Article Text

Long-term outcomes of flow diversion for unruptured intracranial aneurysms: a systematic review and meta-analysis
  1. Mostafa A Shehata,
  2. Mohamed K Ibrahim,
  3. Sherief Ghozy,
  4. Cem Bilgin,
  5. Mohamed Sobhi Jabal,
  6. Ramanathan Kadirvel,
  7. David F Kallmes
  1. Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Mostafa A Shehata, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA; shehata.mostafa{at}


Background Flow diverters have been widely used in clinical practice for more than a decade. However, most outcome data are limited to 1 year timepoints. This study aims to offer meta-analysis data on long-term (>1 year) safety and effectiveness results for patients with aneurysms treated with flow diverters.

Methods PubMed, Web of Science, Embase, and SCOPUS were searched up to February 24, 2022 using the AutoLit platform. We included primary studies assessing the long-term outcomes for flow diverter devices to manage unruptured internal carotid artery aneurysms with a follow-up period of >1 year. The meta-analysis was carried out using Comprehensive Meta-Analysis software (CMA).

Results Eleven studies were included in the meta-analysis. The pooled occlusion rates after flow diversion treatment for unruptured intracranial brain aneurysms were 77%, 87.4%, 84.5%, 89.4%, 96% for 1 year, 1–2 years, 2 years, 3 years, and 5 years follow-up, respectively. The in-stent stenosis rate was 4.8% and the retreatment rate for the long-term follow-up period was 5%. No delayed rupture of the aneurysm was reported, and there was one case of delayed ischemic stroke. The sensitivity analysis of the prospective studies showed a complete occlusion rate of 83.5% and 85.2% for 1 and 3 years of follow-up, respectively.

Conclusion Flow diverters are safe and effective in short- and long-term follow-up and rarely cause serious delayed side effects.

  • aneurysm

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Since the introduction of flow diverters (FDs) into routine clinical care about 15 years ago, they have been a principal constituent of aneurysm therapy procedures, accounting for a significant proportion of all treatments.1 Numerous previous reports, including meta-analyses, have shown good or excellent safety and efficacy profiles up to 1 year after FD treatment.2 At 1 year, complete or near-complete occlusion rates are satisfactory, even for large and giant aneurysms,3 representing a significant advance over previous open surgical and endovascular procedures approaches, with appropriate safety metrics.4 5

Notwithstanding the vast literature focused on the safety and efficacy of FDs for intracranial aneurysms, important ongoing questions remain. Specifically, there remains a relative dearth of clinical reports focused on long-term (>1 year) outcomes after FD therapy. Previous studies have noted relatively promising trends beyond 1 year, with low rates of delayed safety events and excellent durability of aneurysm occlusion; however, there is a lack of collective evidence in this regard. Therefore, this study aims to provide meta-analytic data on long-term (>1 year) safety and efficacy outcomes for patients with aneurysms treated with FD.


The recommended PRISMA guidelines were followed for conducting this systematic review and meta-analysis.6 We used the AutoLit platform (Nested Knowledge, St Paul, Minnesota, USA) for conducting the search, duplicate removal, screening, and full-text screening.7

Search strategy and selection criteria

On February 24, 2022, a literature search was conducted on Web of Science, PubMed, Scopus, and Embase using a combination of the terms (“intracranial aneurysm” OR “intracranial aneurysms” OR “anterior circulation aneurysm” OR “anterior circulation aneurysms” OR “posterior circulation aneurysm” OR “posterior circulation aneurysms” OR “internal Carotid Artery Aneurysm” OR “internal carotid artery aneurysms”) AND (“flow diverter” OR “flow diversion” OR “Pipeline” OR “FRED” OR “Tubridge” OR “SILK” OR “Surpass Streamline”) AND (“long-term” OR “mid-term” OR “long term” OR “mid term”). The search strategy was adjusted based on the database.

Screening and study selection

We included primary studies assessing the long-term outcomes for FD devices to manage unruptured internal carotid artery aneurysms with a follow-up period of >1 year. We excluded non-English literature, reviews, case reports, case series with <10 eligible patients, studies with a total follow-up period of <1 year, studies that did not separate those followed for <1 year and those followed for >1 year, and studies that did not mention the occlusion rate explicitly, FD retreatment studies, or articles with ruptured, fusiform, dissecting aneurysms.

Data extraction

We extracted the aim and the summary of the included studies, the aneurysm site, patient characteristics, the FD device used, study design, and different treatment outcomes. The outcomes included complete occlusion, in-stent stenosis, delayed stroke, rupture, retreatment, and recurrence.

