
==== Front
Neurol Med Chir (Tokyo)
Neurol Med Chir (Tokyo)
Neurologia medico-chirurgica
0470-8105
1349-8029
The Japan Neurosurgical Society

38897939
10.2176/jns-nmc.2024-0034
Original Article
Treatment Outcomes of PED for Unruptured Aneurysms of Internal Carotid Artery: Comparison of PED-Flex and PED-Shield
KAWAMOTO Saki 12
OZAKI Tomohiko 13
ASAI Katsunori 1
KIDANI Tomoki 1
IZUTSU Nobuyuki 1
NAKAJIMA Shin 1
KANEMURA Yonehiro 14
NISHIZAWA Naoki 1
KOBAYASHI Koji 1
FUJIMI Yosuke 1
FUJINAKA Toshiyuki 1
1 Department of Neurosurgery, National Hospital Organization Osaka National Hospital, Osaka, Osaka, Japan
2 Department of Neurosurgery, Hanwa Memorial Hospital, Osaka, Osaka, Japan
3 Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
4 Department of Biomedical Research and Innovation, Institute for Clinical Research, National Hospital Organization Osaka National Hospital, Osaka, Osaka, Japan
Corresponding author: Tomohiko Ozaki, MD, PhD

Department of Neurosurgery, National Hospital Organization, Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka 540-0006, Japan.

e-mail: tomohikoozaki@gmail.com

19 6 2024
8 2024
64 8 316322
5 2 2024
10 4 2024
© 2024 The Japan Neurosurgical Society
https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives International License.
There is a lack of data regarding the safety and effectiveness of implanting the Pipeline Embolization Device with Shield technology (PED-Shield) compared with the previous generation of Pipeline (PED-Flex). This retrospective single-center study aimed to compare treatment outcomes between the PED-Shield and PED-Flex for treating unruptured internal carotid artery aneurysms. The PED-Flex was used in 62 procedures (67 aneurysms, 59 patients) and the PED-Shield in 53 procedures (59 aneurysms, 58 patients). The mean aneurysm diameter was significantly lower in the PED-Shield group than in the PED-Flex group (11.9 ± 7.0 mm vs. 15.2 ± 6.9 mm, p < 0.001). At the 12-month follow-up, the complete angiographic occlusion rate was 72.1% and 72.3% in the PED-Flex and PED-Shield groups, respectively (p = 0.9808). Limited to aneurysms larger than 10 mm, 70.6% and 68.0%, respectively (p = 0.8175). The incidence of more than three high signal intensity areas on diffusion-weighted imaging after treatment was significantly lower in the PED-Shield group than in the PED-Flex group (27.7% vs. 67.7%; p < 0.001). Limited to aneurysms larger than 10 mm, 41.1% and 69.6%, respectively (p < 0.0117). Symptomatic ischemic complications occurred within 30 days of four PED-Flex procedures (6.5%) and one PED-Shield procedure (2.0%) (p = 0.2315). Limited to aneurysms larger than 10 mm, 1.8% and 3.2%, respectively (p = 0.6677). The incidence of mRS score worsening at 6 months was 3.2% and 1.9% in the PED-Flex and PED-Shield groups, respectively (p = 0.6534). The PED-Shield can achieve outcomes equivalent to or better than the PED-Flex. Further large-scale studies are warranted to confirm our findings.

flow diverter stent
PED
shield technology
unruptured aneurysm
internal carotid artery
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pmcIntroduction

The Pipeline Flex Embolization Device (PED-Flex; Medtronic, Irvine, CA, USA) was approved for treatment of cerebral aneurysms in our country in April 2015, while the Pipeline Flex Embolization Device with Shield technology (PED-Shield; Medtronic), which is coated by a methacryloyloxyethyl phosphorylcholine polymer, was approved 4 years later. The polymer coating assists in suppressing thrombogenesis, which should decrease the incidence of thrombotic complications.1,2) It also appears to promote faster endothelial growth and more concentric neointima formation.2,3) Therefore, the PED-Shield is expected to result in early aneurysm occlusion while preventing in-stent stenosis. A recent study compared safety and effectiveness between the PED-Shield and early-generation Pipeline devices for treating unruptured cerebral aneurysms.4) However, further data regarding unruptured internal carotid artery (ICA) aneurysms are needed.

