Graphical Abstract
Abstract
BACKGROUND: The use of a Pipeline Embolization Device (PED) in combination with coils (PEDC) to treat intracranial aneurysms remains unclear as to whether it offers significant benefits for the patients because the results have varied.
PURPOSE: This study aimed to investigate the clinical outcome of the PEDC compared with the PED in treating intracranial aneurysms.
DATA SOURCES: We systematically searched the articles from PubMed, Web of Science, and the Cochrane Library databases published before January 25, 2024.
STUDY SELECTION: We selected studies comparing the PEDC versus the PED to treat intracranial aneurysms. Patients treated with the PEDC but using dense coiling were excluded from the study.
DATA ANALYSIS: The clinical outcomes observed in this meta-analysis were intraprocedural complications, postoperative complications (stenosis, stroke, hemorrhage, mortality), favorable outcome (mRS ≤2), complete occlusion rate, and retreatment rate. A forest plot was used to analyze pooled OR of clinical outcomes.
DATA SYNTHESIS: A total of 3001 subjects from 9 observational studies were included. The PEDC was mainly used to treat larger aneurysms. The PEDC has a significantly higher complete occlusion rate at 6 months (OR = 2.66; 95% CI, 1.26–115.59; P = .01), a lower retreatment rate (OR = 0.18; 95% CI, 0.05–0.07; P = .010), higher stroke-related complications (OR= 1.66, 95% CI, 1.16–2.37; P = .005), and higher hemorrhage-related complications (OR = 1.98; 95% CI, 1.22–13.21; P = .005). There was no significant difference in intraprocedural complications, stenosis-related complications, mortality, favorable outcomes, and complete occlusion at the end of the study.
LIMITATIONS: No randomized controlled trials have been performed comparing the PEDC and PED. Considering that all the included studies were observational, the patients’ baseline characteristics were not completely balanced.
CONCLUSIONS: This meta-analysis study showed that the PEDC in large intracranial aneurysms induces a faster complete occlusion rate at 6 months and a lower retreatment rate. However, it increases the risk of stroke-related postoperative complications, and the faster complete aneurysm occlusion rate found in this study did not correlate with a reduction in long-term aneurysm or distal artery ruptures. Thus, this study suggests the need to find a better strategy to improve long-term hemorrhage-related complications in large intracranial aneurysms.
ABBREVIATIONS:
- FDDs
- flow-diverter devices
- NOS
- Newcastle-Ottawa Scale
- PEDC
- Pipeline Embolization Device in combination with coils
Flow-diverter devices (FDDs) are novel constructive techniques in neuroendovascular surgery to treat intracranial aneurysms.1 FDDs have gained popularity for their safety and efficacy in treating “uncoilable” large and wide-neck intracranial aneurysms.2⇓-4 FDDs could improve intracranial aneurysms by reconstructing the parent vessel, redirecting blood flow, and altering hemodynamic blood flow within the aneurysm dome. These mechanisms result in better aneurysm neck reconstructions and complete occlusion compared with traditional endovascular surgery.5⇓-7 However, FDDs do not provide direct dome protection, show limited efficacy in arterial bifurcation, and could potentially prolapse in large aneurysm sacs, unlike coil embolization.8,9 There are several types of FDDs known today, ie, the Pipeline Embolization Devices (PED; Medtronic), Silk (Balt Extrusion), Flow Re-direction Endoluminal Devices (MicroVention), p64 Flow Modulation Devices (phenox), Surpass flow diverters (Stryker Neurovascular), and novel flow-diverting devices (Tubridge; MicroPort Medical Company).1,10 The FDD that is most commonly studied and used in practice is the PED.11⇓-13
The PED is designed as a stand-alone device for intracranial aneurysm surgery, but some practitioners often combine it with coils. Some practitioners believe that adjunctive coils in PEDs offer direct protection in an aneurysm dome, thus inducing a higher occlusion and a lower retreatment rate than the PED alone,14⇓⇓⇓-18 while others believe it induces a higher complication rate.19⇓-21 Studies have reported the safety and effectiveness of the PED alone versus the PED with coils (PEDC), but the results have varied across studies. The PEDC evaluated here was placed with loose coiling because dense coiling has been shown to significantly increase perioperative complications compared with loose coiling.16,19 To date, it remains unclear whether the PED in combination with loose coiling offers significant benefits for the patients.14⇓⇓⇓⇓⇓⇓⇓⇓-23 Here, we performed a systematic review and meta-analysis to evaluate the clinical outcome of the PED with loose coiling compared with the PED for treating intracranial aneurysms.