Quality assessment

For our observational non-randomized included studies we used the Risk Of Bias In Non-Randomized Studies – of Interventions (ROBINS-I) tool to assess the risk of bias. Based on seven domains, studies with a “Low”, “Moderate”, “Serious”, or “Critical” risk of bias were examined and appraised (confounding bias, selection bias, measurement classification of interventions bias, deviation from intended intervention bias, missing data bias, measurement of outcomes bias, and selection of the reported result bias).8 Quality assessments were completed separately by two authors. Discussions between the two authors were successful in resolving any disagreements of opinion.

Data synthesis

The statistical analysis software Comprehensive Meta-Analysis software (CMA) was used to complete the data analyses. Q-statistics and I2 were used to assess heterogeneity, where p<0.05 and/or I2 >50% were considered significant heterogeneity. The random-effect model was used in the presence of significant heterogeneity; otherwise, the fixed-effect model was used. We used the random-effect model whenever the data were heterogeneous and the fixed-effect model for homogenous results. Sensitivity analyses were carried out to assess whether results would differ if data from high-quality prospective trials had been included only in the meta-analysis. We found four prospective studies that met our criteria.9–12 Three of the prospective studies include data convenient for conducting the meta-analysis for them.9 10 12


Search results

There were 1071 articles available using our search strategy. After removing the duplicates, 436 unique articles remained. After title and abstract screening, 70 articles held some potential to be included. After screening the full text and the data represented and applying our inclusion and exclusion criteria, we excluded 59 additional articles. Finally, 11 studies were included in the quantitative synthesis. The PRISMA diagram is shown in figure 1.

Figure 1

PRISMA flow chart of the search and screening process.

Study characteristics and descriptive overview

A total of 2009 patients were included in the studies at the starting point and 1186 patients were eligible in our inclusion criteria for analysis. Women comprised 78.5%. Four studies were prospective cohorts and seven were retrospective (table 1).

Table 1

Baseline characteristics of the enrolled patients in the included studies

Quality assessment

The 11 studies were graded using the ROBINS-I tool. They showed heterogeneity in their respective inclusion criteria (eg, devices used, aneurysm location, number of devices per patient, follow-up periods). According to the ROBINS assessment tool, nine studies had a moderate risk of bias and the remaining four were low-risk. The results of the quality assessment are shown in online supplemental table 1.

Supplemental material

Complete occlusion rate at different follow-up periods

Eleven studies comprising 1186 patients reported complete occlusion rates across various time periods. The pooled complete occlusion rates were 77.1% (95% CI 74.6% to 79.5%), 87.4% (95% CI 78.6% to 92.9%), 84.5% (95% CI 80.8% to 87.6%), 89.4% (95% CI 83.2% to 93.5%) and 96% (95% CI 92.5% to 97.9%) at 1, 1–2, 2, 3, and 5 years of follow-up, respectively (figure 2). There was significant heterogeneity in the 3-year follow-up, so the random-effect model analysis was used.

Figure 2

Complete aneurysm occlusion at (A) 1 year follow-up; (B) 1–2 years follow-up; (C) 2 years follow-up; (D) 3 years follow-up; and (E) 5 years follow-up.

Sensitivity analysis

After performing a meta-analysis of the prospective studies only,9–12 we found that the occlusion rates were 83.5% (95% CI 78.9% to 87.3%) for the 1-year follow-up and 85.2% (95% CI 80.4% to 89%) for the 3-year follow-up (figure 3).

Figure 3

Complete aneurysm occlusion (prospective studies) at (A) 1 year follow-up and (B) 3 years follow-up.


We included in our pooled analysis the studies that mentioned the complication rate beyond 1 year of follow-up after FD treatment. Five studies reported the delayed aneurysm rupture outcome.12–16 There was no delayed rupture of the aneurysm after 1 year of follow-up. Six studies reported delayed ischemic stroke outcomes,9 12–16 and there was only one case of delayed ischemic stroke.4 In-stent stenosis was reported in 4.8% (95% CI 3% to 7.7%) of cases (figure 4A).

Figure 4

(A) In-stent stenosis. (B) In-stent stenosis (prospective studies). (C) Recurrence rate. (D) Retreatment rate. (E) Recurrence rate (prospective studies).

Sensitivity analysis

In the four prospective studies9–12 there were no cases of delayed rupture of the aneurysm after 1 year of follow-up. There was only one case of delayed ischemic stroke.4 The in-stent stenosis rate was 5.4% (95% CI 3.3% to 8.9%) (figure 4B).

