Flow-diverter devices in the treatment of intracranial aneurysms: A meta-analysis and systematic review

Abstract

Objective

The purpose of this report was to discuss the overall limitations, safety and efficacy of flow-diverter stenting for intracranial aneurysms.

Methods

The authors performed a meta-analysis from January 2009 to September 2014 using the terms “flow diverter” and “intracranial aneurysms.” Additional studies were identified through references in each reviewed article. Data extraction, performed independently by the authors, included demographic data, technical and clinical complications, morbidity and mortality, aneurismal occlusion rates related to flow-diverter devices. The analysis was performed using a fixed effect.

Results

Twenty-nine studies with 1524 patients and three to 62 months of follow-up were identified for analysis. The overall technical failure and complication rate was 9.3% (95% CI 6%–12.6%). The rate of procedure-related complication was 14% (95% CI 10.2%–17.9%) and 6.6% (95% CI 4%–9.1%) for morbidity and mortality. Fusiform, dissecting and circumferential aneurysm (OR 3.10, 95% CI 0.93–10.37) were significant risk factors for technical failure and complication. Posterior circulation location (OR 4.03, 95% CI 2.45–6.61), peripheral location (OR 2.74, 95% CI 1.52–4.94) and fusiform, dissecting and circumferential aneurysm (OR 1.95, 95% CI 1.15–3.30) were statistically significant risk factors for procedure-related complications. Posterior circulation location (OR 4.39, 95% CI 2.44–7.90) and peripheral location (OR 3.64, 95% CI 1.74–7.62) were statistically significant risk factors for morbidity and mortality.

Conclusions

Fusiform, dissecting and circumferential aneurysm, posterior circulation and peripheral locations have greater procedure-related complications.

Introduction

Complex unruptured aneurysms such as fusiform, large and/or giant, or wide neck, as well as very small aneurysms or blood blister aneurysms that might be untreatable by conventional coiling and recurrences, can be considered amenable to flow-diverter devices.¹ However, flow-diverter devices may cause bleeding or ischemic complications, which are a considerable source of neurological morbidity and mortality.² With an accumulating number of studies of flow-diverter device treatment of intracranial aneurysms, our understanding of its role in endovascular treatment of intracranial aneurysms continues to evolve.^2,3 Unfortunately, there is a remarkable degree of heterogeneity in previous studies regarding results and outcomes of flow-diverter devices in the treatment of intracranial aneurysms.³ We performed a meta-analytical review of the literature about their efficacy, safety, limitations and developments.

Methods

A PubMed, Embase and Web of Science search using the terms “flow diverter” and “intracranial aneurysms” was performed from January 2009 to September 2014. We incorporated English-language studies including more than five patients treated with flow-diverter devices and follow-up outcome. References in the reviewed studies were also incorporated if the inclusion criteria were met. Case reports, review studies and studies pertinent to lab experiments and animal experiments were excluded.

Data extraction

We extracted clinical data including patient age, patient sex, aneurysm location, aneurysm size, prior rupture, antiplatelet medication, flow-diverter type, aneurysm occlusion rate, procedure-related complications, morbidity and mortality. We calculated the aneurysm occlusion rate, procedure-related complications, morbidity and mortality across these studies, also making note of subgroup analyses for risk factors. Hazard ratios were extracted for each risk factor.

Data analysis

Statistical analysis was performed using the Meta package in RevMan 5. The primary outcome measure was the procedure-related complications. Procedure-related complications were classified as early (≤30 days) and delayed (>30 days). To explain variability in the primary outcome, we defined priori variables: patient sex, patient age, aneurysm size (<15 mm, ≥ 15 mm), aneurysm location (internal carotid artery (ICA), vertebrobasilar (VB), or peripheral (including anterior cerebral artery (ACA), middle cerebral artery (MCA), posterior cerebral artery (PCA), or ICA bifurcation), and antiplatelet medication. The meta-analyses of odds ratios (ORs) and p values were performed using a fixed-effects approach.

Results

Literature search

After an initial screening of 128 articles, 47 full-text articles were perused for eligibility, affording 29 studies providing adequate information about treated patients. Eighteen studies were excluded for missing detailed demographic and follow-up data. Across the 29 reviewed studies, there were 1524 patients followed up for three to 62 months^4–32 (Figure 1). Twenty-five studies were retrospective and four studies were prospective; two analyses were multicenter and 27 were single-center. Silk (Balt Extrusion, Montmorency, France) was used in 16 studies, Pipeline (Pipeline embolization device(PED), Covidien, Mansfield, MA, USA) was used in 16 studies, flow redirection endoluminal device (FRED) Microvention, Tustin, CA, USA) was used in two studies and Surpass (Stryker, Neurovascular, Fremont, CA, USA) was used in two studies.

