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A Contemporary Review of Endovascular Treatment of Wide-Neck Large and Giant Aneurysms
Literature Review
A Contemporary Review of Endovascular Treatment of Wide-Neck Large and Giant Aneurysms Guilherme J. Agnoletto1, Philip M. Meyers2, Alexander Coon3, Peter Tze Man Kan4, Ajay K. Wakhloo5, Ricardo A. Hanel1
Key words Cerebrovascular - Coil embolization - Endovascular treatment - Intracranial aneurysm -
Abbreviations and Acronyms CI: Confidence interval PUFS: Pipeline for Uncoilable or Failed Aneurysm RCTs: Randomized controlled trials From the 1Baptist Neurological InstituteeLyerly Neurosurgery, Baptist Health, Jacksonville, Florida; 2 Department of Neurointerventional Surgery, Columbia Presbyterian Hospital, New York, New York; 3Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; 4Department of Neurosurgery, Baylor College of Medicine, Houston, Texas; and 5Department of Neurointerventional Radiology, Tufts Medical Center, Boston, Massachusetts, USA To whom correspondence should be addressed: Ricardo A. Hanel, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.06.201 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
INTRODUCTION Despite the approval and widespread use of flow diverters worldwide, many widenecked large and giant aneurysms are still treated with other coiling techniques, such as stent-assisted and balloon-assisted coiling as well as coiling alone. To our knowledge, no randomized controlled trials have been published comparing the available endovascular therapies. Although RCTs are considered to provide the most robust and reliable evidence of the efficacy of therapeutic options, a comprehensive look at empirical studies suggested that reviews based on observational studies generally produce estimates of effect similar to reviews based on RCTs.1 Therefore, a contemporary review of results of different endovascular treatment modalities is timely. We present a literature review of studies
- BACKGROUND:
Despite widespread use of flow diverters, wide-necked large and giant aneurysms are still treated with other techniques as well. A contemporary review of results from different endovascular treatments is timely.
- METHODS:
A literature review of the English language literature since 2011 was conducted using PubMed and Science Direct. Keywords and Medical Subheadings included large and giant aneurysms, ruptured aneurysms, aneurysms located in posterior circulation, and aneurysm occlusion status. Case reports were excluded. A combined model was built including both flow diverter and coil treatments in addition to separate models. Efficacy and safety were pooled using random effects analysis and regression.
- RESULTS:
The review comprised 29 studies. For coiling techniques, complete occlusion was 40.2%e82.8%, and adjusted regression resulted in 53% (95% confidence interval [CI] 22%e81%). Flow diverter complete occlusion rate was 40.5%e87.8%, and adjusted regression resulted in 87% (95% CI 76%e93%). Overall occlusion rate for both techniques combined was 62%e75%, and adjusted regression resulted in 81% (95% CI 68%e89%). Overall stroke and death regression rate was 5% (95% CI 3%e10%); flow diverters showed slightly higher rates than coiling (6% vs. 3%).
- CONCLUSIONS:
All current treatments of large and giant wide-necked aneurysms have comparable safety and efficacy with a trend of superiority of efficacy toward flow diverters. Results of future treatment options and devices can be compared with current technology to evaluate feasibility.
using coiling techniques and flow diverters focused on both efficacy and safety of treating wide-necked large and giant cerebral aneurysms. MATERIALS AND METHODS A protocol was developed before conducting this review covering methods for literature search, publication eligibility, assessment of quality of reporting, data extraction, and analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.2 As this was a systematic review of the literature without sharing any confidential patient information, there was no need for institutional review board or ethics committee evaluation. The scope of search included large and giant wide-neck aneurysms treated with all
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potential endovascular technologies, including stent-assisted coiling, balloonassisted coiling, coiling alone, and flow diversion, published in 2011 or later with a minimum 6-month follow-up. Studies with any of the following characteristics were excluded: 1) not primarily large or giant aneurysms; 2) majority of aneurysms were ruptured; 3) majority of aneurysms were located in posterior circulation; 4) study or relevant population included <30 patients. The literature search was performed to identify relevant literature for endovascular treatment of large and giant wide-neck internal carotid artery aneurysms. All PubMed searches were performed on November 7, 2017, and were limited to articles in English and published since January 1, 2011. Science Direct searches were performed on December 1, 2017, and
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were limited to articles published since January 1, 2011. Search terms were identified (detailed in Supplementary Table 1), citations were obtained, and abstracts and titles were screened for inclusion/ exclusion. The full text of any potentially included citation was then obtained and reviewed for content and final inclusion/ exclusion. Reference lists of included studies were manually searched. Additional identified articles were included in the review. Review articles were not included, but the article bibliography was used to identify other relevant articles. The search included primary level of evidence that addressed safety and efficacy of the therapeutic options of interest. Case series and cohort designs that were included as limited RCT data are available in this area, and therefore cohort data represent most of the available literature. The search process is detailed in Figure 1. Inclusion and Exclusion Criteria Studies with data regarding the safety and/ or performance of treatment of large and giant cerebral aneurysms of the anterior circulation were included. Published results from systematic reviews and clinical research studies had to meet the following criteria: RCTs, meta-analyses, registries, observational studies, postmarket surveillance studies, reports, and presentations Not superseded by a publication with the same sample group or later publication including the data from the same study (unless the article addressed a different objective) The following excluded:
article
types
were
Interim reports In vitro studies and animal studies Nonsystematic letters
reviews,
editorials,
Unsubstantiated opinions Case reports Unrelated to search topic Non-English articles
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Oral presentation without publication Reports related to posterior circulation aneurysms predominantly Reports related to ruptured aneurysms predominantly Reports related to small (<10 mm) aneurysms predominantly Reports related to techniques only Reports related recurrences
to
treatment
of
Reports related primarily to parent artery occlusion as a treatment Reports related to surgical treatment of aneurysms Reports including relevant populations <30 patients The specific search terms and the number of citations obtained from each search are shown in Supplementary Table 1, Supplementary Table 2, and Supplementary Table 3. Data Collection Efficacy data collected included the numerator and denominator for 1) large and giant aneurysms, 2) ruptured aneurysms, 3) aneurysms located in posterior circulation, and 4) aneurysm occlusion status (only complete or Raymond I occlusion was counted). If the numerator was not specified for large and giant aneurysms but the mean and standard deviation were provided, the proportion was determined using a normal distribution. If the median was provided, the proportion was determined using a uniform distribution or most appropriate distribution given the available data. If the proportion of ruptured aneurysms was not provided, the proportion of subjects presenting with acute subarachnoid hemorrhage was used as a surrogate with 75% of that number presenting with subarachnoid hemorrhage used as the proportion ruptured. This proportion is consistent with the data supporting that ruptured cerebral aneurysms account for 75%e85% of nontraumatic subarachnoid hemorrhage.3 In some studies, aneurysm occlusion was not determined at follow-up for all subjects, resulting in a denominator smaller than the total number of subjects in the trial. To account for this incomplete
follow-up, both a missing equals failure analysis and an evaluable subject analysis were performed. Safety data collected included the numerator and denominator for death and stroke. If stroke was not provided, modified Rankin Scale score (2) was used as a surrogate for stroke. Statistical Methods Analysis was performed for both the efficacy endpoint of total occlusion at 1 year and the safety endpoint of death and stroke. A forest plot was generated along with the I2 and the Cochran Q to estimate the initial amount of variability among the articles. Random-effects analyses were performed using the DerSimonian and Laird method with the estimate of heterogeneity being taken from the inversevariance fixed-effects model. Analyses were performed in STATA SE 14.2 (StataCorp LLC, College Station, Texas, USA), with calculations confirmed in Excel (Microsoft Corporation, Redmond, Washington, USA). Next, a regression model was built, including the following key covariates: 1) proportion of nonlarge/ giant aneurysms, 2) proportion of posterior aneurysms, and 3) proportion of ruptured aneurysms.4 A combined model was run including both flow diverter and coil treatments in addition to separate models for each device type: coil versus flow diverter. Before running the regression, the logit transformation was applied to the outcomes to meet the normality assumption of the model. The final model provides an equation that generated a point estimate with confidence interval (CI) on the logit scale for what the occlusion rate or death and stroke rate would be if covariates for small/medium aneurysms, posterior aneurysms, and ruptured aneurysms were set to zero. The estimate and CI for the pooled rate were obtained by taking the inverse logit transformation. Because regression uses summary statistics as the dependent variable, there is a risk of ecological fallacy. RESULTS A total of 480 citations from PubMed and 2179 citations from Science Direct were identified; 240 citations were excluded without review from the Science Direct searches because they represented either
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proportion ruptured resulted in an occlusion rate of 46% (95% CI 11%e85%). In many cases, multiple aneurysm locations were described, but specific outcomes by location were not reported. Kono et al.20 focused on cavernous sinus aneurysms and reported Raymond class at 12 months as 50% class I, 33.3% class II, and 16.7% class III. Chalouhi et al.10 reported recurrence and retreatment rates by aneurysm location. The highest rates were in the paraclinoid aneurysms (49% recurrence and 41.5% retreatment). Other locations, specifically the posterior communicating artery, had a recurrence rate of 33.3% and a retreatment rate of 30.3%.
