Pipeline Flex embolisation device with Shield Technology for the treatment of patients with intracranial aneurysms: periprocedural and 6 month outcomes

Abstract

Background and purpose

The Pipeline Flex embolisation device with Shield Technology (Pipeline Shield) is a novel flow diverter which reduces intra-vessel thrombogenicity. This study summarises periprocedural outcomes and 6-month follow-up results following its introduction in a tertiary interventional neuroradiology centre.

Materials and methods

This prospective, single-arm study assessed 32 aneurysms treated over a 21-month time period from the time of procedure to 6 months post-procedure. Data collected included patient demographics, aneurysm features and intraprocedural and 6-month post-procedural complications.

Results

The mean age of the cohort was 58.8 ± Standard Deviation 8.5 years. Twenty-eight aneurysms were treated electively and four acutely. The elective cases received dual antiplatelet therapy post-procedure. The acute cases received single antiplatelet therapy post-procedure. Of the target aneurysms, 16/32 (50%) were small (<10 mm), 13/32 (41%) were large (10–25 mm) and 3/32 (9%) were giant (≥25 mm). There was no mortality in the series. There were two periprocedural complications (2/32, 6.2%): a stroke and a dissection. There were no post-procedural complications. At 6 months post-procedure, satisfactory occlusion (defined as Raymond–Roy 1 or 2) was achieved in 90.6% and 93.8% by way of magnetic resonance angiography and digital subtraction angiography assessment, respectively. There was no implant migration, no significant intraluminal hyperplasia or in-stent stenosis and no cases of aneurysm recurrence.

Conclusion

The Pipeline Shield has an excellent 6- month safety profile with an acceptable rate of intraprocedural complications, no post-procedure complications and no mortality in this case series of 32 acute and elective cases.

Introduction

The transluminal treatment options for intracranial aneurysms have expanded greatly in recent years.¹ One transluminal treatment that has become routine is the flow diverter, pioneered by the Pipeline Embolisation Device (Medtronic Neurovascular, USA). The device is a self-expanding, microcatheter-delivered, cylindrical mesh stent composed of braided individual cobalt chromium and platinum strands.² This has proved to be a safe and effective treatment for intracranial aneurysms in multicentre studies as a stand-alone treatment and in conjunction with adjuvant coiling.³,⁴ The second generation of the Pipeline Embolisation Device, the Pipeline Flex, had a redesigned device delivery system, allowing greater control over the installation of the device. It received a positive response from the interventional neuroradiology community, has an acceptable safety profile, and has a high rate of successful aneurysm occlusion.⁵,⁶

The third, and most recent, generation of the device has been termed the Pipeline Flex with Shield Technology (Pipeline Shield). This device incorporates a phosphorylcholine surface coating which reduces thrombogenicity.⁷ The coating achieves this by slowing the generation of thrombin and reducing the total number of activated platelets.⁸,⁹ Prospective, single-arm, multicentre studies have demonstrated that at one year of follow-up it has comparable or improved rates of complete aneurysm occlusion, retreatment rates and thromboembolic complication rates compared to previous Pipeline generations for unruptured aneurysms.¹⁰,¹¹ This paper contributes further evidence for the Pipeline Shield’s medium term safety and efficacy at 6 months of follow-up.

Materials and methods

Study design and participants

This prospective, single-arm study reviewed a total of 31 patients with 32 aneurysms, 28 of which were treated electively and four of which were treated acutely, over a 21-month time period between 1 October 2017 and 31 July 2019 at a tertiary centre for interventional neuroradiology. The novel technology used in all cases was the Pipeline Shield flow diverter.

The inclusion criteria were:

• Age 18 years and above

• Wide-necked intracranial aneurysms

• Aspect ratio less than 1.6

• Dome-to-neck ratio less than 2

• Neck length greater than 4 mm

• Blister aneurysms of the supraclinoid internal carotid artery (ICA) and posterior circulation

• Intracranial aneurysms not amenable to balloon-assisted coiling.

The exclusion criteria are listed below:

• Inability to receive antiplatelet agents prior to or following the procedure

• Active infection if the aneurysm is being treated electively.

Aneurysm dimensions were measured by a single interventional neuroradiology consultant using reformatted angiography images.

Preoperative assessment

All patients underwent a preoperative assessment consisting of a neurological examination and routine blood tests. Patients with unruptured intracranial aneurysms being treated for the first time underwent a computed tomography (CT) angiogram, while patients being treated for a recurrence had a magnetic resonance angiogram.

