Pipeline Embolization Device in Treatment of 50 Unruptured Large and Giant Aneurysms

Accepted Manuscript Pipeline Embolization Device in treatment of 50 unruptured large and giant aneurysms Nimer Adeeb, MD, Christoph J. Griessenauer, MD, Hussain Shallwani, MD, Hakeem Shakir, MD, Paul M. Foreman, MD, Justin M. Moore, MD, PhD, Adam Dmytriw, MD, Raghav Gupta, Adnan H. Siddiqui, MD, PhD, Elad I. Levy, MD, Kenneth Snyder, MD, PhD, Mark R. Harrigan, MD, Christopher S. Ogilvy, MD, Ajith J. Thomas, MD PII:

S1878-8750(17)30830-6

DOI:

10.1016/j.wneu.2017.05.128

Reference:

WNEU 5822

To appear in:

World Neurosurgery

Received Date: 23 December 2016 Revised Date:

21 May 2017

Accepted Date: 23 May 2017

Please cite this article as: Adeeb N, Griessenauer CJ, Shallwani H, Shakir H, Foreman PM, Moore JM, Dmytriw A, Gupta R, Siddiqui AH, Levy EI, Snyder K, Harrigan MR, Ogilvy CS, Thomas AJ, Pipeline Embolization Device in treatment of 50 unruptured large and giant aneurysms, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.05.128. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Pipeline Embolization Device in treatment of 50 unruptured large and giant aneurysms

Nimer Adeeb MD1, Christoph J. Griessenauer MD1, Hussain Shallwani MD2, Hakeem Shakir

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MD2, Paul M. Foreman MD3, Justin M. Moore MD, PhD1, Adam Dmytriw MD1, Raghav Gupta1, Adnan H. Siddiqui MD, PhD2, Elad I. Levy MD2, Kenneth Snyder MD, PhD2, Mark R.

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Harrigan MD3, Christopher S. Ogilvy MD1, Ajith J. Thomas MD1

Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston,

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Department of Neurosurgery, State University of New York at Buffalo, Buffalo, NY

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Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL

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Keywords: Pipeline, intracranial, large, giant, aneurysm, occlusion, complications

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Correspondence: Ajith J. Thomas, M.D.

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Neurosurgical Service

Beth Israel Deaconess Medical Center 110 Francis Street, Suite 3B Boston, MA 02215-5501 Phone: (617) 632-7246 [email protected]

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Abstract

Introduction

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Treatment of large (≥ 20 mm) and giant (≥ 25 mm) intracranial aneurysms is challenging, and can be associated with a high rate of morbidity and mortality. The Pipeline Embolization Device (PED) has been effectively used for the treatment of intracranial aneurysms achieving a high rate

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of complete occlusion. However, its safety and efficacy in treatment of large and giant

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aneurysms has not been fully evaluated.

Methods

A retrospective analysis of consecutive aneurysms treated with PED between 2009 and 2016 at three academic institutions within the United States was performed. Large (≥ 20 mm) and giant

placement.

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Results

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(≥ 25 mm) were selected for evaluation of occlusion and complication rates associated with PED

A total of 50 large and giant aneurysms were individually treated using PED. Aneurysms were

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fusiform (74%) or saccular (26%) in morphology. PED alone was used for treating 78% of the aneurysms, while PED with adjunctive coiling was used for treating 22%. The median length of angiographic follow-up was 13 months (mean 20.4 months). At last follow-up, complete or near complete occlusion (90-100%) was achieved in 76.9% of aneurysms. Symptomatic thromboembolic complications were encountered in 12% of procedures and symptomatic hemorrhagic complications in 8%.

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Conclusion The use of PED for treatment of large and giant intracranial aneurysms is associated with good

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occlusion rate, but higher complication rate compared to aneurysms smaller in size. There was no significant difference in occlusion rate based on aneurysm shape and size, number of PEDs

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placed, or adjunctive coiling.

