J Mol Neurosci DOI 10.1007/s12031-016-0723-x

Meta-Analysis of the Efficiency and Prognosis of Intracranial Aneurysm Treated with Flow Diverter Devices Gengfan Ye 1 & Meng Zhang 1 & Lin Deng 1 & Xiaohui Chen 2 & Yunyan Wang 1

Received: 10 October 2015 / Accepted: 19 January 2016 # Springer Science+Business Media New York 2016

Abstract Flow diverter devices (FDDs) are increasingly used in the treatment of intracranial aneurysm. The safety and feasibility of FDD were assessed in published literature. In accordance with strict inclusion criteria, Medline, Embase, Cochrane, China National Knowledge Infrastructure, and Web of Science databases were searched for literature that covers a period until February 2015. The baseline characteristics of patients, aneurysms, aneurysm occlusion, morbidity, and mortality were also collected. A meta-analysis was conducted using STATA 12.0, and a chi-squared test was performed to evaluate whether statistically significant differences existed between complications and mortality of aneurysm patients. Finally, a total of 48 studies were selected, including 2508 patients with 2826 aneurysm cases. The mean follow-up interval is 6.3 months, and the aneurysm occlusion rate is 77.9 % (95 % CI 73.8–81.9, I2 = 43.4 %). The total morbidity and mortality rates are 9.8 and 3.8 %, respectively. The rates of spontaneous rupture and intraparenchymal hemorrhage are 2.0 and 2.5 %, respectively. The rate of ischemic stroke is 5.5 %. The morbidity and mortality rates of giant aneurysms are significantly higher than those of small and large aneurysms (χ2 = 56.96, p < 0.05; χ2 = 14.88, p < 0.05). The morbidity rates of posterior aneurysms are significantly higher than those of anterior (χ2 = 11.29, p < 0.05) and unruptured aneurysms (χ 2 = 10.36, p < 0.05), respectively. The

* Yunyan Wang [email protected]

1

Department of Neurosurgery, Qilu Hospital, Shandong University, No. 107, West Wenhua Road, Jinan, Shandong Province 250012, China

2

Department of Neurology, Shengli Oilfield Central Hospital, No. 34, Jinan Road, Dongying, Shandong Province 257034, China

publication bias of aneurysm occlusion was detected by Begg’s rank, and the corrected result is less than 0.05. Our meta-analysis suggests that the treatment of intracranial aneurysm with FDD is feasible and effective with a high occlusion rate, acceptable morbidity, and mortality. However, the morbidity or mortality of giant aneurysms is still high. Keywords Intracranial aneurysm . Flow diverter devices . Meta-analysis

Introduction Intracranial aneurysm (IA) is prevalent in the adult population and increasingly detected because of frequent cranial imaging (Gao et al. 2015; Woo et al. 2009). Previous research indicated that IA rupture caused subarachnoid hemorrhage (SAH) with a significant fatality rate (Cummings et al. 2000; Lebedev et al. 1988; Pandit et al. 1999). Although partially biased by IA selection, these findings show that particularly small IA generally has a low rate of rupture. In most instances, SAH is caused by small aneurysms because small IA is highly prevalent. However, which small IA is likely to rupture is still unclear. Case–control research investigated the factors, such as IA morphology, family history, smoking, or hypertension, that may increase the risk of IA rupture (Kang et al. 2015; Korja et al. 2014). This observation is further complicated by the existence of a few established factors for the complications during aneurysm repair even if various elements are considered. Thus, all these data with different evidence must be analyzed before treating the patients with IA, which will result in high-level variation in the clinical management of IA.

J Mol Neurosci

Flow diverter devices (FDDs) are new and important tools in IA treatment (Arrese et al. 2013; Brinjikji et al. 2014; Kallmes et al. 2015). FDDs have high metal coverage and low porosity. They can influence the hemodynamics of aneurysm by remodeling parent artery vessels, thereby inducing thrombosis within an aneurysm and subsequently promoting the repair of aneurysm neck’s tunica intima. Many singlecenter or multicenter experiences of treating intracranial aneurysm using FDD have become available in recent years (Briganti et al. 2012; Keskin et al. 2015). A high occlusion rate of aneurysm has been reported, but the associated morbidity and mortality cannot be neglected (Chalouhi et al. 2015a; Chalouhi et al. 2015b). With the prevalence of FDD, similar to other endovascular treatments, various complications appear inevitably, including spontaneous rupture, intraparenchymal hemorrhage (IPH), ischemic stroke, parent artery aneurysms stenosis, and neurological complications (Cruz et al. 2012). A meta-analysis and system review were performed with focus on aneurysm occlusion, morbidity, and mortality after the IA treatment with FDD.