Materials and Methods

This retrospective study reviewed consecutive unruptured ICA aneurysms treated using PED in our institution between December 2015 and June 2022. The PED-Flex was used until May 2019, and the PED-Shield was used thereafter. Recurrent aneurysms after coil embolization or aneurysms caused by dissection or infection were excluded. Dual antiplatelet therapy (aspirin 100 mg and clopidogrel 75 mg daily) was initiated 2 weeks before device implantation. Preprocedural platelet aggregation testing using light transmission aggregometry was initiated in December 2020 to guide antiplatelet therapy. Either clopidogrel was switched to prasugrel (3.75 mg daily) or cilostazol (200 mg daily) was added in patients who were not responding to clopidogrel. One physician (T.F.) performed PED deployment in all cases. Patients were heparinized during the procedure to maintain an activated clotting time more than double the patient's baseline value. Percutaneous transluminal angioplasty (PTA) after stent deployment was performed regularly with exception of the early period of PED-Flex group. Argatroban (2.5 mg/hour) was administered intravenously for 48 h after implantation. Dual antiplatelet therapy was continued for at least 6 months after the procedure, while single agent therapy was continued for at least 1 year. Magnetic resonance imaging (MRI) of the brain was performed within 72 h of the procedure. Follow-up angiography was performed at 6 and 12 months to assess aneurysm occlusion. Patient age, gender, and preoperative anticoagulant use were evaluated. The number of devices deployed was evaluated on a per aneurysm basis. Aneurysm size and location, presence of an arterial branch arising from the aneurysm dome, and use of adjunctive coiling were recorded. Aneurysm size was classified as small (<10 mm), large (≥10 mm), or giant (≥25 mm). Aneurysm location was classified according to ICA segment: C1, C2/3, or C4/5. The procedure time to deploy PED (time between placement of microcatheter and deployment of whole portion of first PED) and whole procedure time (from puncture to final angiography) were evaluated per procedure. A number of high signal intensity areas on diffusion-weighted magnetic resonance imaging (DWI) after treatment, symptomatic ischemic complications within 30 days, modified Rankin scale (mRS) score at 6 months, and aneurysm occlusion status at 6 and 12 months after treatment were evaluated per procedure. In-stent stenosis was defined as stenosis ≥50%. Aneurysm occlusion status was evaluated using the Raymond-Roy occlusion classification: class I, complete occlusion; class II, neck remnant; and class III, dome remnant.5) The institutional ethics committee approved the study (approval number: ONH23020). This study was performed in accordance with the committee's guidelines.

Statistical analysis

The two-sided Student's t-test or one-way analysis of variance with the post hoc Tukey-Kramer test was used to compare the continuous variables, while the χ2 test or Fisher's exact test was used to compare the categorical variables. A P value of <0.05 was considered statistically significant. All statistical analyses were conducted using JMP Pro 17 software (SAS Institute Inc., Cary, NC, USA).

Results

A total of 115 procedures were analyzed. A single aneurysm was treated in 105 and multiple aneurysms in 10 (two aneurysms in nine and three aneurysms in one). Therefore, 126 ICA aneurysms were treated. The PED-Flex was used in 62 procedures (67 aneurysms, 59 patients) and the PED-Shield in 53 procedures (59 aneurysms, 58 patients). A total of 56 PED-Flex procedures (56 aneurysms) and 31 PED-Shield procedures (31 aneurysms) were performed for aneurysms ≥10 mm in diameter (Fig. 1).

Fig. 1 Study flowchart.

Aneurysm and patient characteristics

Table 1 shows aneurysm characteristics in the PED-Flex and PED-Shield groups. The mean aneurysm diameter was significantly lower in the PED-Shield group than in the PED-Flex group (11.9 ± 7.0 mm vs. 15.2 ± 6.9 mm, p < 0.001), mainly because aneurysms >5 mm were added as a treatment indication in September 2020. Distribution of location also significantly differed between the groups (p = 0.0012). The prevalence of an arterial branch arising from the aneurysmal dome was 9.0% and 13.6% in the PED-Flex and PED-Shield groups, respectively (p = 0.5715).