Figure 1. Search process.
listings or tables of contents for abstract presentations. Therefore, a total of 2419 citations were retrieved from the combined database searches. During these searches, it was attempted to retrieve unique citations from each of the database searches independently. Similarly, because of the overlap of giant and large aneurysms in many reports, 1520 citations were identified as duplicates (Figure 2). An additional 49 articles were identified by manual review of references in publications or review articles. One citation was added for completeness because it represented the primary report for the Pipeline for Uncoilable or Failed Aneurysm (PUFS) trial, although longer follow-up reports that included some of the initial findings had been included.5 The remaining 899 citations underwent initial screening based on title and abstract, and an additional 701 citations were excluded. Full texts of the remaining 198 citations were obtained and screened for eligibility. Finally, 29 studies were included in this review (Figure 2).
Coiling Techniques Eleven studies in this review included performance data for coiling techniques.6-19 Follow-up duration was predominantly 6 or 12 months, and the technique was stent-assisted coiling in most cases. This approach is what would be expected in large or giant wide-neck aneurysms. These studies did not use core laboratories in their analyses. The analysis and regression results for coiling techniques are provided in Table 1. Complete occlusion (Raymond class I) was 40.2%e82.8%. Simple analysis of total occlusion values resulted in an occlusion rate of 62% (95% CI 51%e72%). The regression results adjusting for proportion large/giant, proportion posterior, and proportion ruptured resulted in an occlusion rate of 53% (95% CI 22%e81%). When a missing equals failures analysis was employed, the simple analysis of total occlusion values resulted in an occlusion rate of 52% (95% CI 40%e64%). The regression results adjusting for proportion large/ giant, proportion posterior, and
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Flow Diverters In the literature review, 14 reports were identified (including PUFS) with sufficient data to include in this analysis.21-38 The analysis and regression results for flow diverters are provided in Table 2. In these reports, occlusion (Raymond class I) was 40.5%e87.8%. The simple analysis of the total occlusion values resulted in an occlusion rate of 74% (95% CI 67%e 81%). Most of these studies did not use core laboratories in their analyses. The regression results adjusting for proportion large/giant, proportion posterior, and proportion ruptured resulted in an occlusion rate of 87% (95% CI 76%e93%). When employing a missing equals failures analysis for the flow diverter literature, the complete occlusion simple analysis rate was 64% (95% CI 55%e73%). The regression results adjusting for aneurysm size and location resulted in an occlusion rate of 73% (95% CI 49%e88%). Combined Results To further examine the current experience in the literature for treatment of large and giant wide-neck aneurysms, data from all treatment modalities were combined. Comparable to the above-mentioned analyses, both a simple analysis and a regression adjusting for aneurysm size and location were conducted. In addition, similar analyses were performed where missing data were considered as failures. This combined dataset represents the most appropriate dataset to use for purposes of comparison.
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giant wide-neck aneurysms are considered, the reported death and stroke rate was 2.7%e19.7%. Simple analysis rate for combined stroke and death was 7% (95% CI 6%e9%). When a regression was performed adjusting for proportion large/giant, proportion posterior, and proportion ruptured, the adjusted combined stroke and death rate was 5% (95% CI 3%e10%). The rates for flow diverters were slightly higher than the rates for coiling techniques (simple analysis rate was 8% for flow diverters vs. 6% for coils, adjusted regression model rate was 6% for flow diverters vs. 3% for coils). These rates were based on site reporting of events and did not incorporate the use of an adjudication committee to assess safety events, something that could be expected from future studies of technologies and devices. DISCUSSION
Figure 2. Results of search.
The analysis and regression of these data are shown in Table 3. When analyzing the data as reported, the overall occlusion rate was 69% (95% CI 62%e75%). The regression results adjusting for proportion large/giant, proportion posterior, and proportion ruptured resulted in an occlusion rate of 81% (95% CI 68%e89%). When employing a missing equals failures analysis for the combined literature, the complete occlusion simple analysis rate was 59%
(95% CI 51%e67%). The regression results adjusting for aneurysm size and location resulted in an occlusion rate of 67% (95% CI 49%e81%). Safety In the review of the literature, 26 reports included safety data.8,10,12-14,16,17,21,22,24,27,32-42 The analysis and regression results for safety endpoint are provided in Table 4. When all endovascular treatments for large and
Table 1. Coiling Techniques Analysis and Regression Aneurysm Occlusion Results Missing
Estimate
95% CI
Analysis
Omitted
62%
51%e72%
Regression*
Omitted
53%
22%e81%
Analysis
Treated as failure
52%
40%e64%
Regression*
Treated as failure
46%
11%e85%
CI, confidence interval. *Regression estimate for 0% small, 0% posterior, 0% ruptured.
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This literature review was performed to understand the current state of the art for endovascular treatment of large and giant wide-neck aneurysms. Based on a review of the current available treatments, a combined literature review of coiling techniques and flow diverters as the comparator seems most appropriate. In the systematic reviews described, c2 tests for homogeneity were rejected for all analyses performed, and all had high values of I2, further supporting a large degree of heterogeneity across studies. Both the analysis and the regression results are described; however, given that none of the factors considered in the model reached statistical significance, related to the significant heterogeneity among them, the simple analysis approach can best be used to support the current state of the published literature and the performance goals for the targeted assessment. Many of the articles included are singlecenter studies, and in many cases the outcome findings are site assessed and not subject to a rigorous core laboratory review process. Core laboratory assessments of outcome tend to be more conservative than site-reported assessments. These differences need to be considered when evaluating the results of possible future treatments in the literature. Although the Raymond-Roy classification (or a modified classification) for assessing aneurysm
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Table 2. Flow Diverters Analysis and Regression Aneurysm Occlusion Results Missing
Estimate
95% CI
Analysis
Omitted
74%
67%e81%
Regression*
Omitted
87%
76%e93%
Analysis
Treated as failure
64%
55%e73%
Regression*
Treated as failure
73%
49%e88%
Table 4. Analysis and Regression Safety Endpoint Results Safety Analysis
Estimate
95% CI
Analysis
7%
6%e9%
Regression*
5%
3%e10%
Analysis
6%
3%e9%
Regression*
3%
4%e25%
Analysis
8%
6%e11%
Regression*
6%
3%e13%
All
Coils
CI, confidence interval. *Regression estimate for 0% small, 0% posterior, 0% ruptured.
Flow diverters
occlusion was commonly applied, it may not accurately reflect the results in flow diverter treatments in terms of long-term risk of bleeding or rupture. Finite element modeling of fluid dynamics comparing flow diversion with coiling demonstrated that for flow diverters there was a decrease in inflow velocity as opposed to coiling, where flow continued to penetrate the aneurysm volume.6 With coiling techniques, branches that arise from the aneurysm are generally occluded by the coil mass and therefore cannot contribute to further flow of the aneurysm itself. Without coiling, flow diverters may preserve these branches. The short-term effect of not potentially creating ischemia in the side-branch distribution is unknown, as is the long-term effect of maintained patency. It is also recognized that the presence of a neck remnant with flow diversion may not have the same implication for bleeding risk as is seen with coiling, where coil compaction and aneurysm expansion may still occur. At least 1 new classification takes these factors into account and attempts to assess the stability of the angiographic results after endovascular treatment with any technique.7 This proposed classification is as follows:
Class 1: Complete occlusion of the aneurysm sac. When there is a branch integrated with the aneurysm sac (i.e., coming off the aneurysm) at any point of the sac, further analysis is carried out with subgroups. 1A: Complete occlusion with the full patency of the integrated branch. 1B: Complete occlusion with the branch reduced in caliber. 1C: Complete occlusion with no antegrade filling of the branch. Class 2: Neck filling. Class 3: Incomplete occlusion with aneurysm filling. Class 4: Aneurysm filling. This class is reserved for an immediate postoperative result based on end-of-treatment digital subtraction angiography, after extra-anchor intrasaccular flow modification treatment. 4A: With contrast stagnation—contrast stagnation refers to when there happens to be any change in the duration of the contrast within the aneurysm sac after treatment. 4B: Without contrast stagnation.