Device characteristics and sizing

The Pipeline Shield is a braided, multi-alloy, mesh cylinder with a soft low-profile distal tip designed for placement in a parent vessel. This iteration of the Pipeline flow diverter claims to reduce thrombogenicity by way of a surface layer of synthetic phosphorylcholine biocompatible polymer. This is covalently bonded to the braided strands of the stent.⁷ Its macrostructure is unchanged from the Pipeline Flex, achieving a high level of operator control in deployment with easy tracking, vessel deflection and the ability to reposition and redeploy.¹²

The Pipeline Shield is supplied in multiple sizes, from 2.5 mm × 10 mm to 5 mm × 35 mm. Pipeline sizing is aided by the use of the software application Sim&Size (Sim&Cure, France). This software assists in precise sizing of the device, ensuring the length of the diverter is the shortest necessary to bridge the aneurysm neck, therefore reducing procedure-related complications and technical issues related to trackability.

Treatment description

Elective patients received single oral doses of aspirin 300 mg and clopidogrel 600 mg the night before the procedure. The VerifyNow P2Y12 assay (Werfen, Spain) was used to confirm an adequate response to dual antiplatelet therapy. All unruptured, elective aneurysm patients with a good P2Y12 antagonist response were placed on a post-procedure regimen of oral clopidogrel 75 mg once daily for 5 months and oral aspirin 75 mg once daily for 12 months.

There were no P2Y12 antagonist poor or non-responders in the cohort. If there had been, the procedure would have been abandoned in P2Y12 antagonist non-responders and the post-procedure regimen would have been altered for P2Y12 antagonist poor responders. Poor P2Y12 antagonist responders would have been given oral prasugrel 5–10 mg once daily for 5 months.

Acute patients received a single intravenous dose of aspirin 500 mg immediately prior to the deployment of the Pipeline device during the procedure. All acute patients received a single antiplatelet therapy regimen post-procedure of oral aspirin 75 mg once daily for 12 months.

No evaluation of aspirin response was conducted for acute patients. This was due to aspirin’s antiplatelet mechanism of action being reported as effective in 99.6% of patients.¹³ Monotherapy was continued post-procedure due to operator preference, acceptable local safety evidence and acceptable safety evidence from other neurointerventional centres.¹⁴,¹⁵

All procedures were carried out under general anaesthesia. Arterial access was established by way of ultrasound-guided common femoral artery puncture in all cases except one, in which access was established by way of surgical cut-down of the left common carotid artery. After the establishment of arterial access, intravenous heparin was administered. The dose was titrated to achieve an activated clotting time of twice the patient’s baseline. Activated clotting times were measured at regular intervals during the procedure, with additional heparin boluses administered as required to maintain an optimal level of anticoagulation.

Deployment of all devices was conducted by a single operator working in conjunction with an experienced theatre team. All devices were deployed using a triaxial system that utilised catheters including the Neuron MAX (Penumbra, USA), Navien (Covidien Vascular Therapies, USA) and Phenom (Cathera, USA).

Aneurysms less than 15 mm in maximum diameter were flow diverted with no additional coiling. Aneurysms greater than 15 mm in maximum diameter were flow diverted and coiled using a jailed catheter technique. All acute aneurysms were coiled.

Follow-up assessments

Patients had immediate periprocedural monitoring and follow-up angiography (magnetic resonance angiography (MRA) and digital subtraction angiography (DSA)) at 6 months after the procedure. Images were assessed for the degree of aneurysm occlusion using the Raymond–Roy scale: class 1 = complete occlusion; class 2 = residual neck; and class 3 = residual aneurysm.¹⁶ The occurrence of implant migration, in-stent stenosis and intraluminal hyperplasia was also assessed on the follow-up angiography. Parent artery stenosis was classified into four categories: 0–25%; 25–50%; 50–75% and > 75% stenosis. Assessments were conducted by a single operator (AS) with 2 years of experience.

All patients were scheduled to have further angiographic imaging at 2 years and 5 years post-procedure.

Study endpoints

The primary endpoint of the study was 6 months post-procedure. The secondary endpoint was an unacceptable rate of mortality or stroke, intraprocedural complications, or serious adverse events in the cohort within the study timeframe. Study investigators were required to report all mortalities, intraprocedural complications and serious adverse events.

