ruptured and unruptured aneurysms

For unruptured aneurysms, five studies representing 379 patients reported favorable neurological outcomes in 100% of cases (95% CI 99.31–100) (Supplementary Figure 1). Complete or near-complete occlusion was achieved in 84.7% of cases (95% CI 78.81–90.71), based on five studies representing 331 patients. Complications occurred in 7.7% of cases (95% CI 4.09–11.43), derived from seven studies involving 581 patients. In-stent thrombosis or intimal hyperplasia occurred in 2.1% of cases (95% CI 0–4.21), based on five studies. Mortality was 0.25% (95% CI 0–0.85), based on data from eight studies (Table 4).

For ruptured aneurysms, two studies with 13 patients reported favorable neurological outcomes in 100% of cases (95% CI 87.61–100) (Supplementary Figure 2). Complete or near-complete occlusion was observed in 59.6% of cases (95% CI 25.17–94.13), based on two studies with 23 patients. Procedure-related complications occurred in 0.52% of cases (95% CI 0–6.18), based on four studies involving 41 patients. Mortality was 9.19% (95% CI 0–25.95), based on five studies (Table 4). Details of complications and their management are presented in Supplementary Tables 3, 4. Leave-one-out results are presented in Supplementary Figures 3-5.

Discussion

This meta-analysis, encompassing data for 780 patients with 869 aneurysms reported in nine studies, underscores several key findings. Favorable neurological outcomes were achieved in 97.71% of cases, with a low overall mortality rate of 0.60%. Most aneurysms were unruptured (92.52%) and predominantly located in the anterior circulation, especially in the internal carotid artery. Complete or near-complete occlusion was achieved in 86.9% of aneurysms, while complications occurred in only 9.28% of cases. Although outcomes for ruptured and unruptured aneurysms were generally comparable, unruptured aneurysms exhibited significantly lower complication rates. Despite the relatively short follow-up periods reported in the nine studies, their findings highlight the efficacy and safety of the FRED X device, particularly in achieving high rates of complete occlusion.

While FD technology has revolutionized the treatment of intracranial aneurysms, its use is not without limitations and potential complications. Since FDA approval, multiple studies have assessed the safety and efficacy of FDs, frequently reporting high occlusion rates. However, the overall complication rate, including major and minor events, has been reported to reach up to 17%, with ischemic complications being the most prevalent.¹⁶ Notably, compared with the pipeline embolization device, the FRED device has been associated with higher rates of in-stent stenosis, potentially elevating the risk of ischemic events.¹⁷

To address these concerns, MicroVention, now Terumo Neuro, developed the next-generation FRED X, incorporating advanced X technology. This technology introduces a protective hydration layer across the stent’s surface, aiming to reduce platelet adhesion and enhance endothelialization. By minimizing thrombogenicity and promoting natural vascular healing, the FRED X endeavors to improve safety and clinical outcomes. Furthermore, the novel surface coating facilitates improved device delivery without altering the core stent design. Importantly, the FRED X retains the same dual-layer design as the FRED, which features 16 + 48 wires, achieving 35%–40% metal coverage. In contrast, the FRED Jr, another variant, uses 16 + 36 wires with approximately 30% metal coverage. The specific impact of the surface coating, however, remains a subject of ongoing investigation.

Retrospective analyses, such as that by Cortez et al.¹⁸, comparing the Pipeline^TM Flex with and without Shield Technology^TM, found no significant differences in diffusion-weighted imaging lesions. However, the study’s small sample size and retrospective design limit the generalizability of these findings, emphasizing the need for further research. An in vitro blood loop model study by Yoshizawa et al.¹⁹ demonstrated reduced platelet adhesion on the FRED X surface compared with the uncoated FRED. Additionally, multicenter trials suggest that the FRED X may have a lower complication rate than the uncoated FRED. For example, the SAFE study²⁰ reported thromboembolic events in 4.9% of cases and a morbidity rate of 3.0%. Moreover, Guimaraens et al.² highlighted that the FRED X achieved higher medium-term occlusion rates while maintaining a favorable safety profile.