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Introduction

Large (≥ 20 mm) and giant (≥ 25 mm) intracranial aneurysms pose a significant challenge for

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both surgical and endovascular treatments, and are often associated with a high recurrence rate and an increased rate of procedural morbidity and mortality.1–3 The Pipeline Embolization Device (PED) was approved by the Food and Drug Administration for treatment of wide-necked

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brain aneurysms of the internal carotid artery (ICA) greater than 10 mm in adults.4 Nonetheless, PED has also become a mainstay for the treatment of intracranial aneurysms with varying

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morphologies, sizes, and anatomical locations.5–10 Despite its approval for wide neck aneurysm, only a few reports with small numbers of aneurysms have evaluated the use of PED in the treatment of unruptured large and giant aneurysms.11–13 In one case series of 47 aneurysms, the findings were limited due to smaller aneurysm size (≥ 15 mm) and short duration of follow-up.12

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Moreover, although the use of adjunctive coiling along PED placement has been reported in few

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large series14–16, it was rarely evaluated for unruptured aneurysms this size

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Methods

A retrospective analysis of consecutive aneurysms treated with PED placement between 2009

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and 2016 at three academic institutions in United States was performed. All adult patients with large (≥ 20 mm) and giant (≥ 25 mm) intracranial aneurysms treated with PED placement with or without adjunctive coiling were included. Both saccular and fusiform aneurysms in all

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intracranial locations were included. Institutional Review Board approval was obtained at all three centers prior to the commencement of the study. The following information was collected:

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patient demographics, aneurysm and treatment characteristics, procedural complications, and angiographic and functional outcomes. For saccular aneurysms, both maximal aneurysms diameter and neck size were measured. For fusiform aneurysms, both aneurysm length and width

Procedure details

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were measured.

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Patients received aspirin 325 mg and clopidogrel 75 mg daily for 3 to 14 days prior to the intervention. Platelet function testing was routinely performed using whole blood lumi-

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aggregometer, light transmission aggregometry (LTA), or VerifyNow®. Clopidogrel nonresponders were identified based on established cut off values at the individual institutions and were guided by the manufacturer recommendations. If a patient was identified as a clopidogrel responder, the clopidogrel was continued. If a patient was identified as a clopidogrel nonresponder, the choice to continue on same dose clopidogrel, administer a one-time 600 mg clopidogrel boost dose within 24 hours pre-procedure, or switch to ticagrelor was at the

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discretion of the interventionalist performing the procedure. Patients underwent local anesthesia with sedation or general anesthesia at the discretion of the individual institutions and all patients were anti-coagulated with heparin throughout the procedure. The type of the guide catheter and

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micro catheter used for PED deployment was also at the discretion of the individual institution. The deployment and apposition of the PED to the ICA wall was documented by fluoroscopy. Dual antiplatelet therapy was continued for at least 3 months after the procedure and aspirin

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Angiographic and clinical outcome

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indefinitely thereafter.

Angiographic outcome was assessed using digital subtracted angiography (DSA) magnetic resonance angiography (MRA), or computed tomography angiography (CTA) based on follow-

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up protocols utilized at each individual institution. Aneurysm occlusion on follow-up DSA imaging was assessed by the treating interventionalist. Follow-up MRAs were assessed by a radiologist and the treating interventionalist. Occlusion was categorized as complete or near

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complete occlusion (90-100%), and partial occlusion (< 90%). Functional outcomes were

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assessed using the modified Rankin Scale (mRS) at last follow-up.

Thromboembolic complications occurring from the date of the procedure up to last follow-up were included. Intra-procedural thromboembolic complications were identified on DSA as either thrombus formation, slow filling of a previously normally filling vessel, or vessel dropout. Postprocedural thromboembolic complications were identified using a combination of clinical and radiographic findings. Post-procedural imaging was performed at the discretion of the individual

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institutions and was only obtained due to clinical concern. Routine screening for clinically silent ischemic strokes was not performed. Post-procedural imaging obtained to detect an ischemic stroke could include any combination of a non-contrast CT, CTA, or magnetic resonance

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imaging (MRI). Only ischemic strokes in the territory of the treated vessel were included. An ischemic complication was considered symptomatic if the patient reported symptoms attributable

transient or resolving signs and symptoms.