Materials and Methods Literature Search The following keywords were used: Bdivert,^ Bdiverter,^ Bdiversion,^ Bdiverting,^ Bpipeline,^ Bsilk,^ BFred,^ and Bsurpass^ for an intervention therapy; Bintracranial aneurysm,^ Bintracranial aneurysms,^ Bcerebral aneurysm,^ and Bcerebral aneurysm^ were used for aneurysm patients. All keywords for intervention and patients were restricted by logic Band^ retrieval on the Medline, Embase, Cochrane, China National Knowledge Infrastructure (CNKI), and Web of Science databases before searching the literature up to February 2015. Literature Selection The following methods were used during literature selection: (1) duplicate checking, in which duplicate literature was removed from different databases; (2) preliminary screening, in which the literature was excluded if it did not satisfy the eligibility criteria according to the title and abstract; (3) full text screening, in which the literature was excluded if its texts did not satisfy the eligibility criteria according to the full text; (4) all the data were obtained from randomized, double-blind, and sham-controlled clinical trials; and (5) preliminary and fulltext screening were conducted by two independent researchers simultaneously and subsequently discussed and checked together. A decision could be made by a third individual’s opinion when a difference existed in the grading score given by their reviewers.

Eligibility and Exclusion Criteria The characteristics of clinical trials, such as eligibility and exclusion criteria, often affect the conduct, interpretation, and impact of trials. The following eligibility criteria were used: (1) a single-center or multicenter series of IA treated by FDD, (2) at least 10 patients undergoing IA treatment with a FDD, (3) documenting the aneurysm occlusion and a follow-up interval, and (4) documenting the morbidity and mortality rates during follow-up. Furthermore, the following exclusion criteria were used: (1) the number of patients < 10, (2) no baseline characteristics are available for aneurysm patients, and (3) the reported cases are subsets of another literature. Data Extraction Two researchers analyzed the full text of all eligible literature independently and then extracted the data and specific contents as follows: (1) character of literature, authors and published time of literature; (2) character of patients, number, sex, age, clinical presentation, and whether with or without previous treatment; (3) character of aneurysm, number, location (anterior or posterior circulation), size (small <10 mm, large 10–24 mm, and giant ≥25 mm), shape (saccular, fusiform, dissection, and blood blister-like aneurysms (BBAs)), and condition (ruptured SAH or carotid cavernous sinus fistula; unruptured) of aneurysms; (4) character of stents, number and type (pipeline, silk, Fred, and surpass); (5) aneurysm occlusion, aneurysm occlusion rate and follow-up period, and (6) prognosis, neurologic morbidity and mortality rates, period, and number of follow-up (the steering committee defined neurologic Bclinical safety events of interest^ a priori, including spontaneous rupture of the target aneurysm that causes SAH or cavernous carotid fistula, IPH, ischemic stroke, parent artery stenosis, and permanent cranial neuropathy). We extracted the data according to the above categories, and perforator infarction was incorporated into ischemic stroke. Evaluation of Methodological Quality The methodological quality was assessed in this study by using a Jadad scale, which has been widely used in metaanalyses (Olivo et al. 2008). Scores range from zero point (very poor) to five points (rigorous). The scale has the following characteristics: randomization (one point if the trial was randomized and an additional point if a random number or computer-generated randomization was considered), doubleblind design (one point if the trial was double blind and an additional point if masking was used), and subsequent reporting (one point if the trial stated the numbers and reasons for withdrawal in every experimental group). All the trials

J Mol Neurosci

were classified with a score of 4 or less versus 5. Furthermore, subgroup analyses were performed. Data Analysis Meta-analysis was performed for the occlusion rate of aneurysm. Heterogeneity was determined by I2 values within the range from 0 to 100 %. When I2 < 40 %, the heterogeneity is acceptable, and an effect model will be fixed. When I2 ≥ 40 %, the heterogeneity is large and a random effect model should be used. Furthermore, the sources of heterogeneity were searched via a subgroup analysis. The rates of clinical safety incidence were divided into subgroups according to the follow-up periods, aneurysm size, and location. Chi-squared test was used to estimate whether statistically significant differences existed between complications and mortality with corresponding subgroups. Publication bias of aneurysm occlusion was detected by using Begg’s rank correlation. All analyses were performed with the STATA 12 statistical package.

middle, and high degrees of heterogeneity are I2 = 25, 50, and 75 %, respectively. To determine the source of heterogeneity, subgroup analysis was conducted according to stent types, aneurysm size, location, and condition. Aneurysm occlusion rate was stratified by years and is shown in Fig. 2. The heterogeneity of group 1 is acceptable, whereas the I2 values of all the other subgroups are above 40 %. Table 2 lists the aneurysm occlusion rate of each subgroup. The group of surpass and Fred includes one literature each, which is negligible because their I2 = 0. All I2 values are more than 40 % in other groups. Adverse Events The neurological morbidity after FDD treatment is 9.8 %. The neurological mortality after FDD treatment is 3.8 %. All kinds of neurological morbidity and neurological mortality are subgrouped according to different periods (<30 and >30 days; Table 3), aneurysm sizes (small, large, and giant; Table 4), aneurysm locations (anterior and posterior; Table 5), and conditions (Table 6).