Table 1 Characteristics of target aneurysms

	Flex group (n = 67)	Shield group (n = 59)	P value	
Size: mm, mean ± SD	15.2 ± 6.9	11.9 ± 7.0	<0.001	
Small (<10 mm): n (%)	11 (16.4)	28 (47.4)		
Large (≥10 mm): n (%)	50 (74.6)	28 (47.4)		
Giant (≥25 mm): n (%)	6 (9.0)	3 (5.1)		
Main location: n (%)			0.0012	
C1	0 (0)	6 (10.2)		
C2/3	30 (44.8)	36 (61.0)		
C4/5	37 (55.2)	17 (28.8)		
Multiple stent: n (%)	12 (17.9)	10 (17.0)	0.8872	
Incorporated branch: n (%)	6 (9.0)	8 (13.6)	0.5715	
Adjunctive coiling: n (%)	13 (19.4)	11 (18.6)	1.0000	

Age and sex were analyzed with respect to each aneurysm. The mean age of the patients in the PED-Flex and PED-Shield groups was 64.7 ± 15.2 and 62.4 ± 14.7 years, respectively (p = 0.3910). The proportion of women in each group was 86.6% and 83.1%, respectively (p = 0.5821).

Two patients in the PED-Flex group were using warfarin before the procedure, and none of the patients in the PED-Shield group were. One patient in each group was using a direct oral anticoagulant. Four patients in the PED-Shield group were nonresponsive to clopidogrel: clopidogrel was switched to prasugrel in three and cilostazol was added in one.

The prevalence of multiple stent deployment was 17.9% and 17.0% in the PED-Flex and PED-Shield groups, respectively (p = 0.8872). The prevalence of adjunctive coiling was 19.4% and 18.6%, respectively (p = 1.0000). PTA after stent deployment was performed in 75.8% (47/62) of the patients in the PED-Flex group and 96.2% (51/53) in the PED-Shield group. The procedure time to deploy PED (time between placement of microcatheter and deployment of whole portion of first PED) was significantly shorter in the PED-Shield group than in the PED-Flex group (25.7 ± 2.2 and 12.4 ± 2.4 min, p < 0.0001). The whole procedure time was also significantly shorter in the PED-Shield group than in the PED-Flex group (103.6 ± 4.9 and 88.5 ± 5.3 min, p = 0.0369).

DWI outcomes

MRI was not performed after treatment in two PED-Shield cases due to the presence of a pacemaker. The incidence of more than three high signal intensity areas on DWI after treatment was significantly lower in the PED-Shield group than in the PED-Flex group (27.7% vs. 67.7%; p < 0.001; Fig. 2A). When analyzing only aneurysms ≥10 mm in diameter, this incidence rate was also significantly lower in the PED-Shield group than in the PED-Flex group (41.1% vs. 69.6%; p = 0.0117; Fig. 2B).

Fig. 2 The incidence of more than three high signal intensity areas on diffusion-weighted imaging after treatment overall (A) and in aneurysms ≥10 mm (B).

AN, aneurysm

In the PED-Flex group, the rates showing more than three high signal intensity areas on DWI after treatment were 68.1% (32/47) in the cases with PTA after stent deployment and 66.7% (10/15) in the cases without PTA (p = 1.0). In the PED-Shield group, the corresponding rates were 28.6% (14/49, two cases were excluded due to lack of MRI) and 0% (0/2), respectively (p = 1.0).

Pre-procedural platelet aggregation testing using light transmission aggregometry could be performed on 29 patients in the PED-Shield group. The mean platelet aggregation rates under 1 μM of ADP were 27.8 ± 7.6 and 27.4 ± 2.6 in the group having more than three high signal intensity areas on DWI after treatment and having less than three high signal intensity areas on DWI after treatment, respectively (p = 0.9605). The corresponding rates under 10 μM of ADP were 66.7 ± 8.4 and 65.9 ± 2.9, respectively (p = 0.9286).

Clinical outcomes

Symptomatic ischemic complications occurred within 30 days of four PED-Flex procedures (6.5%) and one PED-Shield procedure (2.0%), and there was no significant difference (p = 0.2315; Fig. 3A). When analyzing only aneurysms ≥10 mm, the corresponding rates were 5.4% and 3.5%, respectively (p = 0.6494; Fig. 3B).