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to thromboembolism or demonstrated signs attributable to thromboembolism; this includes

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Hemorrhagic complications were identified intra-operatively as contrast extravasation on DSA or on post-procedure imaging obtained due to clinical concern. Hemorrhagic complications occurring from the time of the procedure up until last follow-up were included. Hemorrhages were counted as symptomatic if the patient reported symptoms or demonstrated signs attributable

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to a hemorrhage. In contrast to ischemic complications, all vascular territories and arterial puncture sites were included.

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Statistical analysis

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Statistical analysis was performed using SPSS 21.0 (IBM Corp. Armonk, NY). In univariable analysis, variables were compared between groups by using Mann-Whitney test for nonparametric numerical variables and Chi-square tests for categorical variables. Statistical significance was defined as p < 0.05.

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Results

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Baseline and aneurysms characteristics

A total of 50 large and giant aneurysms (median age 61.5 years, female-to-male ratio was 2:1) were treated at the three institutions using PED. Current smoking and multiple aneurysms at

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other locations were present in 18% and 32% of patients, respectively. Incidental aneurysms were found in 36% of patients at time of presentation, while minor (mRS 1-2) and major (mRS

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3-5) neurologic deficits were present in 56% and 8% of patients, respectively. Aneurysms were primarily located along the ICA (62%), followed by the posterior circulation (30%). Aneurysms had fusiform (74%) or saccular (26%) morphology. Fusiform aneurysms had a median length of 27 mm and a median width of 20 mm. Saccular aneurysms had a median maximal diameter of 26

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Treatment outcome

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mm and a median neck size of 10.8 mm. None of the aneurysms had any prior treatment (Table

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PED alone was used for treating 78% of the aneurysms, while PED with adjunctive coiling was used for 22%. Aneurysms that underwent PED with adjunctive coiling was significantly larger than aneurysms that underwent PED placement alone (median maximal diameter 33 mm vs 25 mm, p = 0.01). The median number of PEDs used was 2 (range 1-9). The median duration of angiographic follow-up was 13 months (mean 20.4 months). At last follow-up, complete or near complete occlusion (90-100%) was achieved in 76.9% of

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aneurysms, while partial occlusion (< 90%) was achieved in 23.1% (Figure 1). Complete or near complete occlusion was achieved in 80% of saccular aneurysms, and 75.9% of fusiform aneurysms (p = 0.79). Moreover, there was no significant correlation between aneurysms

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location (p = 0.53), aneurysm size (p = 0.76), the number of PEDs placed (p = 0.49), or the use of adjunctive coiling (p = 0.7) with the rate of complete or near complete occlusion. Retreatment was performed in 16% of aneurysms; 62.5% of those were fusiform aneurysms. At last follow-

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up, mRS improved in 30.4% and worsened in 23.9%. Symptomatic thromboembolic complications were encountered in 12% of procedures, and symptomatic hemorrhagic

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complications in 8%. Although the rate of symptomatic thromboembolic complications was higher following PED with adjunctive coiling compared to PED alone, the difference was not statistically significant (27.3% vs 7.7%, p = 0.08). Similarly, there was no significant difference in the rate of symptomatic thromboembolic complications following treatment of aneurysms

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located in the anterior circulation versus the posterior circulation (11.4% vs 13.3%, p = 0.85), based on the shape of aneurysm (p = 0.15), or based on the number of PEDs deployed (p = 0.48). There was also no significant increase in the rate of symptomatic thromboembolic complications

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among clopidogrel non-responders as compared to responders (p = 0.2). The mortality rate was 6.6%; 1 patient died due to unrelated causes, while the other 2 patients had progressive

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neurological decline following initial presentation with brainstem infarction. (Table 2).