Table 3. Combined Treatments Analysis and Regression Aneurysm Occlusion Results Missing
Estimate
95% CI
Analysis
Omitted
69%
62%e75%
Regression*
Omitted
81%
68%e89%
Analysis
Treated as failure
59%
51%e67%
Regression*
Treated as failure
67%
49%e81%
CI, confidence interval. *Regression estimate for 0% small, 0% posterior, 0% ruptured.
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CI, confidence interval. *Regression estimate for 0% small, 0% posterior, 0% ruptured.
Class 5: Stable remodeling with flow modification. Filling in the neck region, which stays unchanged or reduced. To be included in this group, there have to be at least 2 consecutive control angiograms, by definition, at least 6 months apart, and expanding for a period of not <1 year exceptionally; 1 control angiogram could be sufficient for definition of class 5 only in selected cases of contrast filling the branch coming off the sac, with an appearance of a different vessel course than the original (e.g., tortuous or dilated), given that it is in continuation with the parent artery with no sac filling.7 In the studies reviewed where retreatment rates were reported, recurrence with coiling techniques was high, frequently >20%.13,16,17,20-24 This rate of recurrence is noteworthy and often an identified disadvantage of endovascular coiling.25 Future proposed treatments and devices can possibly use as a criterion for success the fact that no retreatment was necessary to pair up and adequately measure equipoise. It also should be noted that the coiling experience from the literature may be inflated by the more recent studies after the Pipeline embolization device (Medtronic, Minneapolis, Minnesota, USA) became available, where coiling was performed in a more selected population given the alternative therapy being available.8,12,13,16,17 The PUFS trial provides important data on the early clinical experience with flow
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diverters.5 Of 106 aneurysms, 78 met the primary endpoint (aneurysm occlusion, parent artery stenosis 50%, and no additional embolic agent) at 6 months. The 1-year results reported an occlusion rate of 74.5% (79 of 106 aneurysms included in the efficacy population).5 Recurrence or retreatment was not reported at 1 year. The PUFS trial is important when assessing long-term outcome from flow diverter therapy. The 5-year outcome from this study is now available and points to the stability of the therapy, particularly in reference to neck remnants.26 In this recent report, of 8 subjects with residual necks (Raymond class II) at 6 months, 7 had assessments at 3 years, and 2 continued to show a residual neck, whereas 5 had gone on to complete occlusion. In addition, 7 subjects with residual aneurysms at 6 months showed complete aneurysm occlusion at 3 years. Six subjects had retreatments. Of the 4 subjects without retreatment and with imaging available at 5 years, 1 subject had a residual neck that remained stable, and 3 subjects with residual aneurysms had occlusion. As described earlier, the Raymond classification, which was originally used to assist in the prediction of long-term outcomes, such as bleeding and aneurysm growth after coil embolization, may not be the optimal approach with flow diverter therapies. Stable neck remnants have not been associated with higher frequencies of long-term adverse events and therefore should be considered a successful outcome when flow diverter is the primary therapy for large and giant wide-neck aneurysms.7 Additional components of overall success could also be used in future treatment and devices studies, such as no retreatment before 1-year angiographic assessment and no parent artery stenosis. In the literature, it is difficult to account for these additional components of the primary endpoint uniquely. Parent artery status and additive retreatment events at followup were reported in the PUFS trial only for large and giant wide-neck aneurysms during the publication period of this literature review. Using the PUFS trial data, which systematically accounted for these additive rates, 8 carotid occlusions, parent artery stenosis >50%, and retreatments were reported through 1 year, resulting in an estimated 7.5% additional
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reduction over the complete occlusion success criterion for the study success performance goal.5 Using this rate from the flow diverter literature would be a conservative approach to accounting for this additional component of the primary study endpoint. Using the missing equals failure analysis lower bounds of the analysis (51%) and allowing for an additional 7.5% reduction for the additive success criteria based on the PUFS trial additional components of the primary safety endpoint, a performance goal of 43.5% would be derived. These analyses in totality support that an originally derived performance goal of 50% was reasonable and perhaps even conservative. The current literature review reflects the current state of all treatment modalities for large and giant wide-neck aneurysms. A performance goal of 50% is supported by the analyses and regression models conducted given the lower bound of the 95% CI for all analyses for aneurysm occlusion rates (combined 51%, coils 40%, and flow diverters 55%) using a missing equals failures analysis approach is in range of the 50% threshold. When considering the possibility of an added success criterion of no parent artery stenosis and no reintervention, accounting for an additional 7.5% reduction in Pipeline, the 50% threshold would in fact be conservative. As with the performance data, safety data were inconsistently described and in general site reported and not adjudicated. No analysis exists that relates site-reported event rates to adjudicated events, and therefore no similar discounting approach to that used for efficacy data can be applied to the safety data. However, it is well recognized that published data describing site-reported rates generally underestimate the rates that are reported in rigorously performed clinical trials with independent assessments of adverse events. The primary safety endpoint rate for PUFS was 5.6% (posterior probability interval 2.6%e11.7%).5 Two recent trials, SCENT (Safety and Effectiveness of an Intracranial Aneurysm Embolization System for Treating Large or Giant Wide Neck Aneurysms) and PREMIER (Prospective Study on Embolization of Intracranial Aneurysms with Pipeline Embolization Device), may show promising data, but published results are not
yet available and thus are not included on the present analysis. CONCLUSIONS All current treatments of large and giant wide-neck aneurysms have comparable safety and efficacy with a trend of superiority of efficacy toward flow diverters. Results of future treatment options and devices can be compared with current technology to evaluate feasibility. It is important to include all treatment modalities in this analysis, as both flow diverters and coiling technologies are available, and physicians choose the technique that they believe is the best treatment for an individual patient based on presentation, anatomy, and the physician’s familiarity with the techniques. REFERENCES 1. Shrier I, Boivin JF, Steele RJ, et al. Should metaanalyses of interventions include observational studies in addition to randomized controlled trials? A critical examination of underlying principles. Am J Epidemiol. 2007;166:1203-1209. 2. Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. 3. D’Souza S. Aneurysmal subarachnoid hemorrhage. J Neurosurg Anesthesiol. 2015;27:222-240. 4. Sterne JA, Bradburn MJ, Egger M. Meta-analysis in Stata. In: Egger M, Smith GD, Altman DG, eds. Systematic Reviews in Health Care: Meta-Analysis in Context. London: BMJ Publishing Group; 2008: 347-369. 5. Becske T, Kallmes DF, Saatci I, et al. Pipeline for uncoilable or failed aneurysms: results from a multicenter clinical trial. Radiology. 2013;267: 858-868. 6. Damiano RJ, Ma D, Xiang J, Siddiqui AH, Snyder KV, Meng H. Finite element modeling of endovascular coiling and flow diversion enables hemodynamic prediction of complex treatment strategies for intracranial aneurysm. J Biomech. 2015;48:3332-3340. 7. Cekirge HS, Saatci I. A new aneurysm occlusion classification after the impact of flow modification. AJNR Am J Neuroradiol. 2016;37:19-24. 8. Almandoz DJ, Kayan Y, Fease J, et al. E-063 The pc400 system safely coils large cerebral aneurysms with high packing densities and low retreatment rates. J Neurointerv Surg. 2017;9(Suppl 1):A72. 9. Chalouhi N, Starke RM, Yang S, et al. Extending the indications of flow diversion to small, unruptured, saccular aneurysms of the anterior circulation. Stroke. 2014;45:54-58.
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27. Burrows AM, Cloft H, Kallmes DF, Lanzino G. Periprocedural and mid-term technical and clinical events after flow diversion for intracranial aneurysms. J Neurointerv Surg. 2015;7:646-651.
16. Qu RB, Jin H. Endovascular treatment of intracranial ophthalmic segment aneurysms: a series and literature review. Turk Neurosurg. 2016;26: 223-228. 17. Suzuki K, Suzuki R, Takigawa T, et al. A single center experience with coil embolization for cerebral aneurysms greater than 10 mm in the internal carotid artery. Neurol Med Chir (tokyo). 2017; 57:231-237. 18. Wang B, Gao BL, Xu GP, Xiang C, Liu XS. Endovascular embolization is applicable for large and giant intracranial aneurysms: experience in one center with long-term angiographic followup. Acta Radiol. 2015;56:105-113. 19. Rezek I, Mousan G, Wang Z, Murad MH, Kallmes DF. Effect of core laboratory and multiple-reader interpretation of angiographic images on follow-up outcomes of coiled cerebral aneurysms: a systematic review and meta-analysis. AJNR Am J Neuroradiol. 2013;34:1380-1384. 20. Kono K, Shintani A, Okada H, Tanaka Y, Terada T. Stent-assisted coil embolization for cavernous carotid artery aneurysms. Neurol Med Chir (tokyo). 2014;54:126-132. 21. Adeeb N, Griessenauer CJ, Foreman PM, et al. Comparison of stent-assisted coil embolization and the pipeline embolization device for endovascular treatment of ophthalmic segment aneurysms: a multicenter cohort study. World Neurosurg. 2017;105:206-212.