Result Publication Bias of Aneurysm Occlusion Studies Included in the Meta-Analysis The articles in all databases were listed in Table 1. Figure 1 shows the randomized, double-blind, and sham-controlled trials that are relevant to the present subjects. A total of 422 papers were retrieved by searching all the databases and relevant references. We excluded 23 duplicate studies, 282 articles irrelevant to present subjects, and an additional 69 papers that did not satisfy the including criteria. After reviewing the full texts of final articles, we included 48 randomized, doubleblind, and sham-controlled trials. After retrieving the relevant studies, all references were searched for potential papers that were not found during the initial investigation. A total of 48 studies were included in this analysis, including 2508 patients with 2826 aneurysm cases (Table 1). All literature was published from 2009 to 2015. The number of stents is more than that of aneurysm patients. Most literature is related to neurosurgery. Among these trials, the average scores on the scale are 4.2 points; the scores are 5 points for 28 trials, 4 points for 16 trials because inappropriate methods were used, and 3 points for 1 trial because the loss in follow-up investigation is not described. Aneurysm Occlusion The mean follow-up interval is 6.3 months. The aneurysm occlusion rate is 77.9 % (95 % CI 73.8–81.9, I2 = 43.4 %). When I2 = 0, no heterogeneity is demonstrated. The heterogeneity will increase as the I2 values become higher. The low,

Publication bias of aneurysm occlusion was detected via Begg’s rank correlation, and the corrected result is p = 0.014. The funnel plot (Fig. 3) also demonstrated the publication bias. More cases in the literature will result in a closer incline of statistics to the merged result. Biases often appear in the literature with a small number of cases.

Discussion Aneurysm occlusion is a common criterion that is used to evaluate the therapeutic results of intracranial aneurysm. Single-center and multicenter studies showed that the aneurysm occlusion rates of 6 months are within the range of 38– 100 % (Briganti et al. 2014; Zhou et al. 2015). The aneurysm often occludes gradually after FDD treatment. Many longterm follow-up studies confirmed that the extension of occlusion rate also increases with increased time (Arrese et al. 2013; Brinjikji et al. 2014; Kocer et al. 2014; Malatesta et al. 2013; Toma et al. 2013). Arrese’s meta-analyses demonstrated that the aneurysm occlusion was 76.2 % at a mean 9-month follow-up (Arrese et al. 2013). Brinjikji’s research demonstrated that the aneurysm occlusion is 76 % (Brinjikji et al. 2014). Our research showed that the aneurysm occlusion rate is 77.9 % at an average of 6.3 months. The results are homologous because of the similar follow-up period. We conducted the subgroup analysis and determined the source of the heterogeneity because of high heterogeneity. The subgroup analysis results showed that the aneurysm occlusion rate after pipeline

J Mol Neurosci Table 1 Studies included in meta-analysis

Author

Journal

Year

Number of stent

Number of patient

Number of aneurysms

Chalouhi Chalouhi

Journal of Neurosurgery Neurosurgery

2015 2015

124 21

100 20

100 20

Keskin Wakhloo

Neurological Research American Journal of Neuroradiology

2015 2015

29 193

24 161

25 186

Lubicz Moon

American Journal of Neuroradiology Neurological Research

2015 2014

66 46

54 29

66 38

Monteith

Journal of Neurosurgery

2014

50

24

24

MartinezGaldamez Saleme

Journal of Neurointerventional surgery

2014

34

25

25

Neurosurgery

2014

40

32

37

Agarwal Briganti

Asian Journal of Neurosurgery European Journal of Radiology

2014 2014

36 38

23 35

23 35

Kocer Chalouhi

Journal of Neurosurgery Journal of Neurosurgery

2014 2014

37 23

33 15

37 15

Brinjikji Cruz Shankar

Clinical Neurology and Neurosurgery American Journal of Neuroradiology Journal of Neurointerventional surgery

2014 2013 2013

16 20 29

13 20 25

13 20 29

Malatesta

2013

43

28

35

Lin Toma Jabbour Becske Cinar

Journal of Vascular and Interventional Radiology Surgical Neurology International British Journal of Neurosurgery Neurosurgery Radiology Interventional Radiology

2013 2013 2013 2013 2013

47 156 168 324 66

41 80 109 108 45

53 84 120 108 55

Piano Yu Pistocchi Kan

Journal of Neurosurgery Radiology Stroke Neurosurgery

2013 2013 2012 2012

120 213 32 123

101 143 26 56

104 178 30 58

Saatci Velioglu Chitale Briganti Berge

American Journal of Neuroradiology Interventional Radiology Neurosurgery Interventional Radiology American Journal of Neuroradiology