Fig. 3 Thirty-day incidence of symptomatic ischemic stroke in all patients (A) and in patients with aneurysms ≥10 mm (B). Six-month incidence of >1-point worsening of modified Rankin Scale score in all patients (C) and in patients with aneurysms ≥10 mm (D).

AN, aneurysm

The incidence of mRS score worsening at 6 months (excluding visual disturbance) was 3.2% and 1.9% in the PED-Flex and PED-Shield groups, respectively (p = 0.6534; Fig. 3C). When analyzing only aneurysms >10 mm, the corresponding rates were 1.8% and 3.2%, respectively (p = 0.6677; Fig. 3D).

The median follow-up was 50 months (range, 5-84) and 21 months (range, 4-42) in the PED-Flex and PED-Shield groups, respectively. There was no aneurysmal rupture or in-stent stenosis during follow-up.

Angiographic outcomes

A 6-month follow-up angiography was performed in 61 PED-Flex group aneurysms (91.0%) and 57 PED-Shield group aneurysms (96.6%). The 12-month angiographic follow-up rates were 91.0% and 79.7%, respectively. The 6- and 12-month rates of complete occlusion did not significantly differ between the groups. At 6 months, the complete occlusion rate was 60.7% and 66.7% in the PED-Flex and PED-Shield groups, respectively (p = 0.4978; Fig. 4A). The corresponding rates at 12 months were 72.1% and 72.3%, respectively (p = 0.9808; Fig. 4B). When analyzing only aneurysms ≥10 mm, the complete occlusion rates were 56.6% and 58.6%, respectively, at 6 months (p = 0.4926; Fig. 4C) and 70.6% and 68.0%, respectively, at 12 months (p = 0.8175; Fig. 4D). When analyzing only giant aneurysms ≥25 mm, all six aneurysms of PED-Flex group and two among three aneurysms of PED-Shield group could be followed. The complete occlusion rates were 33.3% (2/6) and 0% (0/2), respectively, at 6 months (p = 1.0) and 50.0% (3/6) and 0% (0/2), respectively, at 12 months (p = 0.4643).

Fig. 4 Six-month (A) and 12-month (B) rates of complete occlusion overall. Six-month (C) and 12-month (D) rates of complete occlusion in aneurysms ≥10 mm.

AN, aneurysm

In older patients aged over 70, the complete occlusion rate at 6 months was 38.5% (10/26) and 52.2% (12/23) in the PED-Flex and PED-Shield groups, respectively (p = 0.3355). The corresponding rates at 12 months were 50.0% (13/26) and 64.7% (11/17), respectively (p = 0.3424).

Discussion

This retrospective study clarified the effectiveness of Pipeline-Shield for the unruptured ICA aneurysm. A previous study comparing first-generation Pipeline devices and the PED-Flex with the PED-Shield reported similar rates of complications, aneurysm occlusion, and in-stent stenosis.4) Although there was no difference in the rate of symptomatic ischemic complications between PED-Flex and PED-Shield, the number of high signal intensity areas on postprocedural DWI was lower with PED-Shield than with PED-Flex. In two previous studies of early-generation Pipeline devices, the ischemic stroke rates were approximately 4%. The first study was retrospective and reported a 4.7% ischemic stroke rate and median follow-up of 19.3 months.6) The second study was a prospective single-arm trial and reported a 3.7% ischemic stroke rate at the 6-month follow-up.7) More recent studies of the PED-Shield have reported lower 1-year ischemic stroke complication rates ranging from 1.5% to 2.0%.8-10). Our study found a 1.9% rate of symptomatic ischemic stroke with PED-Shield implantation, which is similar.