Recurrence and retreatment

The recurrence rate was mentioned in five studies, and the pooled analysis showed a recurrence rate of 1% (95% CI 0.4% to 2.6%) (figure 4C). Similarly, five studies mentioned retreatment after 1 year of follow-up. The overall retreatment rate was 5% (95% CI 4% to 6.2%) (figure 4D).

Sensitivity analysis

The recurrence rate in the prospective studies only9–12 was 1.6% (95% CI 0.6% to 4.1%) (figure 4E).


This meta-analysis compiled compelling long-term efficacy and safety data in support of flow diversion therapy for intracranial aneurysms. The well-known increases in complete occlusion over time during the first year continued over the time period in our current study, with >95% complete occlusion rates at 5 years. Furthermore, safety events such as delayed rupture and ischemic stroke were extremely rare, and parent artery stenosis and retreatment rates were quite low. As such, this study offers strong evidence in favor of flow diversion for aneurysm therapy. The Pipeline for Uncoiled or Failed Aneurysms (PUFS) trial reported no delayed neurological deaths or hemorrhagic or ischemic cerebrovascular accidents beyond 6 months. There was no evidence of recanalization of a previously occluded aneurysm.12 The study by Lylyk et al is the largest trial on the Pipeline Embolization Device to date (PEDESTRIAN), showing high rates of long-term aneurysm occlusion, stable or better functional results, and minimal morbidity and mortality rates. Over time, clinical and angiographic outcomes improved. It was retrospective and did not have core laboratory adjudication.17 The PREMIER trial was the first prospective, independently adjudicated trial to describe 3-year follow-up after FD treatment. The findings showed that the device is safe and effective over time, with higher rates of complete occlusion and no occurrences of aneurysm rupture.9 Our meta-analysis is the first to our knowledge to pool the long-term follow-up of >1 year after FD treatment and to include 1186 patients in the analysis, making it a more robust supporting evidence for the literature and future trials.

The sensitivity analysis showed an underestimation of the complete occlusion rate at 1-year follow-up as it was 83.5% in the pooled analysis of the high-quality prospective studies and 77.1% in the pooled analysis of the included studies. This observation may be due to the lack of laboratory adjudication in retrospective studies and the limitations of the retrospective design. The complication rates were very low.

According to this meta-analysis, routine follow-up after the first year and invasive angiography follow-up has no significant clinical benefit and is considered unnecessary as a high percentage of the aneurysms will be completely occluded as time passes. At the same time, long-term follow-up will not help in predicting or preventing major side effects.

Our meta-analysis is single-arm. Accordingly, the absence of a control group in this trial made it difficult to directly compare FD devices to other aneurysm treatment modalities. In addition, the study included unruptured aneurysms, making its generalizability limited. The included studies are not randomized, so unknown confounding factors may have affected the results. The heterogeneity in aneurysm sizes, neck width, morphologies, number of devices, and the type of device used to treat each aneurysm which can severely impact the long-term occlusion rate make it hard to draw conclusions about individual aneurysms.

Our study analysis did not separate different types of FD devices nor the specific location of each treated aneurysm because the number of studies that mention the long-term outcomes for each were not sufficient. However, it is the first meta-analysis to discuss the long-term safety outcomes after 1 year of follow-up for FD treatment.

The long-term safety and efficacy of the PED for the treatment of unruptured intracranial aneurysms are excellent. However, further prospective studies with larger sample sizes are needed to fully determine the feasibility and safety of FDs beyond 5 years.

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Supplementary materials

  • Supplementary Data

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  • MAS, MKI and SG are joint first authors.

  • Twitter @khaledorad, @SobhiJabal

  • Contributors All authors contributed to the study design and drafting of the manuscript. The search was completed by MAS and MSJ, screening of articles by MAS and CB, data extraction by MAS and MKI with quality control by MAS, MKI, and SG. Statistical analysis was provided by MAS and SG. All authors contributed to feedback and finalization of the manuscript.

  • Funding This study was in part supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number R01 NS076491 and R43 NS110114.

  • Competing interests DFK holds equity in Nested Knowledge, Superior Medical Editors, and Conway Medical, Marblehead Medical; is a consultant for MicroVention, Medtronic, Balt, and Insera Therapeutics; Data Safety Monitoring Board for Vesalio; and receives royalties from Medtronic. RK reports NIH funding (R01 NS076491, R43 NS110114, and R44 NS107111), is a research consultant for Cerenovus, Insera Therapeutics, Marblehead Medical, Microvention, MIVI Neuroscience, Neurogami Medical, and Triticum, and has stock in Neurosigma (money paid to institution).

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.