The occurrence of a stroke was defined by the World Health Organization criteria for a stroke, namely a disturbance of cerebral function due to a vascular cause with symptoms lasting 24 hours or longer.¹⁷ Serious adverse events were defined based on the US Food and Drug Administration’s guidelines as events in which the outcome was life threatening, required hospitalisation, disability, or required intervention to prevent permanent impairment.¹⁸

Statistical analysis

Data were analysed by the intention-to-treat approach. Discrete variables were summarised using frequency and percentage calculations; while continuous variables were analysed using frequency, mean, standard deviation (SD), median and minimum and maximum values as deemed appropriate. Statistical analysis was performed using Microsoft Excel (Microsoft, USA).

Results

In total, 31 patients with 32 aneurysms were treated. The mean age was 58.8 ± SD of 8.5 years, and 26 patients were women (male:female ratio of 1:5.3). The mean maximum aneurysm diameter was 11.0 mm (median 9.8 mm, range 2–40 mm) and the mean aneurysm neck size was 5.9 ± SD of 3.0 mm (see Table 1).

Table 1.

Patient and aneurysm characteristics.

Mean age ± SD	M:F	Mean and median aneurysm maximum diameter (range)	Mean neck size ± SD
58.8 ± 8.5	1:5.3	11.0 mm, 9.8 mm (2–40 mm)	5.9 mm ± 3.0 mm

M:F: male:female ratio; SD: standard deviation.

Of the target aneurysms, 16/32 (50%) were small (<10 mm), 13/32 (41%) were large (10–25 mm) and three of 32 (9%) were giant (≥25 mm). There were two (6%) aneurysms located in the posterior circulation and 30 (94%) were in the anterior circulation (see Table 2). Out of 32 aneurysms, four aneurysms were treated acutely. First time treatment was performed on 23 aneurysms and nine aneurysms were re-treated after previous coiling.

Table 2.

Summary of aneurysm locations demonstrating the majority of treated aneurysms were located in the anterior circulation.

Location	Number
Anterior circulation (30/32, 93.8%)
Anterior choroidal artery	1 (3.1%)
Cavernous ICA	5 (15.6%)
Hypophyseal artery	2 (6.3%)
MCA bifurcation	1 (3.1%)
Paraophthalmic ICA	6 (18.8%)
Posterior communicating artery	15 (46.9%)
Posterior circulation (2/32, 6.3%)
Distal basilar artery	1 (3.1%)
Proximal basilar artery	1 (3.1%)

ICA: internal carotid artery; MCA: middle cerebral artery.

Sample case

A 46-year-old woman presented with a large 12 mm × 6 mm right parophthalmic ICA aneurysm found during investigation of an intractable headache. Following deployment of a 4 mm × 16 mm Pipeline device across the aneurysm neck, there was complete occlusion of the aneurysm with no recurrence at 6 months post-procedure (Figures 1 and 2).

Three of the acute aneurysms were located in the anterior circulation: two were located in the posterior communicating artery and one was located in the cavernous ICA. The posterior circulation aneurysm was located between the superior cerebellar artery and the anterior inferior cerebellar artery.

There were three aneurysms treated with a second Pipeline Shield device due to fore-shortening of the first device post-deployment or suboptimal neck coverage (3/32, 9.3%). Intra-aneurysmal stasis in 24 cases was present immediately post-flow diversion. Additional coiling through a jailed Echelon-10 microcatheter (Medtronic Neurovascular, USA) was performed on eight patients.

There was no post-procedure mortality in the series. However, there were two intraprocedural complications: one haemorrhagic stroke (affecting the left-sided basal ganglia and left temporal lobe) and one ICA dissection (affecting the petro-cavernous segment).

The stroke occurred during a complex procedure. The patient presented with a wide-necked 20 mm × 15 mm left posterior communicating artery aneurysm. This patient had blocked bilateral iliac vessels. Direct access to the left common carotid artery was obtained by vascular surgery specialists and a short 6 French sheath was inserted. This approach was preferred to a transradial or transbrachial approach due to operator preference. A Navien catheter (Covidien Vascular Therapies, USA) was advanced to the left ICA. The left ICA was dysplastic and narrowed in several segments. Two Pipeline Shield devices were deployed across the neck of the aneurysm. The second device was required due to immediate foreshortening of the device and subsequent migration following angioplasty. The aneurysm was coiled through an Echelon microcatheter (Medtronic Neurovascular, USA). Attempts to widen the dysplastic left ICA led to the formation of a traumatic left carotico-cavernous fistula. Vascular surgery specialists obtained a left internal jugular vein access and a Benchmark catheter (Penumbra, USA) was advanced into the left internal jugular vein. A Headway DUO microcatheter (MicroVention, USA) was inserted into the left cavernous sinus, and the cavernous sinus and the carotico-cavernous fistula were occluded with coils. The patient woke up with a right-sided neurological deficit. CT imaging demonstrated a left-sided basal ganglia and left temporal lobe intracranial haemorrhage, probably secondary to wire perforation. A CT angiogram showed the Pipeline device remained patent and correctly sited. The patient underwent neurorehabilitation and had moderate disability (modified Rankin score of 3)¹⁹ at 6 months post-procedure (Figure 3).