2012 2012 2012 2012 2012

324 92 68 333 73

191 76 36 273 65

251 87 42 295 77

Deutschmann McAuliffe McAuliffe Wagner Fischer Tahtinen Lubicz Chan Faria Leonardi Nelson Szikora Kulcsar Byrne Lubicz Lylyk

American Journal of Neuroradiology

2012

15

12

12

American Journal of Neuroradiology American Journal of Neuroradiology Interventional Radiology Interventional Radiology Neurosurgery World Neurosurgery Hong Kong Medical journal American Journal of Neuroradiology Interventional Neuroradiology American Journal of Neuroradiology American Journal of Neuroradiology Stroke PLoS ONE Stroke Neurosurgery

2012 2012 2012 2012 2012 2011 2011 2011 2011 2011 2010 2010 2010 2010 2009

98 17 24 201 29 27 15 51 25 47 39 13 67 36 72

54 11 22 88 24 20 9 23 25 31 18 12 70 29 53

56 11 26 101 24 27 13 23 25 31 19 12 70 34 63

J Mol Neurosci

Fig. 1 Flow chart illustrates the selection of studies that are evaluated in the present meta-analysis

embolization device (PED) treatment was significantly higher than that after silk treatment. The high occlusion rate (77.9 %) in our series and others in the postoperative follow-up suggests the effectiveness of FDD treatment. On the basis of subgroup analysis, the aneurysm occlusion rate was improved after 5 years; this observation might be related to the development of FDD techniques. The present research shows that the aneurysm occlusion rate is 78.8 % after an average of 6.3-month followup, and neurological morbidity and mortality rates are 9.8 and 3.8 % after FDD treatment, respectively. The singlecenter and multicenter results showed that the neurological mortality and mortality rates are within the range of 0– 20 and 0–9 %, respectively (Briganti et al. 2014). Arrese demonstrated that early (<30 days) neurological mortality and morbidity rates are 2.8 and 7.3 %, respectively; the late mortality and neurological complication rates are 1.3 and 2.6 %, respectively (Arrese et al. 2013). Brinjikji found that procedure-related morbidity and mortality rates are 5, and 4 %, respectively (Brinjikji et al. 2014). A multicenter experience by Kallmes demonstrated that early neurological morbidity rate is 5.5 %, late neurological complication rate is 1.9 % (Kallmes et al. 2015), early mortality rate is 2.5 %, and late neurological complication rate is 1.3 %. Although the parent artery stenosis rates (0.4 %) and cranial neuropathy rates (0.3 %) are extremely low in our selected studies, the neurological morbidity and mortality rates are 9.8 and 3.8 % after FDD treatment, respectively. Our findings suggest that FDD treatment of intracranial aneurysms may be feasible and effective with high complete occlusion rates. Moreover, the rates of procedure-related morbidity and mortality cannot be negligible.

Spontaneous rupture of aneurysm is very rare but can develop as a life-threatening disease (Sundram-Novelend et al. 2008). A low spontaneous rupture rate occurs after FDD treatment. Brinjikji and Kallmes found spontaneous rupture rates of 4.0 and 0.6 %, respectively (Brinjikji et al. 2014; Kallmes et al. 2015). Our results showed a spontaneous rupture rate of 2.0 %. The spontaneous rupture rate after FDD therapy in giant aneurysms is significantly higher (χ2 = 51.36, p < 0.05) than that in small or large aneurysms. The rate of spontaneous rupture after FDD therapy in ruptured aneurysms is significantly higher than that in unruptured aneurysms (7.5 vs 1.3 %; χ2 = 4.85, p < 0.05). Considering that delayed rupture is serious and sometimes fatal, Balt Extrusion issued a medical advisory that warns against the use of the silk flow diverter without coils because of the potential risk of rupture (Leonardi et al. 2011). According to the therapeutic results of 26 and 32 patients treated with first-generation and new silk stents, respectively, new silk stents showed a high-rate aneurysm occlusion (89 %) with fewer side effects (Lubicz et al. 2011). A new silk stent may be safer and more effective than the first-generation one for treating aneurysms. IPH is another fatal complication after FDD therapy and often results in permanent neurological complications. Brinjikji and Kallmes reported IPH rates of 3.0 and 2.4 %, respectively (Brinjikji et al. 2014; Kallmes et al. 2015). Our results indicate that the IPH rate is 2.5 % totally and significantly higher in giant aneurysms than in small or large aneurysms (5.4 vs 2.1 %; χ2 = 11.67, p < 0.05). The high inhibition of P2Y12 may be the important pathogenesis of the IPH. P2Y12 receptor is also important in the process of platelet activation and aggregation. Almandoz found that preprocedure and last-recorded P2Y12 reaction unit values are an independent predictor of all major perioperative thromboembolic and hemorrhagic complications after PED procedures (Almandoz et al. 2013). Furthermore, hemorrhagic transformation from ischemic stroke, hemodynamic alteration from flow diverter placement, and dual antiplatelet therapy may contribute to IPH (Cruz et al. 2012). Clarencon found that the discontinuation of clopidogrel and maintenance treatment with aspirin only effectively relieves intracranial hemorrhage after IPH (Clarencon et al. 2013). A review and metaanalysis reported by Skukalek showed that high-dose aspirin for >6 months is associated with fewer permanent thrombotic and hemorrhagic events, and loading doses of aspirin and clopidogrel are associated with a decreased incidence of hemorrhagic events (Skukalek et al. 2014). Ischemic stroke is the most common postoperative complication of FDD. This complication is caused by embolization of distal vessels through spontaneous thrombosis after the placement of FDD, which results in parent artery occlusion or falling-off embolus. The ischemic stroke rates are 6.0 and 4.7 % according to Brinjikji and Kallmes, respectively (Brinjikji et al. 2014; Kallmes et al. 2015). Our study shows