MATERIALS AND METHODS
Search Strategy
This meta-analysis was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. We systematically searched the articles from PubMed, Web of Science, and the Cochrane Library databases for observational studies and randomized controlled trials comparing the PEDC versus the PED to treat intracranial aneurysm published before January 25, 2024. We used Endnote 20 reference manager (https://libguides.nie.edu.sg/c.php?g=942031&p=6820754) to retrieve the articles from PubMed and the Web of Science. The articles were retrieved using the keywords in the Title, Abstract, and Keyword sections with “and/or” for the following terms: pipeline, flow-diverter, flow diversion, coil, embolization, assisted, and combination. Separately, the articles from the Cochrane Library databases were retrieved independent of the Web site and imported to the Endnote 20 reference manager. We removed all the retrieved articles that were duplicates. Then, 2 researchers systematically screened the remaining articles using the Title and Abstract according to the inclusion and exclusion criteria.
Inclusion and Exclusion Criteria
The inclusion criteria for this study were the following: 1) patients with intracranial aneurysms (unruptured and ruptured), 2) the treatment choices being the PEDC in comparison with the PED alone, 3) data for 2 groups provided in the literature, and 4) a randomized controlled trial or observational study (case-control and cohort study). Meanwhile, the exclusion criteria included the following: 1) studies with similar registry or overlapping data, 2) case series on either the PEDC or PED-only with <10 patients, 3) patients treated with the PEDC but using dense coiling, ie, complete occlusion of aneurysm (Class I–II Raymond-Roy Classification System) because it showed a higher complication rate,16,19 4) literature that did not compare the EDC and PED, and 5) case reports, review articles, news and editorials, and conference abstracts.
Two researchers extracted the data from selected articles, and any disagreements were discussed with an independent senior neurosurgeon at our hospital. We extracted primary information from the selected articles, including the first author’s name, year, study design, sample size, total aneurysms, age, sex, aneurysm size, location, shape, and rupture. The primary outcome and analyzed data included the following: 1) intraprocedural complications (due to its rare incidence, we accumulated all complications into 1 variable); 2) postoperative complications such as stenosis, consisting of in-stent stenosis and parent artery stenosis; 3) stroke, consisting of TIA and ischemic stroke, 4) hemorrhage, consisting of a ruptured aneurysm and distal artery rupture; 5) mortality at the latest follow up; and 6) the mentioned postoperative complications above accumulated into overall postoperative complications; 7) favorable outcome, with (mR) ≤ 2 at the latest follow-up, 8) complete occlusion rate in the latest follow-up, 9) 6 months’ follow-up, and 10) retreatment rate. Using the Newcastle-Ottawa Scale (NOS), we assessed the risk of bias in all eligible articles, considering that all the included studies are either case-control or cohort studies. Studies were graded on a scale of 0–9, with 0–2 representing poor quality, 3–5 representing fair quality, and 6–9 representing good quality.24
Statistical Analysis
We used the “meta” package within the R Foundation for Statistical Computing Platform (Version 4.2.1 (http://www.r-project.org/) to conduct statistical analyses. Heterogeneity among studies was assessed using the Cochran Q test, while the I2 statistic investigated its magnitude. Pooled outcomes and their respective 95% CIs were calculated using the Mantel-Haenszel test with either a random-effects (if I2 > 50%) or a fixed-effects model (if I2 < 50%). We used funnel plots and the Egger test to assess publication bias. A P value < .05 was considered significant. Sensitivity analysis was performed by excluding studies with an NOS of <6 and with zero events, to ensure the robustness of the pooled results in our study.
RESULTS
Study Selection and Quality Assessment
A total of 1470 articles were identified from the database search. Among them, 402 duplicates were removed and 1040 studies were excluded through an initial screening. This meta-analysis included 9 studies after a full-text assessment of the eligibility of the remaining 28 articles. The flow chart of the literature search, reasons for literature exclusion, and the results of the study selection are available in the Online Supplemental Data.
All 9 studies were observational, consisting of 4 case-control studies and 5 cohort studies. Eight of the 9 studies had a good quality assessment, with an NOS score of >6 (Online Supplemental Data).
Patient Characteristics
A total of approximately 3001 subjects with 3269 aneurysms were included. Among these, 949 underwent PEDC treatment, while 2320 underwent PED-only treatment. The mean age for both groups was older than 50 years, predominantly women, and most cases were ICA aneurysms with a saccular type. In all 9 studies, the PEDC was mainly used to treat larger aneurysms compared with the PED. The detailed patient characteristics are provided in the Online Supplemental Data.
Outcome of PEDC versus PED
Four studies reported intraprocedural complications, with no significant difference in incidence between the PEDC and PED groups (3.85% versus 3.51%) (OR = 1.24; 95% CI, 0.50–13.08; P = .643) (Fig 1A).
Forest plot and meta-analysis of intraprocedural (A), stenosis-related (B), stroke-related (C), hemorrhage-related (D), mortality-related (E), overall postoperative complications (F), favorable outcome (G), complete occlusion rate (H), complete occlusion rate at first 6 months (I), and retreatment rate (J).
