Long-term outcomes of flow diversion for unruptured intracranial aneurysms: A systematic review and meta-analysis

Abstract

Background:

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

Methods:

We searched PubMed, Web of Science, Embase, and SCOPUS until Feb 24, 2022, using the AutoLit platform (Nested Knowledge, St. Paul, MN). 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> one year. The meta-analysis was carried out using Comprehensive Meta-Analysis software (CMA).

Results:

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

Conclusion:

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

Introduction

Since the introduction of flow diverters (FD) into routine clinical care about 15 years ago, flow diverters 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 one 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 FD for intracranial aneurysms, important ongoing questions remain. Specifically, there remains a relative dearth of clinical reports focused on long-term (>1yr) outcomes after FD therapy. Previous studies have noted relatively promising trends beyond one 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 (>1yr) safety and efficacy outcomes for aneurysm patients treated with FD.

Methods

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

Search strategy & selection criteria

On Feb 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 flow diverter devices to manage unruptured internal carotid artery aneurysms with a follow-up period of more than one year. We excluded non-English literature, reviews, case reports, case series with less than ten eligible patients, studies with a total follow-up period < 1 year, studies that did not separate those who have been followed for less than a year and more than a year, and studies that did not mention the occlusion rate explicitly, flow diverter retreatment studies, or articles with ruptured, fusiform, dissecting aneurysms.

We excluded reviews, case reports, case series, studies with a total follow-up period < 1 year, studies that did not separate those who have been followed for less than a year and more than a year, and studies that did not mention the occlusion rate explicitly, flow diverter retreatment studies, articles with dissecting or ruptured aneurysms, studies that have high percentage of fusiform aneurysms, or intrasaccular flow diverters or flow disruptors.

Data extraction

We extracted the aim and the summary of the included studies, the aneurysm site, patient characteristics, the flow diverter 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, nonrandomized 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. The Q-statistics and I-square were used to assess heterogeneity, where P-value < 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 one was used. We used the random-effect model whenever the data were heterogeneous; and the fixed-effect model for homogenous results. Sensitivity analyses were done 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).

Results

Search results

There were 1071 articles available using our search strategy. After removing the duplicates, there were 436 unique articles remaining. After title and abstract screening, we had 70 articles that 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, eleven studies were included in the quantitative synthesis. The PRISMA diagram is displayed 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 within the included studies at the starting point, and 1186 patients were eligible in our inclusion criteria for the analysis. The female percentage was 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

Author	Study Design	Device Name	Patients Number	Aneurysm Number	Aneurysm location	Aneurysm size, mean (SD) * Median with IQR	Age mean (SD) * Median with IQR	Female (%)	Aim/Objective	Conclusion
Lylyk et al., 2021(13)	Retrospective Cohort	PED	835	1000	Anterior and Posterior circulation	8.1 (6.9)	55.9 (14.7)	671 (80.4)	Looks at the long-term outcomes of the Pipeline Embolization Devices for the Treatment of Intracranial Aneurysms (PEDESTRIAN) Registry.	Endovascular Treatment of IA with PED is safe and effective.
Becske et al., 2016 (12)	Prospective Cohort	PED	107	109	Complex ICA aneurysms	18.2 (6.5)	57 (11.3)	96 (88.9)	Patients treated in the Pipeline for Uncoilable or Failed Aneurysms clinical study followed up for 5 years.	PED is a safe and effective therapy for large and gigantic wide-necked cerebral ICA aneurysms, with high rates of full occlusion and low rates of delayed adverse effects.
Hanel et al., 2022 (9)	Prospective Cohort	PED	141	141	Small- and medium-sized unruptured intracranial aneurysms located at the ICA and VA	4.5 (5)	54.6 (11.3)	124 (90)	Investigate the efficacy of PEDs in the treatment of small and medium-sized wide-necked aneurysms.	The PED device is a safe and effective treatment option for small and medium-sized cerebral aneurysms.
Pérez et al., 2020 (14)	Retrospective Cohort	P64	530	617	Anterior circulation	4.8	55.9	388 (73.2)	The safety and efficacy of p64 for the treatment of intracranial saccular unruptured aneurysms resulting from anterior circulation over long term follow up	The use of p64 to treat cerebral saccular unruptured anterior circulation aneurysms is a safe and effective therapeutic option with a high incidence of occlusion at long-term follow-up and minimal morbidity.
Tanweer et al., 2014 (15)	Retrospective Cohort	PED	43	43	Cavernous carotid aneurysms	24.3 (9.7)	57(14.2)	36 (83.7)	The Pipeline Embolization Device’s results and complications in unruptured cavernous carotid aneurysms	Endoluminal repair with flow diversion for large unruptured cavernous carotid aneurysms may be effective with few morbidities.
Zhu et al., 2012 (11)	Prospective Cohort	Willis covered stent	41	45	The distal ICA or VA	11.36 (8.02)	41.8 (11.6)	16 (60)	The immediate/late endoleaks and long-term patency after stent-graft insertion for the treatment of intracranial aneurysms in the distal internal carotid artery ICA or VA	Willis stent-grafts have a satisfactory immediate and late occlusion rate and a long-term stented arterial patency rate when treating intracranial aneurysms.
Fischer et al., 2015 (16)	Retrospective Cohort	P64	121	130	Anterior+Posterior circulation	4 *	58 *	86 (71)	The safety and efficacy of p64 in the endovascular treatment of cerebral sidewall aneurysms were evaluated retrospectively	P64 is an effective treatment option for intracranial sidewall aneurysms with a high aneurysm occlusion rate and a low complication rate.
Fuji et al., 2022 (10)	Prospective Cohort	PED	84	90	ICA aneurysms	16.6 (6.8)	61.5 (13.2)	73 (86.9)	The three-year result in Japan after FD therapy with PED for ICA aneurysms	Both angiographically and clinically, the long-term effects of FD therapy are favorable.
Muhl-Benninghaus et al., 2019 (17)	Retrospective Cohort	PED, FRED, DERIVO	18	18	ICA aneurysms	4.8 (3.4)	53 (14)	13 (72)	On angiographic short and long-term follow-up after treatment with flow diverters, assess the incidence and dynamics of in-stent stenosis.	Short-term follow-up after flow diverter treatment often reveals in-stent stenosis, which improves over time.
Briganti et al., 2014 (18)	Retrospective Cohort	PED, SILK	35	39	Anterior+Posterior circulation	N/A	53.9	29 (82)	The findings of FDD over a long period (2–4 years) are presented in this article from a single center	FDD is a safe and effective treatment for cerebral aneurysms, with a high occlusion rate and minimal complication rate. It should be the therapy of choice for ICA large-neck aneurysms.
Hellstern et al., 2021 (19)	Retrospective Cohort	p64	54	54	Posterior circulation	3.6	55.1	45 (83.3)	The safety and effectiveness of p64 FD for the treatment of saccular, unruptured aneurysms in the posterior circulation over a lengthy period of time	The p64 FD is a safe and effective device for endovascular treatment of saccular aneurysms in the posterior circulation, with a high success rate and low morbidity.