J Mol Neurosci

Fig. 2 Meta-analysis of aneurysm occlusion stratified by different periods

an ischemic stroke rate of 5.5 %, which is significantly higher in giant aneurysms than in small or large aneurysms (9.5 vs 5.0 %; χ2 = 10.33, p < 0.05). This result might be due to the need of a giant aneurysm for more FDD and longer operative time than a small or large aneurysm (Brinjikji et al. 2014).

With abundant perforator vessels in posterior cerebral circulation, a significantly higher rate of ischemic stroke is found in posterior aneurysms than in anterior aneurysms after PED therapy (10.0 vs 4.9 %; χ2 = 13.61,p < 0.05). To prevent intraoperative ischemic stroke, prompt injection of Abciximab can

J Mol Neurosci Table 2

Aneurysm occlusion stratified by subgroup

Aneurysm occlusion Subgroup Stent

Rate (%) 95 % CI (%) I (%) 2

Pipeline

81.7

76.9–86.4

48.1

Silk Surpass Fred

71.4 80.0 80.0

62.0–80.8 44.9–100.0 73.8–86.2

Size

Small or large 78.4 Giant 72.0

72.1–84.7 62.6–81.4

49.2 0 0 41.7 48.6

Location Condition

Anterior Posterior Ruptured

78.4 74.4 73.9

72.4–84.4 51.5–97.3 66.5–81.3

40.6 49.8 45.1

Total

Unruptured

78.6 77.9

74.3–82.6 73.8–81.9

46.1 43.4

be used (Tahtinen et al. 2012). Sufficient anticoagulation and antiplatelet aggregation treatment may also reduce thromboembolic complications as well. A review and meta-analysis were performed by Skukalek et al. on the effect of antiplatelet therapy on hemorrhagic and thrombotic complications in patients with cerebral aneurysms after PED treatment (Skukalek et al. 2014). The results demonstrated that clopidogrel therapy for >6 months is associated with higher rates of thrombotic events (Clarencon et al. 2013). Unfortunately, the anticoagulation and antiplatelet aggregation treatment differs considerably in various studies, and a standard prescription is not confirmed. Individualized antiplatelet therapy should be conducted according to the levels of platelet inhibition rate, the length, the number of implanted FDD, and aneurysm size and location. Our results show that neurological morbidity and mortality of giant aneurysms are significantly higher than those of small or large aneurysms through an analysis of the main complications after FDD treatment. Neurological morbidity of posterior circulation aneurysms is significantly higher than that of the anterior circulation aneurysms. Neurological morbidity of ruptured aneurysms is obviously higher than that of unruptured ones. However, the FDD therapy for giant aneurysms is not satisfactory. In a report from Zhou et al., a total of

