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Clinical outcomes of pipeline embolization devices with shield technology for treating intracranial aneurysms

Introduction As a common endovascular treatment for intracranial aneurysms, the pipeline embolization device (PED) is considered a standard treatment option, especially for large, giant, wide-necked, or dissecting aneurysms. A layer of phosphorylcholine biocompatible polymer added to the surface of the PED can substantially improve this technology. This PED with shield technology (pipeline shield) is relatively novel; its early technical success and safety have been reported. We conducted a systematic literature review with the aim of evaluating the efficacy and safety of the pipeline shield. Methods We searched the PubMed, Embase, and Cochrane databases, following the preferred reporting items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Results We selected five prospective and two retrospective studies for review. A total of 572 aneurysms were included; of these, 506 (88.5%) were unruptured. The antiplatelet regimens were heterogeneous. The rate of perioperative and postoperative complications was 11.1% [95% confidence interval (CI): 6.5–18.9%]. The adequate occlusion rate at 6 months was 73.9% (95% CI: 69.1–78.7%). The adequate occlusion rate of more than 12 months was 80.9% (95% CI: 75.1–86.1%). The mortality rate was 0.7% (95% CI: 0.2–1.5%). Subgroup analyses showed that aneurysm rupture status had no effect on aneurysm occlusion rate, patient morbidity, or mortality. Conclusion This review demonstrates the safety and efficacy of the pipeline shield for treating intracranial aneurysms. However, direct comparisons of the pipeline shield with other flow diverters are needed to better understand the relative safety and effectiveness of different devices.


Introduction
Flow diverters (FDs) enable the application of endovascular therapy for intracranial aneurysms in an increased number of indications. The utilization of FDs has become the preferred treatment option for various types of aneurysms (1)(2)(3). Despite their relatively recent development, numerous FDs have been introduced for clinical use. Currently available coating FDs include the pipeline embolization device (PED) with shield technology (referred to as the pipeline shield), derivo embolization device (DED), and p64/p48 MW HPC ( Table 1). The pipeline shield incorporates a phosphorylcholine surface coating (4), which is a thirdgeneration PED. It has been shown to reduce intimal hyperplasia (5) and increase early neointimal growth in preclinical studies (6). In ex vivo (4) and in vitro studies (7,8), the pipeline shield significantly reduced thrombogenicity in comparison with other FDs. As a new therapeutic technique for intracranial aneurysms, the efficacy of complications associated with the pipeline shield remains unclear, and there is currently no relevant literature that summarizes existing findings. Therefore, this meta-analysis aimed to explore the efficacy and safety of the pipeline shield in treating intracranial aneurysms.

Search strategy
We searched the PubMed, Embase, and Cochrane databases to identify studies using the pipeline shield for treating intracranial aneurysms. We used the following search terms: "flow diverter, " "pipeline embolization device, " "PED, " "shield technology, " "surface modification, " and "aneurysm." We followed the applicable Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (9). We reviewed literature published between device inception and March 2022 and carefully screened the search results to select studies that were particularly relevant to pipeline shield devices in the neurointerventional field.

Selection criteria
For this review, we included all English-language articles on the use of the pipeline shield for treating intracranial aneurysms. Case reports were excluded. Animal, in vitro, and cadaveric studies were excluded. We also excluded nonprimitive research and conference abstracts. We assessed the center and time frame of included studies with the aim of excluding articles with overlapping cohorts and identifying the most recent and complete studies. We included studies on pipeline shield devices for treating intracranial aneurysms and pooled data on aneurysm occlusion rates, procedural complications, and mortality. The initial search results and screening process are shown in a PRISMA-based (9) flowchart ( Figure 1).

Data selection
We extracted the following data from the included studies: the number of patients, sex ratio, mean age, total number of aneurysms, proportion of ruptured aneurysms at presentation, sizes and neck width of aneurysms, shapes of aneurysms (i.e., blister, fusiform, pseudoaneurysm, or dissecting), locations of aneurysms, devices per aneurysm, mortality rates, morbidity rates, adequate occlusion rate, antiplatelet regimens, and usage of detachable devices.

Statistical analysis
We used the R package "META" (https://cran.r-project. org) to analyze the acquired data. We calculated proportions across studies and performed meta-analyses using fixed-and random-effects (RE) models for the weighted estimation of the overall rates of each outcome of interest (i.e., periprocedural and postoperative complications, adequate occlusion, and mortality). We also estimated 95% confidence intervals (CIs) and event rates for each outcome. I 2 statistics were used to assess statistical heterogeneity between studies. For data with I 2 heterogeneity values >50%, RE models were used. Forest plots were generated based on the proportions and estimated overall rates ( Figure 2). Subgroup analyses were conducted using Stata 14.0.