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Discussion

In the present study, we report the largest multicenter experience with PED placement for

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treatment of unruptured large and giant intracranial aneurysms. Overall or near complete occlusion was achieved in 76.9% of cases. While the rate of complete or near complete occlusion was higher (80%) for saccular aneurysms when compared to fusiform (75.9%), this difference

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was not statistically significant. Symptomatic thromboembolic complications occurred in 12% of

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cases, while symptomatic hemorrhagic complications occurred in 8%.

Endovascular treatment of large and giant intracranial aneurysms

Large and giant intracranial aneurysms are associated with a high rate of morbidity and mortality

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when compared to smaller aneurysms, due to direct neural compression and/or brain edema caused by aneurysm thrombosis, higher risk of aneurysm rupture, and greater procedural technical complexities.17 The 5-year cumulative rupture rates of untreated large and giant

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aneurysms can be as high as 50% if the aneurysm is located within the posterior circulation or posterior communicating artery, and only slight lower (40%) in aneurysms located in the anterior

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circulation.1,17 This high risk could be mitigated by early definitive surgical or endovascular treatment. Endovascular treatment of large and giant aneurysms using coil embolization is technically challenging given then long procedure time, low packing density, and high recurrence rate.2,3,18–20 Moreover, in large and giant aneurysms with wide necks, an assistive device, such as stent or balloon, is often needed to prevent coil migration. Sluzewski et al. reported complete aneurysm occlusion in 31% of large and giant aneurysms (≥ 20 mm) treated

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with primary coil embolization at 6-month follow-up, and retreatment was required in 41.4%.3 Gruber et al., on the other hand, reported a complete occlusion rate of 71% for giant aneurysms treated with primary coil embolization.2 The low efficacy of coil packing in giant aneurysms is

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attributed to the inability of the coils to induce permanent thrombosis and endothelial lining of the neck. In such lesions, thrombus organization and neck endothelization were not found 2–6

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months after treatment with coils.21,22

Based on the results of the Pipeline Embolization Device for the Intracranial Treatment of

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Aneurysms (PITA) trial10 and the Pipeline for Uncoilable or Failed Aneurysms (PUFS) trial6, treatment of large and giant ICA aneurysms with the PED is becoming a standard treatment option. However, in these studies, all aneurysms with maximal diameter ≥ 10 mm were included, with only 24 giant (≥ 25 mm) aneurysm treated in both studies combined, with no distinction

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from smaller aneurysms in term of occlusion and complications rate. In a meta-analysis of all reported aneurysms treated with flow diversion, Brinjikji et al. found a 76% occlusion in giant aneurysms following treatment with PED. However, these aneurysms were associated with a

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higher rate of ischemic stroke and post-procedural aneurysm rupture compared to smaller aneurysms.23 The latter is in concordance with the results of this study, where the rate of

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thromboembolic and hemorrhagic complications was high when compared to our experience with smaller aneurysms.7

In a multicenter study, Kim et al. reported on the treatment of 47 aneurysms ≥ 15 mm using PED. After a median of follow-up of 3 months, complete occlusion was achieved in 77.4% of aneurysms. Treatment-related morbidity was detected 4.4% of cases and was due to ischemic stroke.12

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There are several factors that may contribute to the lower rate of complete occlusion in large and giant aneurysms following PED placement. PEDs are expected to initially reduce the intra-

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aneurysmal flow leading to aneurysm thrombosis, and to seal the aneurysm off from the circulation by inducing neointimal coverage of the PED surface at the neck.22 This seal would allow the thrombus to be eventually organized. Intimal growth over the luminal surface of a flow

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diversion device is expected to be seen as a tissue layer consisting of smooth muscle cells covered by endothelium (endothelization), while thrombus organization is expected to be

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visualized in the form of smooth muscle cell invasion and connective tissue formation within the clot.22 Lack of either or both of these factors can be associated with failed aneurysm occlusion. In a histological study of giant aneurysms that had undergone flow diversion and failed to occlude, the authors found a lack of endothelization along the surface of the flow diversion