28. Cinar C, Bozkaya H, Oran I. Endovascular treatment of cranial aneurysms with the Pipeline flowdiverting stent: preliminary mid-term results. Diagn Interv Radiol. 2013;19:154-164. 29. Fennell VS, Martirosyan NL, Palejwala SK, Lemole GM Jr, Dumont TM. Morbidity and mortality of patients with endovascularly treated intracerebral aneurysms: does physician specialty matter? J Neurosurg. 2016;124:13-17. 30. O’Kelly CJ, Spears J, Chow M, et al. Canadian experience with the Pipeline embolization device for repair of unruptured intracranial aneurysms. AJNR Am J Neuroradiol. 2013;34:381-387. 31. Peker A, Akgul E, Daglioglu E, et al. Tapered flow diverters in the treatment of intracranial aneurysms. Turk Neurosurg. 2017;27:863-866. 32. Peschillo S, Caporlingua A, Resta MC, et al. Endovascular treatment of large and giant carotid aneurysms with flow-diverter stents alone or in combination with coils: a multicenter experience and long-term follow-up. Oper Neurosurg (hagerstown). 2017;13:492-502.
the significance of adenosine diphosphate inhibition, fluoroscopy time, and aneurysm size. Interv Neuroradiol. 2016;22:34-41. 35. Raymond J, Gentric JC, Darsaut TE, et al. Flow diversion in the treatment of aneurysms: a randomized care trial and registry. J Neurosurg. 2017; 127:454-462. 36. Shankar JJ, Tampieri D, Iancu D, et al. SILK flow diverter for complex intracranial aneurysms: a Canadian registry. J Neurointerv Surg. 2016;8: 273-278. 37. Toma AK, Robertson F, Wong K, et al. Early single centre experience of flow diverting stents for the treatment of cerebral aneurysms. Br J Neurosurg. 2013;27:622-628. 38. Velioglu M, Kizilkilic O, Selcuk H, et al. Early and midterm results of complex cerebral aneurysms treated with Silk stent. Neuroradiology. 2012;54: 1355-1365. 39. Kallmes DF, Brinjikji W, Boccardi E, et al. Aneurysm study of pipeline in an observational registry (ASPIRe). Interv Neurol. 2016;5:89-99. 40. Kallmes DF, Brinjikji W, Cekirge S, et al. Safety and efficacy of the Pipeline embolization device for treatment of intracranial aneurysms: a pooled analysis of 3 large studies. J Neurosurg. 2017;127: 775-780. 41. McDonald RJ, McDonald JS, Kallmes DF, Lanzino G, Cloft HJ. Periprocedural safety of Pipeline therapy for unruptured cerebral aneurysms: analysis of 279 patients in a multihospital database. Interv Neuroradiol. 2015;21:6-10. 42. Song J, Yeon JY, Kim JS, Hong SC, Kim KH, Jeon P. Delayed thromboembolic events more than 30 days after self expandable intracranial stent-assisted embolization of unruptured intracranial aneurysms. Clin Neurol Neurosurg. 2015;135: 73-78.
Conflict of interest statement: P. M. Meyers is a consultant for Stryker. A. Coon is a consultant for Stryker, Medtronic, and MicroVention. P. T. M. Kan is a consultant for Stryker and Medtronic and has InNeuroCo stock ownership interest. A. K. Wakhloo is a consultant for Codman and Stryker; has research grants from the National Institutes of Health, Philips Healthcare, and Wyss Institute; and is a cofounder of InNeuroCo. R. A. Hanel is a consultant for Covidien, Stryker, Codman, and MicroVention. G. J. Agnoletto has nothing to disclose. Received 10 April 2019; accepted 26 June 2019
33. Piano M, Valvassori L, Quilici L, Pero G, Boccardi E. Midterm and long-term follow-up of cerebral aneurysms treated with flow diverter devices: a single-center experience. J Neurosurg. 2013; 118:408-416. 34. Raychev R, Tateshima S, Vinuela F, et al. Predictors of thrombotic complications and mass effect exacerbation after pipeline embolization:
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Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.06.201 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
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SUPPLEMENTARY DATA
Supplementary Table 1. Search Terms PubMed Citations Science Direct Citations (Jan 1, 2011eNov 7, 2017) (Jan 1, 2011eDec 1, 2017)
Search Term “Search (Raymond classification) AND flow diversion”
8
23
“Search (balloon assisted coiling) AND ((large) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
17
456
“Search (balloon assisted coiling) AND ((giant) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
12
“Search (flow diversion) AND ((large) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
82
“Search (flow diversion) AND ((giant) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
74
“Search (stent assisted coiling) AND ((large) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
61
“Search (stent assisted coiling) AND ((giant) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
37
“Search (embolization) AND ((large) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
121
“Search (embolization) AND ((giant) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
68
Total
480
235
911
2179
Supplementary Table 2. Level 1 Exclusions—Abstract Title Screening Exclusion Criterion
Number of Articles Excluded
Articles not related to the device of interest, an equivalent device, or a predecessor device
87
Articles not related to the population or anatomy of interest
343
Articles using the device of interest in ways unrelated to its indicated use
2
Letters to the editor, opinions, editorials, surveys, manufacturer’s advertisements, and press releases
2
Nonclinical studies, e.g., laboratory research, animal studies, in vitro or ex vivo studies, postmortem studies, and biomechanical studies
40
Abstracts or conference proceedings
1
Review articles
62
Isolated case reports, unless new risks are described
118
Articles in which the full text is non-English
1
Articles inadequate by appraisal/weighting criteria, e.g., lacking sufficient clarity or detail to correlate patient outcomes with the product of interest or lacking scientific soundness
3
Total exclusions at level 1
7.E1
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Supplementary Table 3. Level 2 Exclusions—Full Text Screening Exclusion Criterion
Number of Articles Excluded
Articles not related to the device of interest, an equivalent device, or a predecessor device
19
Articles using the device of interest in ways unrelated to its indicated use
60
Articles that did not provide data on the clinical safety and/or performance of the device of interest
34
Studies with <30 subjects
8
Studies with <50% large/giant aneurysms
15
Studies with >50% ruptured aneurysms at presentation
2
Letters to the editor, opinions, editorials, surveys, manufacturer’s advertisements, and press releases
4
Nonclinical studies, e.g., laboratory research, animal studies, in vitro or ex vivo studies, postmortem studies, and biomechanical studies
1
Review articles
18
Duplicate articles or duplicate publications of the same study data
2
Isolated case reports, unless new risks are described
1
Articles in which the full text is non-English
1
Articles inadequate by appraisal/weighting criteria, e.g., lacking sufficient clarity or detail to correlate patient outcomes with the product of interest or lacking scientific soundness
4
Total exclusions at level 1
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169
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A Contemporary Review of Endovascular Treatment of Wide-Neck Large and Giant Aneurysms Guilherme J. Agnoletto1, Philip M. Meyers2, Alexander Coon3, Peter Tze Man Kan4, Ajay K. Wakhloo5, Ricardo A. Hanel1
Key words Cerebrovascular - Coil embolization - Endovascular treatment - Intracranial aneurysm -
Abbreviations and Acronyms CI: Confidence interval PUFS: Pipeline for Uncoilable or Failed Aneurysm RCTs: Randomized controlled trials From the 1Baptist Neurological InstituteeLyerly Neurosurgery, Baptist Health, Jacksonville, Florida; 2 Department of Neurointerventional Surgery, Columbia Presbyterian Hospital, New York, New York; 3Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; 4Department of Neurosurgery, Baylor College of Medicine, Houston, Texas; and 5Department of Neurointerventional Radiology, Tufts Medical Center, Boston, Massachusetts, USA To whom correspondence should be addressed: Ricardo A. Hanel, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.06.201 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
INTRODUCTION Despite the approval and widespread use of flow diverters worldwide, many widenecked large and giant aneurysms are still treated with other coiling techniques, such as stent-assisted and balloon-assisted coiling as well as coiling alone. To our knowledge, no randomized controlled trials have been published comparing the available endovascular therapies. Although RCTs are considered to provide the most robust and reliable evidence of the efficacy of therapeutic options, a comprehensive look at empirical studies suggested that reviews based on observational studies generally produce estimates of effect similar to reviews based on RCTs.1 Therefore, a contemporary review of results of different endovascular treatment modalities is timely. We present a literature review of studies
- BACKGROUND:
Despite widespread use of flow diverters, wide-necked large and giant aneurysms are still treated with other techniques as well. A contemporary review of results from different endovascular treatments is timely.