In this study, the procedure duration was significantly shorter in the PED-Shield group than in the PED-Flex group. One of the reasons of this might be the difference of aneurysmal size between two groups. The aneurysmal size was larger in the PED-Flex group than in the PED-Shield group. Rice et al. reported 100.5 min of mean procedure duration in their study using PED-Shield for the aneurysm with the mean size 8.5 mm.8) El Naamani et al. reported 49.2 min of mean procedure duration in their study using PED-Shield for the aneurysm with the mean size 5.5 mm.4) These results suggested that procedure duration became long in accordance with the aneurysmal size. Although the first stent length was almost the same between the PED-Flex and PED-Shield groups (mean ± SD; 25.5 ± 7.5 and 25.2 ± 7.1 mm, respectively), the procedure time to deploy PED (time between placement of microcatheter and deployment of whole portion of first PED) was significantly shorter in the PED-Shield group than in the PED-Flex group in this study. This result indicated that shield technology had a possibility to contribute to the ease of stent deployment and presumably be another reason for shortening of procedure duration.

Evidence of ischemic lesions on DWI after endovascular aneurysm treatment is an important issue. A 2017 meta-analysis reported that flow diverter placement was associated with a higher incidence of postprocedural ischemic lesions on DWI than coil embolization (67% vs. 45%; p = 0.07).11) Moreover, Cortez et al. reported a 62% incidence of DWI lesions after PED-Shield implantation,12) while Pikis et al. reported only a 16.7% incidence.13) In our study, the incidence of more than three high signal intensity areas on DWI was significantly lower in the PED-Shield group than in the PED-Flex group.

Matsuda et al. examined neointimal development after flow diverter placement in a swine model and reported that endothelial formation was earlier with the PED-Shield than with the PED-Flex; however, there was no significant difference.3) They suggested that the polymer coating on the PED-Shield might shorten the early steps of neointima development. In a clinical study of ICA aneurysms ≤12 mm in diameter, Arai et al. reported that time to complete occlusion was shorter with the PED-Shield than with early-generation Pipeline devices.14) In previous studies, reported complete occlusion rates for the PED-Shield at 6 months range from 69.2% to 70.8% and increase to between 77.2% and 81.8% at 12 months.8-10) The 6- and 12-month complete occlusion rates for early-generation Pipeline devices were 73.6% and 86.8 %, respectively.7) These results are consistent with ours.

Although perioperative antiplatelet therapy is effective for preventing thromboembolism associated with neuroendovascular procedures,15,16) the antiplatelet effects are attenuated in some individuals owing to genetic polymorphisms.16,17) CYP2C19 is a clopidogrel-metabolizing enzyme that has significant influence on the antiplatelet action of clopidogrel, and the frequency of CYP2C19 loss-of-function polymorphisms is high in Japan.18) A meta-analysis of 1,464 cases from 12 studies of platelet reactivity in patients undergoing Pipeline device placement reported that pre-procedural platelet hyporesponsiveness was associated with a higher risk of thrombotic complications.19) In a study of complications in patients undergoing Pipeline device placement for treatment of cerebral aneurysms, pre-procedural P2Y12 reaction unit value >240 was an independent predictor of thrombotic complications.20) In contrast, Neyens et al. defined clopidogrel hyporesponsive as P2Y12 reaction unit value ≥194 and reported no significant difference in thrombotic complications after Pipeline device placement between hyporesponders and responders.21) Further research is needed to determine the optimal P2Y12 reaction unit cutoff value in patients undergoing PED-Shield implantation.

This study has some limitations. The most critical one is its retrospective nature, which may have introduced selection bias. In addition, patients' symptoms may not have been completely represented in the clinical records. Furthermore, 10 of our cases treated multiple aneurysms in one procedure, but the number of high signal intensity areas on DWI, rate of ischemic complications, and neurological outcome were evaluated per procedure and complete occlusion rates were calculated per aneurysm. Finally, platelet aggregation testing was not performed in all patients and no patient in the PED-Flex group underwent testing. Since tailoring antiplatelet therapy based on testing can reduce the incidence of thrombotic events,22) this may have affected the reported incidence of thromboembolism.

Conclusion

This study demonstrated the treatment results of PED-Shield for unruptured ICA aneurysms compared with PED-Flex. PED-Shield reduced incidence of more than three high signal intensity areas on postprocedural DWI and had a possibility to reduce postoperative ischemic complications. Further large-scale studies are needed to confirm our findings.

Conflicts of Interest Disclosure

The authors declare no conflicts of interest. All authors have registered the online self-reported disclosure statement forms through the website for Japan Neurosurgical Society members.

Acknowledgments

We thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
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