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device. In addition, the walls of all treated aneurysms were fragmented with low cell attenuation, signs of inflammation, and lack of smooth muscle cells, which was attributed to partial thrombosis prior to treatmenet.22 This cellular fragmentation and the lack of smooth muscle cells

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inside the wall might be associated with an inability to transform intraluminal thrombus to stable scar tissue leading to incomplete aneurysms occlusion.22

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In the same histological study, the authors also reported no endothelization of the flow diverter inside the giant fusiform aneurysms without any contact with normal vascular wall, for as long as 13 months after treatment. The same phenomenon may occur in giant aneurysms with very wide necks.22 This can be attributed to insufficient wall apposition of the PED in covering giant aneurysms to promote endothelization, which is exclusively derived from cells in the adjacent parent artery as opposed to circulating progenitor cells in the blood.24–26 In animal models, there

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was a strong correlation between wall apposition and aneurysm occlusion following flow diversion.26 However, no studies were done on human patients, mainly due the difficulty and low accuracy of apposition evaluation using conventional angiographic techniques.

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Lastly, the follow-up period in the present study is comparatively short, and as shown by the 3year follow-up of the PUFS trial, PED tends to achieve higher occlusion rates with time particularly with the larger aneurysms.27 Although there was no significant difference in

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occlusion rates with increased number of PEDs deployed, placement of multiple over-lapping PED has not been assessed in this study and might be effective in achieving better neck coverage

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with a subsequent reduction in aneurysm inflow and recurrence.

The increased rate of the thromboembolic complications, on the other hand, may be secondary to the greater utilization of multiple PEDS in large and giant aneurysms and the associated longer

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procedural time.12,23 However, we were unable to confirm these associations given the small number of cases. There was also an increased rate of thromboembolic complications in patient who underwent adjunctive coiling, which can be attributed to the larger aneurysm size (p = 0.01)

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Limitations

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and longer duration of procedure (p = 0.008) in this group of patients.

We acknowledge that our study is limited by its retrospective nature with all the inherent bias of this study design. Although the inclusion of multiple institutions improves the generalizability of the findings, it introduces internal variability in patient management, follow-up protocols, imaging study, and evaluation of aneurysm occlusion. The study combined both saccular and

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fusiform aneurysms in evaluation of outcome, although distinction was made when necessary. The small number of cases limits the statistical comparison and conclusion, which can be drawn

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between different groups. However, this also represents the largest series of its kind in literature.

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Conclusion

The use of PED placement for the treatment of large and giant intracranial aneurysms (≥ 20 mm)

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is associated with a good occlusion rate, but higher complication rate when compared to published reports focusing on smaller aneurysms. There was no significant difference in occlusion rate depending on aneurysm morphology or size, the number of PEDs placed, or the

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use of adjunctive coiling. While our studies has delineated some of the limitations associated with flow diversion in giant aneurysms and will enhance patient discussions and informed

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consent, further studies on larger numbers of aneurysms are required to further delineate the most appropriate patient population to treat with flow diversion and to evaluate the impact of

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different technical nuances on occlusion rates for this challenging group of aneurysms.

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References

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Gruber A, Killer M, Bavinzski G, Richling B. Clinical and angiographic results of endosaccular coiling treatment of giant and very large intracranial aneurysms: a 7-year, single-center experience. Neurosurgery. 1999;45(4):793-803-804.

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10. Nelson PK, Lylyk P, Szikora I, Wetzel SG, Wanke I, Fiorella D. The pipeline embolization device for the intracranial treatment of aneurysms trial. AJNR Am J Neuroradiol. 2011;32(1):34-40. doi:10.3174/ajnr.A2421. 11. Jeon H-J, Kim D-J, Kim B-M, Lee J-W. Pipeline Embolization Device for Giant Internal Carotid Artery Aneurysms: 9-Month Follow-Up Results of Two Cases. J Cerebrovasc Endovasc Neurosurg. 2014;16(2):112-118. doi:10.7461/jcen.2014.16.2.112.