- METHODS:
A literature review of the English language literature since 2011 was conducted using PubMed and Science Direct. Keywords and Medical Subheadings included large and giant aneurysms, ruptured aneurysms, aneurysms located in posterior circulation, and aneurysm occlusion status. Case reports were excluded. A combined model was built including both flow diverter and coil treatments in addition to separate models. Efficacy and safety were pooled using random effects analysis and regression.
- RESULTS:
The review comprised 29 studies. For coiling techniques, complete occlusion was 40.2%e82.8%, and adjusted regression resulted in 53% (95% confidence interval [CI] 22%e81%). Flow diverter complete occlusion rate was 40.5%e87.8%, and adjusted regression resulted in 87% (95% CI 76%e93%). Overall occlusion rate for both techniques combined was 62%e75%, and adjusted regression resulted in 81% (95% CI 68%e89%). Overall stroke and death regression rate was 5% (95% CI 3%e10%); flow diverters showed slightly higher rates than coiling (6% vs. 3%).
- CONCLUSIONS:
All current treatments of large and giant wide-necked aneurysms have comparable safety and efficacy with a trend of superiority of efficacy toward flow diverters. Results of future treatment options and devices can be compared with current technology to evaluate feasibility.
using coiling techniques and flow diverters focused on both efficacy and safety of treating wide-necked large and giant cerebral aneurysms. MATERIALS AND METHODS A protocol was developed before conducting this review covering methods for literature search, publication eligibility, assessment of quality of reporting, data extraction, and analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.2 As this was a systematic review of the literature without sharing any confidential patient information, there was no need for institutional review board or ethics committee evaluation. The scope of search included large and giant wide-neck aneurysms treated with all
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potential endovascular technologies, including stent-assisted coiling, balloonassisted coiling, coiling alone, and flow diversion, published in 2011 or later with a minimum 6-month follow-up. Studies with any of the following characteristics were excluded: 1) not primarily large or giant aneurysms; 2) majority of aneurysms were ruptured; 3) majority of aneurysms were located in posterior circulation; 4) study or relevant population included <30 patients. The literature search was performed to identify relevant literature for endovascular treatment of large and giant wide-neck internal carotid artery aneurysms. All PubMed searches were performed on November 7, 2017, and were limited to articles in English and published since January 1, 2011. Science Direct searches were performed on December 1, 2017, and
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were limited to articles published since January 1, 2011. Search terms were identified (detailed in Supplementary Table 1), citations were obtained, and abstracts and titles were screened for inclusion/ exclusion. The full text of any potentially included citation was then obtained and reviewed for content and final inclusion/ exclusion. Reference lists of included studies were manually searched. Additional identified articles were included in the review. Review articles were not included, but the article bibliography was used to identify other relevant articles. The search included primary level of evidence that addressed safety and efficacy of the therapeutic options of interest. Case series and cohort designs that were included as limited RCT data are available in this area, and therefore cohort data represent most of the available literature. The search process is detailed in Figure 1. Inclusion and Exclusion Criteria Studies with data regarding the safety and/ or performance of treatment of large and giant cerebral aneurysms of the anterior circulation were included. Published results from systematic reviews and clinical research studies had to meet the following criteria: RCTs, meta-analyses, registries, observational studies, postmarket surveillance studies, reports, and presentations Not superseded by a publication with the same sample group or later publication including the data from the same study (unless the article addressed a different objective) The following excluded:
article
types
were
Interim reports In vitro studies and animal studies Nonsystematic letters
reviews,
editorials,
Unsubstantiated opinions Case reports Unrelated to search topic Non-English articles
2
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Oral presentation without publication Reports related to posterior circulation aneurysms predominantly Reports related to ruptured aneurysms predominantly Reports related to small (<10 mm) aneurysms predominantly Reports related to techniques only Reports related recurrences
to
treatment
of
Reports related primarily to parent artery occlusion as a treatment Reports related to surgical treatment of aneurysms Reports including relevant populations <30 patients The specific search terms and the number of citations obtained from each search are shown in Supplementary Table 1, Supplementary Table 2, and Supplementary Table 3. Data Collection Efficacy data collected included the numerator and denominator for 1) large and giant aneurysms, 2) ruptured aneurysms, 3) aneurysms located in posterior circulation, and 4) aneurysm occlusion status (only complete or Raymond I occlusion was counted). If the numerator was not specified for large and giant aneurysms but the mean and standard deviation were provided, the proportion was determined using a normal distribution. If the median was provided, the proportion was determined using a uniform distribution or most appropriate distribution given the available data. If the proportion of ruptured aneurysms was not provided, the proportion of subjects presenting with acute subarachnoid hemorrhage was used as a surrogate with 75% of that number presenting with subarachnoid hemorrhage used as the proportion ruptured. This proportion is consistent with the data supporting that ruptured cerebral aneurysms account for 75%e85% of nontraumatic subarachnoid hemorrhage.3 In some studies, aneurysm occlusion was not determined at follow-up for all subjects, resulting in a denominator smaller than the total number of subjects in the trial. To account for this incomplete
follow-up, both a missing equals failure analysis and an evaluable subject analysis were performed. Safety data collected included the numerator and denominator for death and stroke. If stroke was not provided, modified Rankin Scale score (2) was used as a surrogate for stroke. Statistical Methods Analysis was performed for both the efficacy endpoint of total occlusion at 1 year and the safety endpoint of death and stroke. A forest plot was generated along with the I2 and the Cochran Q to estimate the initial amount of variability among the articles. Random-effects analyses were performed using the DerSimonian and Laird method with the estimate of heterogeneity being taken from the inversevariance fixed-effects model. Analyses were performed in STATA SE 14.2 (StataCorp LLC, College Station, Texas, USA), with calculations confirmed in Excel (Microsoft Corporation, Redmond, Washington, USA). Next, a regression model was built, including the following key covariates: 1) proportion of nonlarge/ giant aneurysms, 2) proportion of posterior aneurysms, and 3) proportion of ruptured aneurysms.4 A combined model was run including both flow diverter and coil treatments in addition to separate models for each device type: coil versus flow diverter. Before running the regression, the logit transformation was applied to the outcomes to meet the normality assumption of the model. The final model provides an equation that generated a point estimate with confidence interval (CI) on the logit scale for what the occlusion rate or death and stroke rate would be if covariates for small/medium aneurysms, posterior aneurysms, and ruptured aneurysms were set to zero. The estimate and CI for the pooled rate were obtained by taking the inverse logit transformation. Because regression uses summary statistics as the dependent variable, there is a risk of ecological fallacy. RESULTS A total of 480 citations from PubMed and 2179 citations from Science Direct were identified; 240 citations were excluded without review from the Science Direct searches because they represented either
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proportion ruptured resulted in an occlusion rate of 46% (95% CI 11%e85%). In many cases, multiple aneurysm locations were described, but specific outcomes by location were not reported. Kono et al.20 focused on cavernous sinus aneurysms and reported Raymond class at 12 months as 50% class I, 33.3% class II, and 16.7% class III. Chalouhi et al.10 reported recurrence and retreatment rates by aneurysm location. The highest rates were in the paraclinoid aneurysms (49% recurrence and 41.5% retreatment). Other locations, specifically the posterior communicating artery, had a recurrence rate of 33.3% and a retreatment rate of 30.3%.
Figure 1. Search process.
listings or tables of contents for abstract presentations. Therefore, a total of 2419 citations were retrieved from the combined database searches. During these searches, it was attempted to retrieve unique citations from each of the database searches independently. Similarly, because of the overlap of giant and large aneurysms in many reports, 1520 citations were identified as duplicates (Figure 2). An additional 49 articles were identified by manual review of references in publications or review articles. One citation was added for completeness because it represented the primary report for the Pipeline for Uncoilable or Failed Aneurysm (PUFS) trial, although longer follow-up reports that included some of the initial findings had been included.5 The remaining 899 citations underwent initial screening based on title and abstract, and an additional 701 citations were excluded. Full texts of the remaining 198 citations were obtained and screened for eligibility. Finally, 29 studies were included in this review (Figure 2).