Results
The preliminary search results contained 67 articles, 30 of which were duplicates. Ultimately, seven articles were selected for further analysis.

Study characteristics
The characteristics of all included studies are presented in Table 2. Of the seven studies, two were retrospective (10, 17) and five were prospective (12-16). Adjunctive coiling was used in six studies, two of which also used adjunctive balloons. One study used the pipeline shield exclusively. A total of 524 patients with 572 intracranial aneurysms were included. A total of 11.5% of the aneurysms had ruptured before treatment. Most aneurysms were in the anterior rather than posterior circulation . /fneur. .

Discussion
FDs are new important tools for treating intracranial aneurysms (18). Considering the novelty of these devices, the risk of thromboembolic events post-implant remains a concern. It is known that patients who have undergone flow shunt placement should be treated with prolonged dual antiplatelet therapy (DAPT) to prevent thrombosis. The pipeline shield is a surface-coated device that improves the hemocompatibility of PEDs and has been shown to reduce surface platelet and fibrin adhesion as well as thrombin generation (4, 7, 19). In our review, these benefits were indirectly verified. Compared to PEDs without shield technology (11), the pipeline shield was found to be associated with higher adequate occlusion and lower mortality rates (Table 3).
Few studies were controlled according to the rupture status of the aneurysms. In fact, the primary treatment for ruptured aneurysms, including antiplatelet and endovascular therapies, differs from that for unruptured aneurysms. For unruptured aneurysms, in addition to encouraging patients to quit smoking and control their blood pressure, clinical decisions are made using PHASES and unruptured intracranial aneurysm treatment scores (20). Unruptured aneurysms show that short-term growth should be treated rapidly (21). Ruptured aneurysms must be treated surgically. In these patients, in addition to basic supportive care, early aneurysm occlusion is critical (22, 23). The choice of treatment depends on the overall condition of the patient, the characteristics of the aneurysm, the presence of associated hematomas and mass effects, and the overall microsurgical and endovascular expertise of the treatment center.
The pipeline shield appears to have similar outcomes to those of other well-established and more widely used FDs. In a study evaluating Silk FDs, Florez et al. reported a mortality rate of 2.8%, total thromboembolic complication rate of 6.06%, Luo et al. .
/fneur. .        in a ruptured group. Perioperative morbidity was 4%, and perioperative mortality was 1% (26). In a meta-regression analysis predicting aneurysm treatment outcomes with PEDs, the estimated aneurysm occlusion rate was 76%, and the estimated death and modified Rankin Scale ≤2 rates at unspecified follow-up times were 2 and 92%, respectively (27). Wakhloo et al. performed a study evaluating Surpass devices and found intraprocedural in-stent clot formation in 3.7% of patients. The overall morbidity rate was 6%, and the mortality rate was 2.7% (28). In another systematic review on the utilization of pipeline flex devices for treating unruptured intracranial aneurysms, a low periprocedural risk of death (0.8%) or major complications (1.8%) was reported. The risk of major complications occurring was significantly higher for large/giant aneurysms (4.4%) than for small aneurysms <10 mm (0.9%) (29). Bhatia et al. performed a systematic review on the utilization of flow redirection endoluminal devices for treating intracranial aneurysms and reported that the occlusion rate between 4 and 6 months was 73.8%, the overall reported morbidity rate was 3.9%, and procedure-related mortality was 1.4%. Complication rates fell into five categories: technical (3.6%), ischemic (3.8%), thrombotic or stenotic (6%), hemorrhagic (1.5%), and non-neurological (0.8%) (30). The DED is another surface-modified FD. In a meta-analysis of its utilization, the rate of periprocedural ischemic and hemorrhagic complications was 4.9%, the complete angiographic occlusion rate was 81.4%, and the mortality rate was 2.1% (31). Moreover, Li et al. performed a meta-analysis on the outcome of FDs with surface modifications and determined that the rate of aneurysm occlusion was 80.5% at 6 months and 85.6% at 12 months. The pooled estimate for the total ischemia rate was 6.7%, of which the severe ischemia rate was 1.8%. Morbidity and mortality rates were 6.0 and 0.7%, respectively (32). When we collated the data, we found that some aneurysms were treated using adjunctive devices in addition to FDs, but details about the patients requiring adjunctive devices were not provided; thus, we could not analyze whether such devices were beneficial. However, in a study on pipeline-assisted coiling vs. pipeline in FDs for treating intracranial aneurysms, the authors reported that joint PED and coiling were safe with no increase in complications when compared with PED alone. Aneurysm occlusion rates and functional outcomes with PED and coiling remained comparable to those of treatment with PED alone (33). Atassoy et al. purported that putative occlusion rate differences were unlikely to be caused by a difference in adjunctive coiling (10). The rates of adjunctive coil use did not appear beneficial for aneurysm occlusion, and evidence for potential benefits is currently lacking (33). Interestingly, adjunctive coiling may be more helpful for preventing aneurysm rupture during thrombosis than for increasing the occlusion rate. Moreover, additional overlapping devices may increase coverage by increasing mesh density, thereby affecting occlusion rate. In endovascular treatments, the aneurysm sac diameter may influence the occlusion rate, especially in aneurysm coiling. As mentioned above, however, a meta-analysis on FDs revealed no relationship between the sac diameter of aneurysms and occlusion rates (34). Compared with the coils alone, combining other techniques can treat complex aneurysms and reduce the recurrence rates. In a study by Lin et al., coils in conjunction with a PED yielded higher aneurysm occlusion rates and reduced the need for retreatment (35). Because FDs cannot provide direct dome protection, large and giant aneurysms could take longer to completely occlude when treated with percutaneous endovascular embolization alone (36). Therefore, until total occlusion is achieved, these aneurysms remain at risk of rupture during the follow-up period (37,38). In addition, studies have found intraoperative device prolapse and postoperative device displacement/shortening (39, 40), which may lead to rupture and the need for retreatment (40). Therefore, for aneurysms at risk of imminent rupture, the combined use of coils and PEDs may be more effective and provide additional mechanical support, thereby reducing the risk of device dislocation and need for retreatment.
In a meta-analysis evaluating the efficacy of FDs in posterior compared to anterior circulation aneurysms, posterior circulation aneurysms were found to be effectively treated using FDs, with comparable occlusion rates to those in anterior circulation aneurysms. However, the risk of periprocedural complications was not negligible (41). Early studies have reported higher complication rates associated with the use of FDs in the posterior circulation (42)(43)(44)(45). This may be due to the presence of numerous perforating arteries supplying the brainstem (46). We could not compare the treatment effects between anterior and posterior circulation aneurysms because we were unable to obtain more detailed information.
Owing to the complexity of patients' conditions and disagreements on antiplatelet regimens for pipeline shield utilization, protocols for antiplatelet therapy among the trials included in our review were not uniform (  Trivelato et al. (15) Patients were asked to take DAPT (aspirin 100 mg/day+ clopidogrel 75 mg/day or ticagrelor 90 mg twice a day) for 5 days prior to the intervention and for 6 months afterward. Aspirin was maintained for another 6 moonths. For ruptured aneurysms, all patients were premedicated with a loading dose of aspirin (300 mg) plus clopidogrel (600 mg) 3 h before the procedure. After treatment, these patients received the standard antiplatelet regimen. No.