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12. Kim BM, Shin YS, Baik MW, et al. Pipeline Embolization Device for Large/Giant or Fusiform Aneurysms: An Initial Multi-Center Experience in Korea. Neurointervention. 2016;11(1):10-17. doi:10.5469/neuroint.2016.11.1.10.

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13. Oh S, Kim MJ, Kim B, Shin YS. Treatment for Giant Fusiform Aneurysm Located in the Cavernous Segment of the Internal Carotid Artery Using the Pipeline Embolization Device. J Korean Neurosurg Soc. 2014;55(1):32-35. doi:10.3340/jkns.2014.55.1.32. 14. Brinjikji W, Piano M, Fang S, et al. Treatment of ruptured complex and large/giant ruptured cerebral aneurysms by acute coiling followed by staged flow diversion. J Neurosurg. 2016;125(1):120-127. doi:10.3171/2015.6.JNS151038.

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15. Nossek E, Chalif DJ, Chakraborty S, Lombardo K, Black KS, Setton A. Concurrent use of the Pipeline Embolization Device and coils for intracranial aneurysms: technique, safety, and efficacy. J Neurosurg. 2015;122(4):904-911. doi:10.3171/2014.12.JNS141259.

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16. Park MS, Kilburg C, Taussky P, et al. Pipeline Embolization Device with or without Adjunctive Coil Embolization: Analysis of Complications from the IntrePED Registry. Am J Neuroradiol. January 2016. doi:10.3174/ajnr.A4678. 17. Wiebers DO, Whisnant JP, Huston J, et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet Lond Engl. 2003;362(9378):103-110.

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18. Griessenauer CJ, Adeeb N, Foreman PM, et al. Impact of Coil Packing Density and Coiling Technique on Occlusion Rates for Aneurysms Treated with Stent-Assisted Coil Embolization. World Neurosurg. 2016;94:157-166. doi:10.1016/j.wneu.2016.06.127.

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19. Ogilvy CS, Chua MH, Fusco MR, et al. Validation of a System to Predict Recanalization After Endovascular Treatment of Intracranial Aneurysms. Neurosurgery. 2015;77(2):168174. doi:10.1227/NEU.0000000000000744.

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20. Ogilvy CS, Chua MH, Fusco MR, Reddy AS, Thomas AJ. Stratification of recanalization for patients with endovascular treatment of intracranial aneurysms. Neurosurgery. 2015;76(4):390-395; discussion 395. doi:10.1227/NEU.0000000000000651. 21. Molyneux AJ, Ellison DW, Morris J, Byrne JV. Histological findings in giant aneurysms treated with Guglielmi detachable coils. Report of two cases with autopsy correlation. J Neurosurg. 1995;83(1):129-132. doi:10.3171/jns.1995.83.1.0129. 22. Szikora I, Turányi E, Marosfoi M. Evolution of Flow-Diverter Endothelialization and Thrombus Organization in Giant Fusiform Aneurysms after Flow Diversion: A Histopathologic Study. Am J Neuroradiol. August 2015. doi:10.3174/ajnr.A4336. 23. Brinjikji W, Murad MH, Lanzino G, Cloft HJ, Kallmes DF. Endovascular Treatment of Intracranial Aneurysms With Flow Diverters. Stroke. 2013;44(2):442-447. doi:10.1161/STROKEAHA.112.678151.

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24. Foin N, Gutiérrez-Chico JL, Nakatani S, et al. Incomplete stent apposition causes high shear flow disturbances and delay in neointimal coverage as a function of strut to wall detachment distance: implications for the management of incomplete stent apposition. Circ Cardiovasc Interv. 2014;7(2):180-189. doi:10.1161/CIRCINTERVENTIONS.113.000931.