Coiling Techniques Eleven studies in this review included performance data for coiling techniques.6-19 Follow-up duration was predominantly 6 or 12 months, and the technique was stent-assisted coiling in most cases. This approach is what would be expected in large or giant wide-neck aneurysms. These studies did not use core laboratories in their analyses. The analysis and regression results for coiling techniques are provided in Table 1. Complete occlusion (Raymond class I) was 40.2%e82.8%. Simple analysis of total occlusion values resulted in an occlusion rate of 62% (95% CI 51%e72%). The regression results adjusting for proportion large/giant, proportion posterior, and proportion ruptured resulted in an occlusion rate of 53% (95% CI 22%e81%). When a missing equals failures analysis was employed, the simple analysis of total occlusion values resulted in an occlusion rate of 52% (95% CI 40%e64%). The regression results adjusting for proportion large/ giant, proportion posterior, and
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Flow Diverters In the literature review, 14 reports were identified (including PUFS) with sufficient data to include in this analysis.21-38 The analysis and regression results for flow diverters are provided in Table 2. In these reports, occlusion (Raymond class I) was 40.5%e87.8%. The simple analysis of the total occlusion values resulted in an occlusion rate of 74% (95% CI 67%e 81%). Most of these studies did not use core laboratories in their analyses. The regression results adjusting for proportion large/giant, proportion posterior, and proportion ruptured resulted in an occlusion rate of 87% (95% CI 76%e93%). When employing a missing equals failures analysis for the flow diverter literature, the complete occlusion simple analysis rate was 64% (95% CI 55%e73%). The regression results adjusting for aneurysm size and location resulted in an occlusion rate of 73% (95% CI 49%e88%). Combined Results To further examine the current experience in the literature for treatment of large and giant wide-neck aneurysms, data from all treatment modalities were combined. Comparable to the above-mentioned analyses, both a simple analysis and a regression adjusting for aneurysm size and location were conducted. In addition, similar analyses were performed where missing data were considered as failures. This combined dataset represents the most appropriate dataset to use for purposes of comparison.
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giant wide-neck aneurysms are considered, the reported death and stroke rate was 2.7%e19.7%. Simple analysis rate for combined stroke and death was 7% (95% CI 6%e9%). When a regression was performed adjusting for proportion large/giant, proportion posterior, and proportion ruptured, the adjusted combined stroke and death rate was 5% (95% CI 3%e10%). The rates for flow diverters were slightly higher than the rates for coiling techniques (simple analysis rate was 8% for flow diverters vs. 6% for coils, adjusted regression model rate was 6% for flow diverters vs. 3% for coils). These rates were based on site reporting of events and did not incorporate the use of an adjudication committee to assess safety events, something that could be expected from future studies of technologies and devices. DISCUSSION
Figure 2. Results of search.
The analysis and regression of these data are shown in Table 3. When analyzing the data as reported, the overall occlusion rate was 69% (95% CI 62%e75%). The regression results adjusting for proportion large/giant, proportion posterior, and proportion ruptured resulted in an occlusion rate of 81% (95% CI 68%e89%). When employing a missing equals failures analysis for the combined literature, the complete occlusion simple analysis rate was 59%
(95% CI 51%e67%). The regression results adjusting for aneurysm size and location resulted in an occlusion rate of 67% (95% CI 49%e81%). Safety In the review of the literature, 26 reports included safety data.8,10,12-14,16,17,21,22,24,27,32-42 The analysis and regression results for safety endpoint are provided in Table 4. When all endovascular treatments for large and
Table 1. Coiling Techniques Analysis and Regression Aneurysm Occlusion Results Missing
Estimate
95% CI
Analysis
Omitted
62%
51%e72%
Regression*
Omitted
53%
22%e81%
Analysis
Treated as failure
52%
40%e64%
Regression*
Treated as failure
46%
11%e85%
CI, confidence interval. *Regression estimate for 0% small, 0% posterior, 0% ruptured.
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This literature review was performed to understand the current state of the art for endovascular treatment of large and giant wide-neck aneurysms. Based on a review of the current available treatments, a combined literature review of coiling techniques and flow diverters as the comparator seems most appropriate. In the systematic reviews described, c2 tests for homogeneity were rejected for all analyses performed, and all had high values of I2, further supporting a large degree of heterogeneity across studies. Both the analysis and the regression results are described; however, given that none of the factors considered in the model reached statistical significance, related to the significant heterogeneity among them, the simple analysis approach can best be used to support the current state of the published literature and the performance goals for the targeted assessment. Many of the articles included are singlecenter studies, and in many cases the outcome findings are site assessed and not subject to a rigorous core laboratory review process. Core laboratory assessments of outcome tend to be more conservative than site-reported assessments. These differences need to be considered when evaluating the results of possible future treatments in the literature. Although the Raymond-Roy classification (or a modified classification) for assessing aneurysm
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Table 2. Flow Diverters Analysis and Regression Aneurysm Occlusion Results Missing
Estimate
95% CI
Analysis
Omitted
74%
67%e81%
Regression*
Omitted
87%
76%e93%
Analysis
Treated as failure
64%
55%e73%
Regression*
Treated as failure
73%
49%e88%
Table 4. Analysis and Regression Safety Endpoint Results Safety Analysis
Estimate
95% CI
Analysis
7%
6%e9%
Regression*
5%
3%e10%
Analysis
6%
3%e9%
Regression*
3%
4%e25%
Analysis
8%
6%e11%
Regression*
6%
3%e13%
All
Coils
CI, confidence interval. *Regression estimate for 0% small, 0% posterior, 0% ruptured.
Flow diverters
occlusion was commonly applied, it may not accurately reflect the results in flow diverter treatments in terms of long-term risk of bleeding or rupture. Finite element modeling of fluid dynamics comparing flow diversion with coiling demonstrated that for flow diverters there was a decrease in inflow velocity as opposed to coiling, where flow continued to penetrate the aneurysm volume.6 With coiling techniques, branches that arise from the aneurysm are generally occluded by the coil mass and therefore cannot contribute to further flow of the aneurysm itself. Without coiling, flow diverters may preserve these branches. The short-term effect of not potentially creating ischemia in the side-branch distribution is unknown, as is the long-term effect of maintained patency. It is also recognized that the presence of a neck remnant with flow diversion may not have the same implication for bleeding risk as is seen with coiling, where coil compaction and aneurysm expansion may still occur. At least 1 new classification takes these factors into account and attempts to assess the stability of the angiographic results after endovascular treatment with any technique.7 This proposed classification is as follows:
Class 1: Complete occlusion of the aneurysm sac. When there is a branch integrated with the aneurysm sac (i.e., coming off the aneurysm) at any point of the sac, further analysis is carried out with subgroups. 1A: Complete occlusion with the full patency of the integrated branch. 1B: Complete occlusion with the branch reduced in caliber. 1C: Complete occlusion with no antegrade filling of the branch. Class 2: Neck filling. Class 3: Incomplete occlusion with aneurysm filling. Class 4: Aneurysm filling. This class is reserved for an immediate postoperative result based on end-of-treatment digital subtraction angiography, after extra-anchor intrasaccular flow modification treatment. 4A: With contrast stagnation—contrast stagnation refers to when there happens to be any change in the duration of the contrast within the aneurysm sac after treatment. 4B: Without contrast stagnation.
Table 3. Combined Treatments Analysis and Regression Aneurysm Occlusion Results Missing
Estimate
95% CI
Analysis
Omitted
69%
62%e75%
Regression*
Omitted
81%
68%e89%
Analysis
Treated as failure
59%
51%e67%
Regression*
Treated as failure
67%
49%e81%
CI, confidence interval. *Regression estimate for 0% small, 0% posterior, 0% ruptured.
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CI, confidence interval. *Regression estimate for 0% small, 0% posterior, 0% ruptured.