The dissection occurred during an elective procedure. This patient underwent flow diversion of a large 8 mm × 10 mm right posterior communicating artery recurrence that had previously been coiled twice. There was a small clot at the distal end of the Pipeline device due to poor opposition; 500 mg intravenous aspirin was administered. The clot was dislodged with a Traxcess guidewire (Microvention, USA) and the distal end of the device was balloon angioplastied with good apposition. During this manoeuvre, there was dissection of the petro-cavernous segment of the ICA by the advancing tip of the intermediate catheter. A single Solitaire stent (Medtronic Neurovascular, USA) sized 6 mm × 30 mm was deployed across the dissection, reopening the vessel. The patient woke up with no new neurological deficits.

Six months’ follow-up

At 6 months post-procedure, satisfactory occlusion (defined as Raymond–Roy 1 or 2) was achieved in 90.6% (29/32) and 93.8% (30/32) by MRA and DSA assessment, respectively (see Table 3). There was no implant migration. None of the cases showed significant (>25% of stent diameter) intraluminal hyperplasia or in-stent stenosis at 6 months’ angiographic follow-up. There were no cases of aneurysm recurrence. There were no symptomatic embolic infarcts post-flow diversion on MRA assessment.

Table 3.

Aneurysm occlusion at 6 months post-procedure demonstrating good angiographic results (defined as Raymond–Roy 1 or 2) in 90.6% (29/32) and 93.8% (30/32) of patients by MRA and DSA assessment, respectively.

	MRA	DSA
Raymond–Roy 1	25 (78.1%)	23 (71.9%)
Raymond–Roy 2	4 (12.5%)	7 (21.9%)
Raymond–Roy 3	2 (6.3%)	1 (3.1%)
Lost to follow-up	1 (3.1%)	1 (3.1%)

MRA: magnetic resonance angiography; DSA: digital subtraction angiography.

Discussion

This study contributes further data to the growing body of evidence that the Pipeline Shield is an effective and safe treatment option for unruptured intracranial aneurysms. A multicentre study has previously shown that use of this device has led to no major strokes or deaths at one year follow-up in a cohort of 50 patients,¹⁰ while a larger study of 151 patients reported two major strokes, one haemorrhage and one death¹¹ – an acceptable complication rate of 2.6% comparable with meta-analyses of studies involving the second generation Pipeline.²⁰ This study corroborates these positive findings with observational 6-month follow-up results from a separate tertiary centre for interventional neuroradiology not involved in previous trials.

In the previously referenced multicentre studies, the majority of aneurysms were small (<10 mm). In this study, half the aneurysms (16/32) were classified as large or giant (>10 mm). The success of the Pipeline Shield in the treatment of large and giant aneurysms reported here is encouraging and provides limited support for previously documented safety outcomes and reduced complication rates with aneurysms of this size.¹⁰,¹¹

In addition, we observed no complications in either of the posterior circulation aneurysms treated. The extremely small sample size prevents any comment being made regarding the Pipeline Shield’s complication rate in posterior circulation aneurysms, but this represents an interesting avenue for future research, especially as previous studies from 2013 and 2017 have suggested a posterior circulation complication rate of 10–15% for flow diverters,²¹,²² and previous generations of the Pipeline devices have shown a comparatively higher rate of complications within the posterior circulation. Kallmes et al. reported that the first generation Pipeline had a 7.3% rate of ischaemic stroke in a cohort of 55 patients,²³ while a systematic review of findings for the second generation Pipeline Flex suggested that an increased risk remains such a concern that practitioners are actively avoiding using flow diverters on posterior circulation aneurysms: only 36 of 794 aneurysms (4.5%) were in the posterior circulation in the pooled studies.²⁰