Despite the widely accepted necessity of dual antiplatelet therapy (typically aspirin and clopidogrel/prasugrel/ticagrelor) following FD implantation, the optimal dosage and duration of post-treatment antiplatelet therapy remain unstandardized when using surface-modified FDs. The reduced thrombogenicity of surface-modified FDs compared with uncoated FDs raises the question of whether adjustments to antiplatelet regimens are warranted. The study by Goertz et al.²¹ investigated single therapy following surface-modified FD implantation; aspirin, ticagrelor, and prasugrel were utilized as monotherapies, with prasugrel being the most frequently chosen agent. Evidence suggests that prasugrel and ticagrelor have a superior safety profile for ischemic events compared with aspirin in single antiplatelet therapy (SAPT) regimens. According to a meta-analysis by Ma et al.²², the rate of thromboembolic complications following surface-modified FD implantation was reported as 20% for aspirin, compared with 2% and 4% for prasugrel and ticagrelor monotherapies, respectively. These findings suggest that SAPT with prasugrel or ticagrelor is favored over aspirin in specific clinical scenarios when using surface-modified FDs.

Current evidence supports the reasonable safety and efficacy of SAPT in treating aneurysms with modified FDs; however, the lack of studies directly comparing modified FDs with dual antiplatelet therapy and uncoated FDs with SAPT, coupled with the scarcity of large, prospective trials, precludes definitive conclusions. The studies included in this meta-analysis reveal a persistent tendency to favor dual therapy. Results from registries and trials investigating new-generation FDs, such as the coating study,²³ have aimed to optimize aneurysm treatment and contribute valuable insights to refine treatment strategies. Notably, most studies included in this meta-analysis assessed platelet function before the procedure. However, no consensus exists on whether such evaluations are necessary for modified FDs. Further research is required to address this uncertainty.

Despite the short follow-up periods, the meta-analysis established that the FRED X had a satisfactory occlusion rate, with a combined major and minor complication rate of 9.2%. The average aneurysm size was 13.12 mm, a noteworthy finding given that the FRED X was used in small parent vessels and more proximal aneurysms, achieving relatively low complication rates. Larger aneurysms are generally associated with higher complication risks, as demonstrated by the study from Sweid et al.²⁴, which identified aneurysm size >10–15 mm as a statistically significantly independent predictor of major ischemic stroke. Additionally, Sweid et al.²⁴ reported a statistically significant association between the time from treatment and the development of in-stent stenosis.

This meta-analysis did not include sufficient data to directly compare outcomes between FRED X with and without adjunctive coiling. However, Goertz et al.²⁵ investigated the impact of coiling in their study and found no significant differences in clinical or angiographic outcomes between coiled and non-coiled cases. In the studies included in this meta-analysis, only one patient experienced technical failure.

Although the preliminary safety and efficacy results for FRED X are promising, long-term follow-up studies, particularly those comparing coated and uncoated FDs, are needed to further evaluate its clinical performance.

This meta-analysis has several limitations, despite efforts to address heterogeneity and publication bias. The retrospective design of the included studies introduces inherent constraints, such as selection bias, missing data, and variability in reporting practices, which may affect the reliability and generalizability of the findings. In comparing ruptured and unruptured aneurysms, differences in aneurysm characteristics, such as location and morphology, and variations in treatment approaches, including the use of adjunctive coiling, may further complicate interpretations and reduce comparability. Additionally, the short- to mid-term follow-up periods in most of the included studies may not sufficiently capture long-term treatment outcomes. These factors should be carefully considered when interpreting the conclusions of this analysis.

In conclusion, this study demonstrates that the FRED X offers high feasibility and procedural safety, surpassing the performance of first-generation devices. While the short-term occlusion rates appear satisfactory, long-term and comparative studies are needed to fully evaluate the potential of the FRED X and other coated FDs.