Figure 1.

Chart of the systematic review.

mRS: modified Rankin Scale score.

Demographic details

In 1524 patients with 1732 aneurysms, only 12.5% were treated after acute rupture (95% confidence interval (CI) 3.1%–21.9%)). The mean age at presentation was 53.7 ± 5.9 years old (range 10–89 years old). A total of 75.3% of patients were female (95% CI 69%–81.6%). Of aneurysms, 85.3% were anterior circulation (95% CI 78%–92.6%), 13.9% were posterior circulation (95% CI 6.7%–21.1%) and 6.2% were peripheral location, including ICA bifurcation, anterior communicating artery (Acoma), MCA, ACA and PCA (95% CI 2.6%–9.7%). A total of 54.7% of aneurysms were small (<10 mm, 95% CI 36.9%–72.5%) and 42.1% of aneurysms were large and giant (≥10 mm, 95% CI 24.6%–59.5%). There were 1656 flow diverters deployed, with an average of 1.1 per patient. Dual-antiplatelet regimens (aspirin and clopidogrel) were used in 26 studies and a mono-antiplatelet regimen (ticlopidine or clopidogrel) was used in three studies. The loading doses varied and more than 300 mg of aspirin and clopidogrel for at least six hours or 75 mg clopidogrel and less than 300 mg aspirin for three to seven days. Platelet inhibition testing was not performed.

Technical failure and complications

The overall technical failure and complication rate was 9.3% (95% CI 6–12.6). The rate of incomplete deployment was 5.2% (95% CI 3.1–7.4), failure was 1.2% (95% CI 0.2–2.3), vessel perforation was 0.9% (95% CI 0.1–1.6), misplacement was 0.9% (95% CI 0–1.7), stent migration was 0.5%(95% CI 0.2–1.2), ICA dissection was 0.5% (95% CI 0–1.0), and wire fracture was 0.1% (95% CI 0–0.2).

Early procedure-related complications

The rate of early procedure-related complication was 14% (95% CI 10.2–17.9), including 5% (95% CI 3–6.9) acute ischemic events (such as side branch and intra-stent thrombosis), 4.2% (95% CI 2.0–6.3) delayed ischemic events, 2.3% (95% CI 0.4–4.2) massive effect, 1.8% (95% CI 0.7–2.9) delayed hemorrhage, and 1.0% (95% CI 0.3–1.7) acute hemorrhage.

Delayed procedure-related complications

The delayed procedure-related complication rate was 6.6% (95% CI 4–9.1), including 3.3% (95% CI 1.4–5.3) morbidity and 3.2% (95% CI 1.8–4.7) mortality. The reasons for morbidity were 2.5% (95% CI 0.5–4.4) thromboembolic, 0.6% (95% CI 0.1–1.1) hemorrhagic and 0.3% (95% CI 0–0.6) mass effect. Reasons for mortality were 1.6% (95% CI 0.6–2.7) hemorrhagic, 0.5% (95% CI 0.1–1.0) thromboembolic, 0.5% (95% CI 0.2–1.2) infection, 0.3% (95% CI 0.1–0.7) myocardial infarct, and 0.2% (95% CI0–0.5) mass effect.

Clinical and follow-up imaging outcome

After three to 62 months of follow-up, the overall favorable clinical outcome (modified Ranking Scale score (mRS) 0 and 1) rate³³ was 88.2% (95% CI 80.9–95.4), and complete or nearly complete (Raymond I and II³⁴) aneurysmal occlusion rate was 84.4% (95% CI 79.9–88.9).

Risk factors for technical failure and complications, procedure-related complications, morbidity and mortality (Table 1)

Table 1.

Odd ratios and p values for potential risk factors for technical failure and complications, procedure-related complications, morbidity and mortality.