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25. Kadirvel R, Ding Y-H, Dai D, Rezek I, Lewis DA, Kallmes DF. Cellular mechanisms of aneurysm occlusion after treatment with a flow diverter. Radiology. 2014;270(2):394-399. doi:10.1148/radiol.13130796. 26. Rouchaud A, Ramana C, Brinjikji W, et al. Wall Apposition Is a Key Factor for Aneurysm Occlusion after Flow Diversion: A Histologic Evaluation in 41 Rabbits. AJNR Am J Neuroradiol. July 2016. doi:10.3174/ajnr.A4848.

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27. Becske T, Potts MB, Shapiro M, et al. Pipeline for uncoilable or failed aneurysms: 3-year follow-up results. J Neurosurg. October 2016:1-8. doi:10.3171/2015.6.JNS15311.

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Figures legend

Figure 1: Digital subtraction angiography (DSA); a patient was found to have a giant aneurysm

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along the superior hypophyseal segment of the ICA (Panel A). The aneurysm was treated with a

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PED and coiling, and DSA confirmed complete occlusion at 3-years follow-up (Panel B).

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Table 1. Baseline characteristics Number 50 50

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33 (66%) 17 (34%) 61.5 (19-82) 9 (18%) 16 (32%)

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18 (36%) 28 (56%) 4 (8%)

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Parameter Number of procedures Number of aneurysms Gender Females Male Median age (median, range in years) Smoking Multiple aneurysms Pretreatment mRS 0 1-2 3-5 Aneurysm location ICA Petrous Cavernous Paraophthalmic Bifurcation ACA MCA Posterior circulation Aneurysm shape Fusiform Saccular Aneurysms measurements (median, range in mm) Fusiform aneurysms Length Width1 Saccular aneurysms Maximal Diameter Neck size2 Daughter sac Subarachnoid Hemorrhage Prior Treatment Clopidogrel responders3 Yes No Switched to ticagrelor Not switched to ticagrelor 1 Data is missing for 12 aneurysms 2 Data is missing for 3 aneurysms

2 (4%) 21 (42%) 7 (14%) 1 (2%) 1 (2%) 3 (6%) 15 (30%) 37 (74%) 13 (26%)

27 (20-60) 20 (5-48) 26 (20-44.5) 10.8 (5-15.6) 12 (24%) 0% 0% 33 (71.7%) 13 (28.3%) 2 (4.4%) 11 (23.9%)

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Data is missing for 4 aneurysms

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3

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Table 2. Outcome measures Number

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39 (78%) 11 (22%) 2 (1-9) 24 (48%) 14 (28%) 10 (20%) 1 (2%) 1 (2%)

13 (1-83)

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Procedure Pipeline only Pipeline and coiling Number of Pipeline Median, range 1 2 3 5 9 Last angiographic follow-up (median, range in months)1 Follow-up occlusion rate1 Complete or near complete (90-100%) Partial (<90%) Retreatment Endovascular Posttreatment mRS2 0 1-2 3-5 6 (Death) Follow-up mRS2 Improved No change Worsened Neurological complications Thromboembolic Symptomatic Hemorrhagic Symptomatic 1 Data is missing for 11 procedures 2 Data is missing for 4 procedures

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Parameter

30 (76.9%) 9 (23.1%) 8 (16%)

21 (45.6%) 16 (34.8%) 6 (13%) 3 (6.6%)

14 (30.4%) 21 (45.7%) 11 (23.9%) 10 (20%) 6 (12%) 6 (12%) 4 (8%)

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

Highlights

Treatment of large (≥ 20 mm) and giant (≥ 25 mm) intracranial aneurysms is

RI PT

•

challenging, and can be associated with a high rate of morbidity and mortality. •

Pipeline embolization device in treatment of large and giant aneurysms has not

•

SC

been fully evaluated, justifying the aim of this large multicenter study.

The use of PED for treatment of large and giant intracranial aneurysms was found

AC C

EP

TE D

to aneurysms smaller in size.

M AN U

to be associated with good occlusion rate, but higher complication rate compared