Table 3 Complications stratified by time

28 giant aneurysms were treated with turbridge stents (a new FDD), and no postoperative hemorrhage or ischemic complications were observed (Zhou et al. 2014). Turbridge FDD seems to have advantages in treating giant aneurysms, but extensive work is needed to confirm the conclusion. Surgical clipping and endovascular embolization or stentassisted embolization are standard methods that are traditionally used to occlude aneurysm. A systematic review and metaanalysis of surgical treatment of unruptured intracranial aneurysms were performed by Kotowski; this analysis found that the complete occlusion rate was 91.8 %, and the nearcomplete occlusion rate is 3.9 % associated with 1.7 % mortality and 6.7 % overall morbidity (Kotowski et al. 2013). Fang et al. found that the rate of immediate and long-term (mean 6 months) complete and near-complete angiographic occlusion rates are 88 and 85 %, respectively (Fang et al. 2014). Overall procedure-related morbidity and mortality rates are 6 and 3 %, respectively. In a study of stentsupported aneurysm coiling, Shapiro found that approximately 45 % of aneurysms are completely occluded during the first treatment session and increased to 61 % in subsequent followup (mean 6 months). The overall procedure complication rate is 19 %, with preprocedural mortality of 2.1 % (Shapiro et al. 2012). McLaughlin found that the rate of immediate complete occlusion was 46.3 %, the aneurysm occlusion is 78.8 % in 6month follow-up, and the intraprocedural and postprocedural intransient thromboses or thromboembolism rates are 4.6 and 4.3 %, respectively (McLaughlin et al. 2013). A meta-analysis that included three high-quality prospective controlled trials by Lanzino showed that despite the higher risk of bleeding, endovascular coil embolization is associated with better outcomes compared with the patients who are amenable to either therapeutic strategy. A retrospective study by Zanaty demonstrated that higher improvement in symptoms and a lower rate of complications might be associated with pipeline treatment (Zanaty et al. 2014). With regard to giant aneurysms, FDD therapy is reliable and can improve aneurysm symptoms significantly. However, for some small aneurysms, clipping and coiling are suitable. Risks of FDD usage and its long-term

Complications

<30 days

>30 days

Total

Number of patient Spontaneous rupture

2508 34 (1.4 %)

2508 16 (0.6 %)

2508 50 (2.0 %)

Intraparenchymal hemorrhage Ischemic stroke Parent artery stenosis

50 (2.0 %) 97 (3.9 %) 7 (0.3 %)

13 (0.5 %) 41 (1.6 %) 4 (0.2 %)

63 (2.5 %) 138 (5.5 %) 11 (0.4 %)

Permanent cranial neuropathy

6 (0.2 %)

2 (0.1 %)

8 (0.3 %)

Neurologic morbidity

170 (6.8 %)

76 (3.0 %)

246 (9.8 %)

Neurologic mortality

60 (2.4 %)

35 (1.4 %)

95 (3.8 %)

Neurologic morbidity and mortality

188 (7.5 %)

85 (3.4 %)

273 (10.9 %)

J Mol Neurosci Table 4 Complications stratified by aneurysm size

Table 5 Complications stratified by aneurysm location

Small/large

Giant

Number of patient

2214

294

Spontaneous rupture

28 (1.3 %)

22 (7.5 %)

Intraparenchymal hemorrhage

47 (2.1 %)

16 (5.4 %)

11.67 (p < 0.05)

Ischemic stroke Parent artery stenosis

110 (5.0 %) 8 (0.4 %)

28 (9.5 %) 3 (1.0 %)

10.33 (p < 0.05) 56.96 (p < 0.05)

Permanent cranial neuropathy

5 (0.2 %)

3 (1.0 %)

14.88 (p < 0.05)

Neurologic morbidity

181 (8.2 %)

65 (22.1 %)

63.55 (p < 0.05)

Neurologic mortality

72 (3.3 %)

23 (7.8 %)

Total neurologic morbidity and mortality

201 (9.1 %)

72 (24.5 %)

Complications

Anterior

Posterior

51.36 (p < 0.05)

χ2 (p)

Number of patient

2197

311

Spontaneous rupture

45 (2.0 %)

5 (1.6 %)

0.27 (p > 0.05)

Intraparenchymal hemorrhage Ischemic stroke Parent artery stenosis

53 (2.4 %) 107 (4.9 %) 7 (0.3 %)

10 (3.2 %) 31 (10.0 %) 4 (1.3 %)

0.72 (p > 0.05) 13.61 (p < 0.05) 11.29 (p < 0.05)

Permanent cranial neuropathy

6 (0.3 %)

2 (0.6 %)

1.04 (p > 0.05)

Neurologic morbidity

199 (9.1 %)

47 (15.1 %)

12.46 (p < 0.05)

Neurologic mortality

80 (2.9 %)

15 (4.8 %)

Total neurologic morbidity and mortality

221 (10.1 %)

52 (16.7 %)

outcome to clinicians are involved in neurovascular therapies. Thus, a balance between innovation and patient safety should be considered carefully. For FDD treatment of intracranial aneurysm, coiling in conjunction with PED (PED + coils) and PED-only are two perspectives. A single-institution experience, including 29 PED + coils cases and 75 PED-only cases, showed that PED + coils have a high aneurysm occlusion rate (Lin et al. 2013). PED + coils could increase the aneurysm occlusion and reduce the morbidity and mortality (Chalouhi et al. 2015b). Compared with the high cost of intracranial aneurysms treated with FDD, the anterior circulation aneurysms treated with

Table 6 Complications stratified by aneurysm condition

χ2 (p)