Analysis of the two complications in this dataset suggests the Pipeline Shield was not the direct cause of either complication. The first complication, a traumatic left carotico-cavernous fistula and left-sided intracranial haemorrhage, was in the context of atypical access, a dysplastic and narrowed parent vessel and challenging device deployment. We suggest the haemorrhagic stroke could not have been foreseen. Retrospective reviews of the intraprocedural images by two interventional neuroradiologists concluded that there was no lead wire perforation on contrast stasis in the brain parenchyma. The second case, in which there was dissection of the ICA during angioplasty with no lasting neurological deficit, is a known complication with this type of procedure and is well described within the literature.²⁴

The coating used in Shield Technology was first shown to lower thrombogenicity in canine models of arteriovenous grafts.²⁵ More recently, the phosphorylcholine coating has been shown to reduce clots significantly when incorporated into the pipeline device in both in-vivo²⁶ and in-vitro work.^7--9 We provide observational evidence to support this claim, as we report no thromboembolic events in any of the 32 treated aneurysms at 6 months’ post-procedure. Further 12-month, 2-year and 5-year monitoring is required to assess the duration of the thromboprotective effects of the Shield Technology. It would also be valuable to assess whether the introduction of a phosphorylcholine surface modification to a flow diverting device mitigates the need for post-procedure dual antiplatelet therapy and the subsequent risks of such treatment. In our cohort, the four acute aneurysms treated with single antiplatelet therapy had no complications at 6 months’ follow-up. While this represents a promising observation, no conclusions can drawn given the small sample size, and more research is needed. Findings at other centres in Australia and Canada in this regard have been promising.¹⁴,¹⁵

At 6 months of follow-up we report no significant in-stent stenosis or intraluminal hyperplasia, with all cases having less than 25% reduction in the intraluminal diameter. This low rate of stenosis is comparable to previous multicentre studies using the Pipeline Flex with Shield Technology, which reported significant stenosis in 19.4% (7/36)¹⁰ and 2.9% (2/69) of cases¹¹ and correlates with a recent porcine study which found reduced in-stent stenosis when comparing Pipeline Shield with Pipeline Flex.²⁷ Clinical studies on previous generations of the Pipeline device showed that 8% of cases had at least moderate (>50%) stenosis in comparison to none of the cases in this series.²⁸ Our findings contribute to the growing body of evidence that Shield Technology does reduce in-stent stenosis and intraluminal hyperplasia.

The use of shorter longitudinal sizes of flow diverter allowed for easier tracking of the device in the microcatheter and facilitated the precise deployment of the flow diverter in straight segments. A further benefit of this precise deployment was the minimisation of the risk of fish mouthing, in which there is a focal structural decrease in luminal diameter without any intimal hyperplasia due to a shift in the diverter configuration.²⁹,³⁰ We therefore suggest that the low rate of complications in this study is in part due to the wide range of sizes available for the Pipeline Shield and its precise deployability.

The Pipeline Shield represents a promising development in the progression of flow diverter technology. This field remains in an exciting phase of innovation, with new flow diverters such as the Pipeline Vantage embolisation device (Medtronic Neurovascular, USA) providing thinner wiring, higher pore density and increased fluoroscopic visibility. Early findings suggest the resulting lower implant profile and optimised pore density may improve endothelial coverage and flow diversion while preserving perforator and branch vessel patency.³¹ The Pipeline Vantage and other new devices such as the DERIVO mini (Acandis GmbH, Germany) and the Silk Vista Baby (Balt Extrusion, France) are also capable of delivery through 0.021” microcatheters, or even 0.017”microcatheters in the case of the Silk Vista Baby. This will allow flow diversion of increasingly smaller, more distal vessels.^31–33 The results of the ADVANCE and FIRST clinical trials into Pipeline Vantage and Silk Vista Baby’s respective safety and effectiveness are awaited with great interest.³⁴,³⁵

This study has significant limitations. Firstly, it is a single-armed study. It was not possible to compare the Pipeline Shield with a comparable treatment due to previous evidence indicating that the Pipeline Shield had better outcomes, therefore rendering a study involving a comparator unethical.³⁶ Furthermore, the study was conducted at a single centre and the procedures were conducted by a single operator on a limited cohort of patients. The low number of patients limits the statistical power of the results.

Conclusion

This study suggests the Pipeline Flex embolisation device with Shield Technology has an acceptable rate of complications and excellent angiographic outcomes, with no post-procedure mortality at 6 months’ follow-up in this small cohort of patients. Further research is needed to establish its safety and effectiveness in large-scale studies, in posterior circulation aneurysms and when used with post-procedure single antiplatelet therapy.