PED: pipeline embolization device; FD: flow diverter; FDD: flow diverter device; ICA: internal carotid artery; VA: vertebral artery

Quality assessment

The eleven studies were graded using the ROBINS-I tool. Studies demonstrated heterogeneity in their respective inclusion criteria (e.g., what devices were used, aneurysms location, number of devices per patient, follow-up periods). According to the ROBINS assessment tool, nine studies were of moderate risk of bias, and the remaining four were low-risk. Results of the quality assessment were presented in Supplementary Table 1.

Characteristics of the included studies & patients

Outcomes

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: 74.6–79.5), 87.4% (95% CI: 78.6– 92.9), 84.5% (95% CI: 80.8– 87.6), 89.4% (95% CI: 83.2– 93.5), and is 96% (95% CI: 92.5– 97.9) at one, one to two, two, three and five years of follow up, respectively (Figure 2). There was significant heterogeneity in three years follow-up, so we used the random effect model analysis.

Figure 2,

Complete Aneurysm Occlusion. A: 1 year follow-up time; B: 1–2 years follow-up time; C: 2 years follow-up time; D: 3 years follow-up time; E: 5 years follow-up time

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: 78.9–87.3) for 1-year follow-up and 85.2% (95% CI: 80.4–89) for three years follow-up (Figure 3).

Figure 3,

Complete Aneurysm Occlusion, (Prospective studies). A: 1 year follow-up time; B: 3 year follow-up time

Complications

We included in our pooled analysis the studies that mentioned the complications rate beyond one-year follow-up after flow diverter treatment. Five studies reported the delayed aneurysm rupture outcome (12,14,15,18,19). There was no delayed rupture of the aneurysm after one year of follow-up. Six studies reported delayed ischemic stroke outcomes (9,12,14,15,18,19), and there was only one case of delayed ischemic stroke(4). The in-stent stenosis was reported in 4.8% (95% CI: 3– 7.7) of the cases (Figure 4A).

Figure 4,

4A: In-stent Stenosis; Figure 4B, In-stent Stenosis (Prospective studies); Figure 4C, Recurrence; Figure 4D, Retreatment; Figure 4Es, Recurrence (Prospective studies

Sensitivity analysis:

In the four prospective studies (9–12), there were no cases of delayed rupture of the aneurysm after one 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– 8.9) (Figure 4B).

Recurrence and Retreatment

The recurrence rate was mentioned in five studies, and the pooled analysis showed a recurrence rate of 0.8% (95% CI: 0.4– 2.6) (Figure 4C). Similarly, five studies mentioned retreatment after one year of follow-up. The overall retreatment rate was 5% (95% CI: 4– 6.2) (Figure 4D).

Sensitivity analysis:

The recurrence rate in the prospective studies only (9–12) was 1.6% (95% CI: 0.6– 4.1) (Figure 4E).

Discussion

This current 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 overtime during the first year continued over the time period in our current study, with >95% complete occlusion rates at five years. Further, 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 current study offers strong evidence in favor of flow diversion for aneurysm therapy. The PUFS trial reported no delayed neurological deaths or hemorrhagic or ischemic cerebrovascular accidents beyond six months. There was no evidence of recanalization of a previously occluded aneurysm(12). Lylyk et al. is the largest trial on the PED 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 lab adjudication(13). Then the PREMIER trial was the first prospective, independently adjudicated trial to describe a 3-year follow-up after flow diverters 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> 1 year after flow diverters treatment and incorporate 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 one-year follow-up complete occlusion rate as it was 83.5% in the pooled analysis of the high-quality prospective studies and 77.1% in pooled analysis of the included studies. This observation may be due to the lack of lab 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 a single-arm. Accordingly, the absence of a control group in this trial made it difficult to directly compare flow diverter devices to other aneurysm treatment modalities. In addition, the study included unruptured aneurysms making its generalizability limited. The included studies are not randomized; thus, unknown confounding factors may have affected the results. The heterogeneity in aneurysm sizes, neck width, morphologies, number of devices, and the type of the device used to treat each aneurysm which can severely impact long-term occlusion rate, make it hard to draw conclusions about the individual aneurysm.

Our study analysis did not separate different types of flow diverter devices nor the specific location of each treated aneurysm because the number of studies that mention the long-term outcomes for each was not enough. However, it is the first meta-analysis to discuss the long-term safety outcomes after 1-year follow-up for flow diverter 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 flow diverters beyond five years.