	Technical failure and complications OR (95% CI), p value	Procedure-related complications OR (95% CI), p value	Morbidity and mortality OR (95% CI), p value
Female sex	0.89 (0.18, 4.35), 0.89	1.59 (0.68, 3.73), 0.29	1.0 5(0.38, 2.90), 0.92
Posterior circulation location	0.73 (0.27, 2.0), 0.54	4.03 (2.45, 6.61), <0.0001	4.39 (2.44, 7.90), <0.0001
Peripheral location	1.45 (0.45, 4.73), 0.54	2.74 (1.52, 4.94), 0.0008	3.64 (1.74, 7.62), 0.0006
Fusiform, dissecting and circumferential	3.10 (0.93, 10.37), 0.07	1.95 (1.15, 3.30), 0.01	1.54 (0.73, 3.24), 0.26
Unruptured	0.45 (0.08, 2.44), 0.36	1.89 (0.80, 4.44), 0.15	1.00 (0.33, 3.00), 1.00
Large and giant size	1.71 (0.17, 17.15), 0.65	1.75 (0.72, 4.26), 0.22	1.04 (0.29, 3.80), 0.95

OR: odds ratio; CI: confidence interval.

Statistically significant risk factors for procedure-related complications were posterior circulation location (OR 4.03, 95% CI 2.45–6.61, p < 0.0001), peripheral location (OR 2.74, 95% CI 1.52–4.94, p = 0.0008) and fusiform, dissecting and circumferential aneurysm (OR 1.95, 95% CI 1.15–3.30, p = 0.01). Posterior circulation location (OR 4.39, 95% CI 2.44–7.90, p < 0.0001) and peripheral location (OR 3.64, 95% CI 1.74–7.62, p = 0.0006) were statistically significant risk factors for morbidity and mortality. Fusiform, dissecting and circumferential aneurysm (OR 1.54, 95% CI 0.73–3.24, p = 0.26) demonstrated a trend toward an increased risk of morbidity and mortality that was not statistically significant. In addition, fusiform, dissecting and circumferential aneurysm (OR 3.10, 95% CI 0.93–10.37, p = 0.07) and peripheral location (OR 1.45, 95% CI 0.45–4.37, p = 0.54) demonstrated a trend toward an increased risk of technical failure and complication. Female sex, unruptured aneurysm and large and giant size were not statistically significant risk factors for any adverse events.

Discussion

Flow-diverter devices in the treatment of intracranial aneurysms has been associated with 88.2% (95% CI 80.9%–95.4%) favorable clinical outcome, 84.4% (95% CI 79.9–88.9%) complete or nearly complete aneurysmal occlusion rate, 3.3% (95% CI 1.4–5.3%) morbidity and 3.2% (95% CI 1.8–4.7%) mortality. Two meta-analyses were attempted to clearly delineate their risks and efficacy in 2013, and they continue to present a considerable challenge owing to a remarkable degree of heterogeneity and publication biases not only in study design but also in results.³ Published aneurysmal complete occlusion rates are often variable, ranging anywhere from 55% to 95%.^22,28 Among larger studies, mortality^25,35 rates have ranged from 0% to 7%, whereas morbidity^25,32 has ranged from 0% to 12%. This is probably in part due to the limited statistical power of an individual study, prompting our meta-analysis.

Overall complication rate

Arrese et al.³ collected 15 studies, and their early mortality rate was 2.8% (95% CI 1.7–3.8) and late mortality rate was 1.3% (95% CI 0.2–2.3). The early neurological morbidity rate was 7.3% (95% CI 5.7–9) and the late morbidity rate was 2.6% (95% CI 1.1–4). In the Brinjikji et al. analysis² of 29 studies, aneurysmal complete occlusion rate was 76% (95% CI 70–81), procedure-related morbidity and mortality rates were 5% (95% CI 4–7) and 4% (95% CI 3–6), respectively. Our analysis of 29 studies demonstrated an technical failure and complication rate of 9.3% (95% CI 6–12.6), procedure-related complication rate of 14% (95% CI 10.2–17.9), morbidity and mortality rate of 6.6% (95% CI 4–9.1), favorable clinical outcome rate of 88.2% (95% CI 80.9–95.4) and complete or nearly complete aneurysmal occlusion rate of 84.4% (95% CI 79.9–88.9). Our results were comparable to two previous studies. This blanket value is highly influenced by the factors discussed below and is crucial to the therapeutic option for intracranial aneurysms.

Posterior circulation location

Flow-diverting stents may be an option for basilar artery (BA) aneurysms that are either difficult to treat by conventional endovascular methods, recur after previous endovascular treatments, or are candidates for high recurrence rates and disease progression. There is a lack of extensive data regarding the use of flow diverters for VB aneurysms. In a series of 12 flow-diverter cases for BA aneurysms, 66% had good functional outcomes, but there were five strokes (41%).²⁹ The first and major concern of using a high-structural-profile device for vessel reconstruction in the BA is the patency of the perforators.²⁹ Patients with posterior circulation aneurysms are at higher risk of ischemic stroke, particularly perforator infarction.² Treatment by endovascular means with flow diversion is one option but is not necessarily the safest or most definitive treatment modality.³⁶ We found that posterior circulation location was a risk factor for ischemic and hemorrhagic procedure-related complications and morbidity and mortality. Matching our experience, the use of flow-diverter devices for posterior circulation aneurysms was associated with more complications, and extra caution is required.