Class 5: Stable remodeling with flow modification. Filling in the neck region, which stays unchanged or reduced. To be included in this group, there have to be at least 2 consecutive control angiograms, by definition, at least 6 months apart, and expanding for a period of not <1 year exceptionally; 1 control angiogram could be sufficient for definition of class 5 only in selected cases of contrast filling the branch coming off the sac, with an appearance of a different vessel course than the original (e.g., tortuous or dilated), given that it is in continuation with the parent artery with no sac filling.7 In the studies reviewed where retreatment rates were reported, recurrence with coiling techniques was high, frequently >20%.13,16,17,20-24 This rate of recurrence is noteworthy and often an identified disadvantage of endovascular coiling.25 Future proposed treatments and devices can possibly use as a criterion for success the fact that no retreatment was necessary to pair up and adequately measure equipoise. It also should be noted that the coiling experience from the literature may be inflated by the more recent studies after the Pipeline embolization device (Medtronic, Minneapolis, Minnesota, USA) became available, where coiling was performed in a more selected population given the alternative therapy being available.8,12,13,16,17 The PUFS trial provides important data on the early clinical experience with flow
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diverters.5 Of 106 aneurysms, 78 met the primary endpoint (aneurysm occlusion, parent artery stenosis 50%, and no additional embolic agent) at 6 months. The 1-year results reported an occlusion rate of 74.5% (79 of 106 aneurysms included in the efficacy population).5 Recurrence or retreatment was not reported at 1 year. The PUFS trial is important when assessing long-term outcome from flow diverter therapy. The 5-year outcome from this study is now available and points to the stability of the therapy, particularly in reference to neck remnants.26 In this recent report, of 8 subjects with residual necks (Raymond class II) at 6 months, 7 had assessments at 3 years, and 2 continued to show a residual neck, whereas 5 had gone on to complete occlusion. In addition, 7 subjects with residual aneurysms at 6 months showed complete aneurysm occlusion at 3 years. Six subjects had retreatments. Of the 4 subjects without retreatment and with imaging available at 5 years, 1 subject had a residual neck that remained stable, and 3 subjects with residual aneurysms had occlusion. As described earlier, the Raymond classification, which was originally used to assist in the prediction of long-term outcomes, such as bleeding and aneurysm growth after coil embolization, may not be the optimal approach with flow diverter therapies. Stable neck remnants have not been associated with higher frequencies of long-term adverse events and therefore should be considered a successful outcome when flow diverter is the primary therapy for large and giant wide-neck aneurysms.7 Additional components of overall success could also be used in future treatment and devices studies, such as no retreatment before 1-year angiographic assessment and no parent artery stenosis. In the literature, it is difficult to account for these additional components of the primary endpoint uniquely. Parent artery status and additive retreatment events at followup were reported in the PUFS trial only for large and giant wide-neck aneurysms during the publication period of this literature review. Using the PUFS trial data, which systematically accounted for these additive rates, 8 carotid occlusions, parent artery stenosis >50%, and retreatments were reported through 1 year, resulting in an estimated 7.5% additional
6
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reduction over the complete occlusion success criterion for the study success performance goal.5 Using this rate from the flow diverter literature would be a conservative approach to accounting for this additional component of the primary study endpoint. Using the missing equals failure analysis lower bounds of the analysis (51%) and allowing for an additional 7.5% reduction for the additive success criteria based on the PUFS trial additional components of the primary safety endpoint, a performance goal of 43.5% would be derived. These analyses in totality support that an originally derived performance goal of 50% was reasonable and perhaps even conservative. The current literature review reflects the current state of all treatment modalities for large and giant wide-neck aneurysms. A performance goal of 50% is supported by the analyses and regression models conducted given the lower bound of the 95% CI for all analyses for aneurysm occlusion rates (combined 51%, coils 40%, and flow diverters 55%) using a missing equals failures analysis approach is in range of the 50% threshold. When considering the possibility of an added success criterion of no parent artery stenosis and no reintervention, accounting for an additional 7.5% reduction in Pipeline, the 50% threshold would in fact be conservative. As with the performance data, safety data were inconsistently described and in general site reported and not adjudicated. No analysis exists that relates site-reported event rates to adjudicated events, and therefore no similar discounting approach to that used for efficacy data can be applied to the safety data. However, it is well recognized that published data describing site-reported rates generally underestimate the rates that are reported in rigorously performed clinical trials with independent assessments of adverse events. The primary safety endpoint rate for PUFS was 5.6% (posterior probability interval 2.6%e11.7%).5 Two recent trials, SCENT (Safety and Effectiveness of an Intracranial Aneurysm Embolization System for Treating Large or Giant Wide Neck Aneurysms) and PREMIER (Prospective Study on Embolization of Intracranial Aneurysms with Pipeline Embolization Device), may show promising data, but published results are not
yet available and thus are not included on the present analysis. CONCLUSIONS All current treatments of large and giant wide-neck aneurysms have comparable safety and efficacy with a trend of superiority of efficacy toward flow diverters. Results of future treatment options and devices can be compared with current technology to evaluate feasibility. It is important to include all treatment modalities in this analysis, as both flow diverters and coiling technologies are available, and physicians choose the technique that they believe is the best treatment for an individual patient based on presentation, anatomy, and the physician’s familiarity with the techniques. REFERENCES 1. Shrier I, Boivin JF, Steele RJ, et al. Should metaanalyses of interventions include observational studies in addition to randomized controlled trials? A critical examination of underlying principles. Am J Epidemiol. 2007;166:1203-1209. 2. Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. 3. D’Souza S. Aneurysmal subarachnoid hemorrhage. J Neurosurg Anesthesiol. 2015;27:222-240. 4. Sterne JA, Bradburn MJ, Egger M. Meta-analysis in Stata. In: Egger M, Smith GD, Altman DG, eds. Systematic Reviews in Health Care: Meta-Analysis in Context. London: BMJ Publishing Group; 2008: 347-369. 5. Becske T, Kallmes DF, Saatci I, et al. Pipeline for uncoilable or failed aneurysms: results from a multicenter clinical trial. Radiology. 2013;267: 858-868. 6. Damiano RJ, Ma D, Xiang J, Siddiqui AH, Snyder KV, Meng H. Finite element modeling of endovascular coiling and flow diversion enables hemodynamic prediction of complex treatment strategies for intracranial aneurysm. J Biomech. 2015;48:3332-3340. 7. Cekirge HS, Saatci I. A new aneurysm occlusion classification after the impact of flow modification. AJNR Am J Neuroradiol. 2016;37:19-24. 8. Almandoz DJ, Kayan Y, Fease J, et al. E-063 The pc400 system safely coils large cerebral aneurysms with high packing densities and low retreatment rates. J Neurointerv Surg. 2017;9(Suppl 1):A72. 9. Chalouhi N, Starke RM, Yang S, et al. Extending the indications of flow diversion to small, unruptured, saccular aneurysms of the anterior circulation. Stroke. 2014;45:54-58.
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10. Chalouhi N, Tjoumakaris S, Gonzalez LF, et al. Coiling of large and giant aneurysms: complications and long-term results of 334 cases. AJNR Am J Neuroradiol. 2014;35:546-552.
22. Chalouhi N, Tjoumakaris S, Starke RM, et al. Comparison of flow diversion and coiling in large unruptured intracranial saccular aneurysms. Stroke. 2013;44:2150-2154.
11. Gu DQ, Zhang X, Luo B, Long XA, Duan CZ. The effect of Neuroform stent-assisted coil embolization of wide-necked intracranial aneurysms and clinical factors on progressive aneurysm occlusion on angiographic follow-up. J Clin Neurosci. 2013;20: 244-247.
23. Lopes DK, Johnson AK, Kellogg RG, Heiferman DM, Keigher KM. Long-term radiographic results of stent-assisted embolization of cerebral aneurysms. Neurosurgery. 2014;74:286-291.
12. Guan N, Mu S, Wang L, et al. Endovascular treatment of 147 cases of cavernous carotid aneurysms: a single-center experience. J Stroke Cerebrovasc Dis. 2016;25:1929-1935.
24. Starke RM, Chalouhi N, Ali MS, et al. Endovascular treatment of carotid cavernous aneurysms: complications, outcomes and comparison of interventional strategies. J Clin Neurosci. 2014;21: 40-46.
13. Linzey JR, Griauzde J, Guan Z, et al. Stent-assisted coiling of cerebrovascular aneurysms: experience at a large tertiary care center with a focus on predictors of recurrence. J Neurointerv Surg. 2017;9: 1081-1085.
25. Thompson BG, Brown RD Jr, Amin-Hanjani S, et al. Guidelines for the management of patients with unruptured intracranial aneurysms: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:2368-2400.
14. Liu YQ, Wang QJ, Zheng T, et al. Single-centre comparison of procedural complications, clinical outcome, and angiographic follow-up between coiling and stent-assisted coiling for posterior communicating artery aneurysms. J Clin Neurosci. 2014;21:2140-2144.
26. Becske T, Brinjikji W, Potts MB, et al. Long-term clinical and angiographic outcomes following pipeline embolization device treatment of complex internal carotid artery aneurysms: five-year results of the Pipeline for Uncoilable or Failed Aneurysms Trial. Neurosurgery. 2017;80:40-48.
15. Mascitelli JR, Oermann EK, De Leacy RA, Moyle H, Mocco J, Patel AB. Predictors of treatment failure following coil embolization of intracranial aneurysms. J Clin Neurosci. 2015;22: 1275-1281.