We evaluated postoperative complications that were stenosis-related, stroke-related, hemorrhage-related, and mortality-related. Stenosis-related complications were reported in 4 studies and were not significantly different between the PEDC- and PED-treated patients (3.76% versus 3.97%) (OR = 0.73; 95% CI, 0.45–1.20; P = .217) (Fig 1B). Stroke-related complications were reported in 6 studies and were significantly lower in the PED compared with the PEDC-treated patients (4.65% versus 7.59%) (OR = 1.66; 95% CI, 1.16–2.37; P = .005) (Fig 1C). Hemorrhage-related complications were reported in 5 studies and were significantly lower in the PED-compared with the PEDC-treated patients (2.76% versus 4.4%) (OR = 1.98; 95% CI, 1.22–3.21; P = .005) (Fig 1D). Mortality-related complications were reported in 6 studies and were not significantly different between the PEDC and PED-treated patients (2.27% versus 2.09%) (OR = 1.64; 95% CI, 0.89–3.05; P = .114) (Fig 1E). Overall, the incidence of postoperative complications was higher in the PEDC- than in the PED-treated patients (16.3% versus 12.1%), with a statistically significant difference between the 2 groups (OR = 1.32; 95% CI, 1.04–1.68; P = .022) (Fig 1F).
Five studies evaluated treatment outcomes on follow-up using the mRS scoring system. The incidence of favorable outcome (mRS ≤2) was not significantly different between the PEDC- and PED-treated patients (93.6% versus 92.8%) (OR = 0.79; 95% CI, 0.53–11.18; P = .246) (Fig 1G). The complete occlusion rate at the end of the study was reported in 7 studies and was not significantly different between the PEDC- and PED-treated patients (66% versus 74.3%) (OR = 1.61; 95% CI, 0.80–13.28; P = .185) (Fig 1H). However, 3 studies reported a significantly higher complete occlusion rate at 6 months’ follow-up, which was significantly higher in the PEDC- compared with the PED-treated patients (83.5% versus 69.2%) (OR = 2.66; 95% CI, 1.26–15.59; P = .01) (Fig 1I). The retreatment rate was reported in 3 studies and was significantly lower in the PEDC- compared with the PED-treated patients (1.75% versus 12.1%) (OR = 0.18; 95% CI, 0.05–10.07; P = .010) (Fig 1J).
Publication Bias and Sensitivity Analysis
Because all the included studies were observational, there is a potential of publication bias in each study. Thus, publication bias was assessed using funnel plots and the Egger test. The funnel plots were mostly symmetric with no significant publication bias (P > .05), except for the complete occlusion rate at the end of the study (P = .02) (Online Supplemental Data). The results of the sensitivity analysis were mostly consistent with the pooled analysis (Online Supplemental Data), except for overall postoperative complications after excluding the study by Park et al, 2016.
DISCUSSION
Here, we systematically reviewed and performed a meta-analysis on 9 observational studies comparing the PEDC and PED to treat intracranial aneurysms to determine whether the PEDC offers a significant benefit for the patients.14⇓⇓⇓⇓⇓⇓⇓-22 The PEDC-treated patients in these studies had larger aneurysms compared with those treated with the PED, indicating the practitioners’ preferences for using the PEDC for complex and difficult aneurysms as well as potentially explaining the significantly higher postoperative complications found in the PEDC-treated patients. Despite this discrepancy in aneurysm size between the 2 groups, no significant difference was found in terms of intraprocedural complications, stenosis-related complications, mortality, mRS-measured outcome, and complete occlusion rate at the end of the study. PEDC-treated patients even showed faster occlusion (<6 months) and a lower retreatment rate. However, PEDC-treated patients also showed a higher incidence of postoperative stroke, indicating that this technique increases the risk of stroke complications.16,19,21 They also experienced more aneurysms and distal artery ruptures, as inferred from the higher incidence of hemorrhage-related postoperative complications compared with PED-treated patients.