Yeomans et al. (16)
The elective cases received dual antiplatelet therapy post-procedure. The acute cases received single antiplatelet therapy post-procedure. 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. The procedure would have been abandoned in P2Y12 antagonist non-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.
(19, 48, 49). In vivo, single antiplatelet therapy with pipeline shield had similar thrombogenicity to that of DAPT with PED-Flex (4). Therefore, pipeline shield devices may reduce the need for antiplatelet drugs, thereby reducing the risk of hemorrhage. The role of antiplatelet and anticoagulant medications in treating unruptured aneurysms has been controversial. Retrospective studies have reported that patients taking long-term aspirin exhibit a reduced risk of rupture, while those taking dipyridamole and new aspirin may be at risk of subarachnoid hemorrhage (50,51). In another study, patients taking aspirin (28%) were found to have lower bleeding rates than those not taking aspirin (40%) (52). Aspirin was also not found to worsen outcomes after subarachnoid hemorrhage (51). In contrast, anticoagulants were associated with poor prognosis . /fneur. .
after subarachnoid hemorrhage (53) but did not increase the risk of aneurysm rupture (54, 55). Our study has the following limitations. As some articles included in our review reported retrospective results based on small samples, our results may be biased. Further, as antiplatelet therapy regimens vary between studies and institutions, no reliable conclusions could be drawn regarding antiplatelet therapy.

Conclusion
Technological improvements have greatly improved endovascular treatment options for aneurysms. As a novel surface-modified PED, the pipeline shield is increasingly used to treat intracranial aneurysms. From our review, we determined that this intervention results in low rates of mortality and a high rate of occlusion.

Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

Author contributions
CL and LJin conceived the project and drafted the manuscript. EL, BL, and ZF searched the databases and analyzed data. JD, SY, PL, and LJia were responsible for the whole process of supervision. SZ and WH revised the manuscript. All authors read and approved the final version of the manuscript.