Complications

PED had lower costs (Colby et al. 2012). In 2014, Chalouhi reported that PED therapy is more expensive than coiling therapy for aneurysms <0.9 cm3 or when multiple devices are used (Chalouhi et al. 2015b). Selecting the most suitable treatment is still a challenge because of various treatments and different sizes, shapes, locations, and states of aneurysms. BBAs are always regarded as arterial lesions that arise from non-branching sites (dorsal or anterior wall) on the internal carotid artery and are suspected to originate from a dissection (Gonzalez et al. 2014). Considering the efficacy of interventional therapy and complication rate, treatment for this controversial entity includes surgery clipping and endovascular

Complications

Ruptured

Unruptured

Number of patient Spontaneous rupture Intraparenchymal hemorrhage Ischemic stroke Parent artery stenosis Permanent cranial neuropathy Neurologic morbidity Neurologic mortality Total neurologic morbidity and mortality

376 13 (3.5 %) 14 (3.7 %) 26 (6.9 %) 2 (0.5 %) 4 (1.1 %) 54 (14.4 %) 20 (5.3 %) 58 (15.4 %)

2132 37 (1.7 %) 49 (2.3 %) 112 (5.3 %) 9 (0.4 %) 4 (0.2 %) 192 (9.0 %) 75 (3.5 %) 215 (10.1 %)

χ2 (p)

4.85 (p < 0.05) 2.65 (p > 0.05) 1.70 (p > 0.05) 10.36 (p < 0.05) 2.85 (p > 0.05) 9.40 (p < 0.05)

J Mol Neurosci Acknowledgments The project was supported by the National Natural Scientific Foundation of China (No. 81141088) and by the Promotive Research Fund for Excellent Young and Middle-Aged Scientists of Shandong Province (No. 2004BS02010). Compliance with Ethical Standards Conflict of Interest The authors declare that they have no conflicts of interest.

References Fig. 3 A funnel plot illustrating publication bias

treatment. The morbidity and mortality rates of surgical treatment are 20.9 % (43/206) and 17.0 % (35/206), respectively, and the rates of the traditional endovascular treatment are 3.7 % (3/81) and 12.3 % (10/81). A multicenter study showed that the BBAs from eight patients treated with PED are completely occluded at a mean of 5.9-month follow-up (Lin et al. 2013). Chalouhi also reported the safety and feasibility of PED therapy for BBAs, and the morbidity and mortality rates of FDD therapy are 4.8 % (1/21) and 9.5 % (2/21), respectively (Chalouhi et al. 2015b). Flow diverting stents seem to be a promising strategy for BBA therapy (Gonzalez et al. 2014). Our research has the following inevitable limitations because of the methodology: (1) heterogeneity is inevitable. The included literature comprises retrospective studies because no finished randomized controlled trial about FDD is available. The baseline characteristics are different among these studies, and the confounding factors are involved in the present analyses. Furthermore, different research institutions may use different standards to evaluate patients’ conditions and prognosis. (2) Publication bias is inevitable. A small sample study often has a significant bias. The most possible explanation for these observations is that studies with a small number of patients may be accepted easily for publication if they reported a higher occlusion rate or fewer adverse events. Several randomized controlled trials were also conducted to evaluate flow diverters for other indications (Alderazi et al. 2014). The completion of these studies will provide a more suitable clinical treatment for different kinds of aneurysms. Taken together, the meta-analysis shows that aneurysm occlusion rate for an average of 6.3 months of follow-up is 78.8 %, and the neurological morbidity and mortality rates are 9.8 and 3.8 % after FDD therapy, respectively. FDDs are safe and feasible for the treatment of intracranial aneurysms. With the development of FDD, FDD therapy has a broad prospect and can be used more widely for clinical therapy of intracranial aneurysms.