The use of coils together with the PED is expected to mitigate delayed aneurysm rupture,25 because 4% of these ruptures were associated with the use of the PED alone, resulting in 80% unfavorable clinical outcomes or even mortality.26⇓-28 Delayed aneurysm rupture shows a peak incidence within the first month, and coil placement offers a direct occlusion strategy to mitigate this rupture after PED placement.29 However, mitigation of delayed aneurysm rupture could not be confirmed in our study because PEDC-treated patients had significantly higher hemorrhage-related postoperative complications compared with PED-treated patients. It remains unclear in our study whether hemorrhage-related postoperative complications are partly attributed to the larger aneurysm size or the plausible lack of PEDC effectiveness in mitigating delayed aneurysm rupture. A large intracranial aneurysm is generally defined in clinical practice by its diameter size of 10–25 mm and is known to have a higher rupture rate.30 Previous studies showed that although PEDC-treated patients had a larger aneurysm size, there was no significant difference in delayed aneurysm and distal artery rupture within the first month compared with the PED-treated patients.15,19
Unfortunately, in our study, we could not perform matching based on aneurysm size and the interval of aneurysm rupture because individual patient data were not reported in the included studies. Our meta-analysis also showed that PEDC-treated patients had significantly higher stroke-related postoperative complications, and previous studies have also reported that the PEDC could prolong surgery time, resulting in higher rates of ischemic stroke or postoperative neurologic morbidity.16,19,21 Other factors, such as operator skills and postoperative maintenance with anticoagulants, could also contribute to patient outcomes but were unfortunately not reported in the included studies. These factors could explain why PEDC-treated patients showed higher postoperative complications than those treated with the PED in this study.
Despite having larger aneurysms, PEDC-treated participants showed no significant difference in intraprocedural complications, mortality, and favorable outcomes. There was also no difference in the complete occlusion rate at the end of the study. This outcome, however, is likely influenced by the high heterogeneity in the follow-up time used to measure this variable: Two studies were followed up to ±6 months,14,20 another 2 up to ±8 months,15,19 and 3 up to 1 year.16,17,22 This heterogeneity could also explain why publication bias was found only in this variable and not in the others. Five of 7 studies included in the meta-analysis of this variable showed a higher complete occlusion rate. We performed additional analysis on 3 studies reporting a follow-up period of 6 months and confirmed that the PEDC does have a faster complete occlusion rate compared with the PED.14,17,20 This finding is further supported by another study documenting that the occlusion in the PED-treated patients mostly occurs more than a year.31 In addition to a faster complete occlusion rate, PEDC-treated patients also showed a lower retreatment rate compared with those treated with the PED.
The PEDC evaluated here is placed with loose coiling as indicated by nonimmediate complete occlusion on angiography follow-up. Insurance often does not cover the PEDC, and the cost of dense coiling is significantly higher than that of loose coiling.16 Studies have reported that the PEDC with dense coiling results in a mass compression effect and causes longer surgery times, leading to higher perioperative complications compared with loose coiling.16,19 This finding highlights the importance of the volume embolization ratio of coils used in the PEDC—that is, 3 studies have shown that a volume embolization ratio of ≤15% in the PEDC has been reported to improve occlusion outcomes, prevent nerve compression, induce aneurysm shrinkage, and reduce the risk of aneurysm rupture.25,32,33 Besides the volume embolization ratio, the use of multiple PEDs to cover the aneurysm neck should also be considered when comparing the PEDC and PED in a future study.
Altogether, our meta-analysis showed that the PEDC induces faster complete occlusion and a lower retreatment rate in large intracranial aneurysms. However, it also increases the risk of postoperative stroke-related complications and may not be an effective strategy to prevent hemorrhage-related postoperative complications in large intracranial aneurysms. Previous studies have proposed that the PEDC is favorable in complex aneurysms, such as large or giant, wide-neck, blister, and morphologically irregular ones.33,34 Coiling subsequently followed by the PED has also been shown to be beneficial for ruptured intracranial aneurysms, in which coils are initially placed during the acute phase, followed by subsequent deployment of the PED postrecovery.35,36 These data highlight a synergistic effect between coils and the PED; ie, Coiling provides direct occlusion within the aneurysm dome and prevents PED prolapse, while the PED prevents coil migration into the parent vessel and induces hemodynamic disturbances within the aneurysm dome.15,37⇓-39 Moreover, other FDDs have garnered interest for use in combination with coils, such as Flow-Redirection Endoluminal Device (FRED; MicroVention) and Tubridge, which further highlight more potential approaches in treating large intracranial aneurysms.40,41
CONCLUSIONS
This meta-analysis showed that the PEDC in large intracranial aneurysms induces a faster complete occlusion rate at 6 months and a lower retreatment rate. However, it increases the risk of stroke-related postoperative complications and may not be an effective strategy to prevent hemorrhage-related postoperative complications. Further study with comparable patients’ baseline characteristics, including aneurysm size, is needed to confirm the effectiveness of coiling in preventing hemorrhage-related postoperative complications. Nevertheless, the faster complete aneurysm occlusion rate found in this study did not correlate with a reduction in long-term aneurysm or distal artery ruptures. This study suggests the need to find a better strategy to improve long-term hemorrhage-related complications in large intracranial aneurysms.
Footnotes
Disclosure forms provided by the authors are available with the full text and PDF of this article at www.ajnr.org.
References
- Received June 3, 2024.
- Accepted after revision August 4, 2024.
- © 2025 by American Journal of Neuroradiology
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