27. Burrows AM, Cloft H, Kallmes DF, Lanzino G. Periprocedural and mid-term technical and clinical events after flow diversion for intracranial aneurysms. J Neurointerv Surg. 2015;7:646-651.
16. Qu RB, Jin H. Endovascular treatment of intracranial ophthalmic segment aneurysms: a series and literature review. Turk Neurosurg. 2016;26: 223-228. 17. Suzuki K, Suzuki R, Takigawa T, et al. A single center experience with coil embolization for cerebral aneurysms greater than 10 mm in the internal carotid artery. Neurol Med Chir (tokyo). 2017; 57:231-237. 18. Wang B, Gao BL, Xu GP, Xiang C, Liu XS. Endovascular embolization is applicable for large and giant intracranial aneurysms: experience in one center with long-term angiographic followup. Acta Radiol. 2015;56:105-113. 19. Rezek I, Mousan G, Wang Z, Murad MH, Kallmes DF. Effect of core laboratory and multiple-reader interpretation of angiographic images on follow-up outcomes of coiled cerebral aneurysms: a systematic review and meta-analysis. AJNR Am J Neuroradiol. 2013;34:1380-1384. 20. Kono K, Shintani A, Okada H, Tanaka Y, Terada T. Stent-assisted coil embolization for cavernous carotid artery aneurysms. Neurol Med Chir (tokyo). 2014;54:126-132. 21. Adeeb N, Griessenauer CJ, Foreman PM, et al. Comparison of stent-assisted coil embolization and the pipeline embolization device for endovascular treatment of ophthalmic segment aneurysms: a multicenter cohort study. World Neurosurg. 2017;105:206-212.
28. Cinar C, Bozkaya H, Oran I. Endovascular treatment of cranial aneurysms with the Pipeline flowdiverting stent: preliminary mid-term results. Diagn Interv Radiol. 2013;19:154-164. 29. Fennell VS, Martirosyan NL, Palejwala SK, Lemole GM Jr, Dumont TM. Morbidity and mortality of patients with endovascularly treated intracerebral aneurysms: does physician specialty matter? J Neurosurg. 2016;124:13-17. 30. O’Kelly CJ, Spears J, Chow M, et al. Canadian experience with the Pipeline embolization device for repair of unruptured intracranial aneurysms. AJNR Am J Neuroradiol. 2013;34:381-387. 31. Peker A, Akgul E, Daglioglu E, et al. Tapered flow diverters in the treatment of intracranial aneurysms. Turk Neurosurg. 2017;27:863-866. 32. Peschillo S, Caporlingua A, Resta MC, et al. Endovascular treatment of large and giant carotid aneurysms with flow-diverter stents alone or in combination with coils: a multicenter experience and long-term follow-up. Oper Neurosurg (hagerstown). 2017;13:492-502.
the significance of adenosine diphosphate inhibition, fluoroscopy time, and aneurysm size. Interv Neuroradiol. 2016;22:34-41. 35. Raymond J, Gentric JC, Darsaut TE, et al. Flow diversion in the treatment of aneurysms: a randomized care trial and registry. J Neurosurg. 2017; 127:454-462. 36. Shankar JJ, Tampieri D, Iancu D, et al. SILK flow diverter for complex intracranial aneurysms: a Canadian registry. J Neurointerv Surg. 2016;8: 273-278. 37. Toma AK, Robertson F, Wong K, et al. Early single centre experience of flow diverting stents for the treatment of cerebral aneurysms. Br J Neurosurg. 2013;27:622-628. 38. Velioglu M, Kizilkilic O, Selcuk H, et al. Early and midterm results of complex cerebral aneurysms treated with Silk stent. Neuroradiology. 2012;54: 1355-1365. 39. Kallmes DF, Brinjikji W, Boccardi E, et al. Aneurysm study of pipeline in an observational registry (ASPIRe). Interv Neurol. 2016;5:89-99. 40. Kallmes DF, Brinjikji W, Cekirge S, et al. Safety and efficacy of the Pipeline embolization device for treatment of intracranial aneurysms: a pooled analysis of 3 large studies. J Neurosurg. 2017;127: 775-780. 41. McDonald RJ, McDonald JS, Kallmes DF, Lanzino G, Cloft HJ. Periprocedural safety of Pipeline therapy for unruptured cerebral aneurysms: analysis of 279 patients in a multihospital database. Interv Neuroradiol. 2015;21:6-10. 42. Song J, Yeon JY, Kim JS, Hong SC, Kim KH, Jeon P. Delayed thromboembolic events more than 30 days after self expandable intracranial stent-assisted embolization of unruptured intracranial aneurysms. Clin Neurol Neurosurg. 2015;135: 73-78.
Conflict of interest statement: P. M. Meyers is a consultant for Stryker. A. Coon is a consultant for Stryker, Medtronic, and MicroVention. P. T. M. Kan is a consultant for Stryker and Medtronic and has InNeuroCo stock ownership interest. A. K. Wakhloo is a consultant for Codman and Stryker; has research grants from the National Institutes of Health, Philips Healthcare, and Wyss Institute; and is a cofounder of InNeuroCo. R. A. Hanel is a consultant for Covidien, Stryker, Codman, and MicroVention. G. J. Agnoletto has nothing to disclose. Received 10 April 2019; accepted 26 June 2019
33. Piano M, Valvassori L, Quilici L, Pero G, Boccardi E. Midterm and long-term follow-up of cerebral aneurysms treated with flow diverter devices: a single-center experience. J Neurosurg. 2013; 118:408-416. 34. Raychev R, Tateshima S, Vinuela F, et al. Predictors of thrombotic complications and mass effect exacerbation after pipeline embolization:
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Citation: World Neurosurg. (2019). https://doi.org/10.1016/j.wneu.2019.06.201 Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2019 Elsevier Inc. All rights reserved.
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SUPPLEMENTARY DATA
Supplementary Table 1. Search Terms PubMed Citations Science Direct Citations (Jan 1, 2011eNov 7, 2017) (Jan 1, 2011eDec 1, 2017)
Search Term “Search (Raymond classification) AND flow diversion”
8
23
“Search (balloon assisted coiling) AND ((large) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
17
456
“Search (balloon assisted coiling) AND ((giant) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
12
“Search (flow diversion) AND ((large) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
82
“Search (flow diversion) AND ((giant) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
74
“Search (stent assisted coiling) AND ((large) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
61
“Search (stent assisted coiling) AND ((giant) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
37
“Search (embolization) AND ((large) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
121
“Search (embolization) AND ((giant) AND ((((““2011/1/1”” [Date e Publication]: ““3000”” [Date e Publication])) AND English [Language]) AND cerebral aneurysm))”
68
Total
480
235
911
2179
Supplementary Table 2. Level 1 Exclusions—Abstract Title Screening Exclusion Criterion
Number of Articles Excluded
Articles not related to the device of interest, an equivalent device, or a predecessor device
87
Articles not related to the population or anatomy of interest
343
Articles using the device of interest in ways unrelated to its indicated use
2
Letters to the editor, opinions, editorials, surveys, manufacturer’s advertisements, and press releases
2
Nonclinical studies, e.g., laboratory research, animal studies, in vitro or ex vivo studies, postmortem studies, and biomechanical studies
40
Abstracts or conference proceedings
1
Review articles
62
Isolated case reports, unless new risks are described
118
Articles in which the full text is non-English
1
Articles inadequate by appraisal/weighting criteria, e.g., lacking sufficient clarity or detail to correlate patient outcomes with the product of interest or lacking scientific soundness
3
Total exclusions at level 1
7.E1
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701
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Supplementary Table 3. Level 2 Exclusions—Full Text Screening Exclusion Criterion
Number of Articles Excluded
Articles not related to the device of interest, an equivalent device, or a predecessor device
19
Articles using the device of interest in ways unrelated to its indicated use
60
Articles that did not provide data on the clinical safety and/or performance of the device of interest
34
Studies with <30 subjects
8
Studies with <50% large/giant aneurysms
15
Studies with >50% ruptured aneurysms at presentation
2
Letters to the editor, opinions, editorials, surveys, manufacturer’s advertisements, and press releases
4
Nonclinical studies, e.g., laboratory research, animal studies, in vitro or ex vivo studies, postmortem studies, and biomechanical studies
1
Review articles
18
Duplicate articles or duplicate publications of the same study data
2
Isolated case reports, unless new risks are described
1
Articles in which the full text is non-English
1
Articles inadequate by appraisal/weighting criteria, e.g., lacking sufficient clarity or detail to correlate patient outcomes with the product of interest or lacking scientific soundness
4
Total exclusions at level 1
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169
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7.E2