Fusiform, dissecting and circumferential aneurysms

Flow-diverter implantation offers a way to treat fusiform, dissecting and circumferential aneurysms that cannot be treated conventionally.²⁶ These aneurysms are often located as posterior circulations and have a giant size.¹ Those patients usually present with ischemic stroke, mass effect and have a dismal natural history^37,38 that will rapidly deteriorate after treatment, most commonly from progressive massive effect, ischemic symptoms and brain-stem infarcts as well as ruptures.³⁶ Currently, we are still at a loss for finding an optimal safe and effective treatment for large or giant VB fusiform aneurysms. Fusiform, dissecting and circumferential aneurysms are risk factors for flow diverter-related complications and show a trend to morbidity and mortality. Strategies applied thus far have had mixed results at best,³⁶ including most recently flow diversion; a careful determination of the risks and benefits of intervention is appropriate.

Peripheral location

Flow diverter devices were originally designed for side-wall aneurysms and its use in bifurcation aneurysms had been limited. Nelson et al.³⁹ reported a left basal ganglion infarct secondary to two pipeline embolization devices placed in the M1 segment of the left MCA with a pre-existing Neuroform stent. Van Rooij and Sluzewski reported another case of left basal ganglion infarction after placement of two telescoping pipeline embolization devices in the A1 segment of the ACA.⁴⁰ Both cases were thought to be related to occlusion of lenticulostriate arteries from M1 and A1 segments of the MCA and ACA, respectively. Nossek et al.⁴¹ found that deployment of a pipeline embolization device from the distal supraclinoid ICA to the M1 may result in reversal of flow in the ACA/Acoma complex and regression of the ipsilateral A1. These reports raise concern about using flow-diverter devices in segments of vessels distal to Willis circle.

Technical complications

Device deployment is successful consistently in 87% to 100% across many studies,^22,26,31,42 technical complications occurred in a range of 3.1% to 33.3% depending on the definition of technical complications in different studies.⁴³ In our analysis, there was a 9.3% (95% CI 6–12.6) technical failure and complication rate, including incomplete deployment, failure, vessel perforation, misplacement, stent migration, ICA dissection, and wire fracture. Incomplete deployment of the flow-diverter device was mainly observed in vessel segments with tight or acute curves.²⁶ Allowance for the anticipated foreshortening of approximately 50% and possible device shift during deployment is critical when choosing the length of the device.²⁷ There is a potential risk of an endoleak-like phenomenon with implantation of an undersized device, which results in poor wall apposition. Similarly, implantation of an oversized device may result in poor coverage of the lesion because of an incomplete compaction of the strands.²⁶ The diameter of the proximal segment of the target vessel and the diameter at the origin of the lesion determine the diameter of the flow-diverter device.⁴⁴ The distal vessel diameter is of lesser importance. Selection of a stent diameter 0.25 to 0.5 mm larger than the distal parent diameter is also recommended.⁴² Most of these complications did not result in clinically significant sequelae.⁴³

Study limitations

Although the incorporated studies adhered to a similar endovascular approach using flow-diverter devices, all drew from patients presenting to a selected hospital or group of hospitals and were not population based. All studies were limited by selection bias, as patients with an anticipated difficulty or failure of conventional microsurgical or endovascular techniques should particularly be considered for flow-diverter device treatment. The follow-up of patients treated by flow-diverter devices was short term and may be more limited. In addition, patients lost to follow-up were often not addressed. According to the publication bias analysis, small studies have reported more adverse outcomes than large studies.³ Our methods were limited by our English-language restriction. We intentionally provide 2009 as a start date for our PubMed search and used very broad search terms because of the learning curve and more technical problems in early cases.⁴³

Conclusions

We demonstrated an overall morbidity rate 3.3% (95% CI 1.4–5.3) and mortality rate of 3.2% (95% CI 1.8–4.7) for flow-diverter devices in the treatment of intracranial aneurysms. Posterior circulation, fusiform, dissecting and circumferential aneurysm and peripheral location are significant risk factors for greater procedure-related complications.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.