Alderazi YJ, Shastri D, Kass-Hout T, Prestigiacomo CJ, Gandhi CD (2014) Flow diverters for intracranial aneurysms. Stroke Res Treat 2014:415653 Almandoz JED, Crandall BM, Scholz JM, Fease JL, Anderson RE, Kadkhodayan Y, Tubman DE (2013) Pre-procedure P2Y12 reaction units value predicts perioperative thromboembolic and hemorrhagic complications in patients with cerebral aneurysms treated with the pipeline embolization device. J Neurointerv Surg 5:Iii3–Iii10 Arrese I, Sarabia R, Pintado R, Delgado-Rodriguez M (2013) Flowdiverter devices for intracranial aneurysms: systematic review and meta-analysis. Neurosurgery 73:193–199 Briganti F, Napoli M, Tortora F, Solari D, Bergui M, Boccardi E, Cagliari E, Castellan L, Causin F, Ciceri E, Cirillo L, De Blasi R, Delehaye L, Di Paola F, Fontana A, Gasparotti R, Guidetti G, Divenuto I, Iannucci G, Isalberti M, Leonardi M, Lupo F, Mangiafico S, Manto A, Menozzi R, Muto M, Nuzzi NP, Papa R, Petralia B, Piano M, Resta M, Padolecchia R, Saletti A, Sirabella G, Bolge LP (2012) Italian multicenter experience with flow-diverter devices for intracranial unruptured aneurysm treatment with periprocedural complications—a retrospective data analysis. Neuroradiology 54: 1145–1152 Briganti F, Napoli M, Leone G, Marseglia M, Mariniello G, Caranci F, Tortora F, Maiuri F (2014) Treatment of intracranial aneurysms by flow diverter devices: long-term results from a single center. Eur J Radiol 83:1683–1690 Brinjikji W, Lanzino G, Cloft HJ, Kallmes DF (2014) Patency of the posterior communicating artery after flow diversion treatment of internal carotid artery aneurysms. Clin Neurol Neurosurg 120:84–88 Chalouhi N, Zanaty M, Whiting A, Tjoumakaris S, Hasan D, Ajiboye N, Hann S, Rosenwasser RH, Jabbour P (2015a) Treatment of ruptured intracranial aneurysms with the pipeline embolization device. Neurosurgery 76:165–172 Chalouhi N, Zanaty M, Whiting A, Yang S, Tjoumakaris S, Hasan D, Starke RM, Hann S, Hammer C, Kung D, Rosenwasser R, Jabbour P (2015b) Safety and efficacy of the pipeline embolization device in 100 small intracranial aneurysms. J Neurosurg 122:1498–1502 Clarencon F, Di Maria F, Biondi A, Chiras J, Sourour NA (2013) Distant and delayed (>7 days) hemorrhage after treatment by flow-diverter stents in intracranial aneurysms: a rare but potentially serious complication. Am J Neuroradiol 34:E81–E82 Colby GP, Lin LM, Paul AR, Huang J, Tamargo RJ, Coon AL (2012) Cost comparison of endovascular treatment of anterior circulation aneurysms with the pipeline embolization device and stent-assisted coiling. Neurosurgery 71:944–948, Discussion 948–950 Cruz JP, Chow M, O’Kelly C, Marotta B, Spears J, Montanera W, Fiorella D, Marotta T (2012) Delayed ipsilateral parenchymal hemorrhage following flow diversion for the treatment of anterior circulation aneurysms. Am J Neuroradiol 33:603–608

J Mol Neurosci Cummings TJ, Johnson RR, Diaz FG, Michael DB (2000) The relationship of blunt head trauma, subarachnoid hemorrhage, and rupture of pre-existing intracranial saccular aneurysms. Neurol Res 22:165– 170 Fang S, Brinjikji W, Murad MH, Kallmes DF, Cloft HJ, Lanzino G (2014) Endovascular treatment of anterior communicating artery aneurysms: a systematic review and meta-analysis. Am J Neuroradiol 35:943–947 Gao BL, Safain MG, Malek AM (2015) Enterprise stenting for intracranial aneurysm treatment induces dynamic and reversible agedependent stenosis in cerebral arteries. J Neurointerv Surg 7:297– 302 Gonzalez AM, Narata AP, Yilmaz H, Bijlenga P, Radovanovic I, Schaller K, Lovblad KO, Pereira VM (2014) Blood blister-like aneurysms: single center experience and systematic literature review. Eur J Radiol 83:197–205 Kallmes DF, Hanel R, Lopes D, Boccardi E, Bonafe A, Cekirge S, Fiorella D, Jabbour P, Levy E, McDougall C, Siddiqui A, Szikora I, Woo H, Albuquerque F, Bozorgchami H, Dashti SR, Almandoz JED, Kelly ME, Turner R, Woodward BK, Brinjikji W, Lanzino G, Lylyk P (2015) International retrospective study of the pipeline embolization device: a multicenter aneurysm treatment study. Am J Neuroradiol 36:108–115 Kang HB, Peng TM, Qian ZH, Li YX, Jiang CH, Ji WJ, Wu J, Xu WJ, Wen XL, Liu AH (2015) Impact of hypertension and smoking on the rupture of intracranial aneurysms and their joint effect. Neurol Neurochir Pol 49:121–125 Keskin F, Erdi F, Kaya B, Poyraz N, Keskin S, Kalkan E, Ozbek O, Koc O (2015) Endovascular treatment of complex intracranial aneurysms by pipeline flow-diverter embolization device: a single-center experience. Neurol Res 37:359–365 Kocer N, Islak C, Kizilkilic O, Kocak B, Saglam M, Tureci E (2014) Flow re-direction endoluminal device in treatment of cerebral aneurysms: initial experience with short-term follow-up results. J Neurosurg 120:1158–1171 Korja M, Lehto H, Juvela S (2014) Lifelong rupture risk of intracranial aneurysms depends on risk factors a prospective Finnish cohort study. Stroke 45:1958–1963 Kotowski M, Naggara O, Darsaut TE, Nolet S, Gevry G, Kouznetsov E, Raymond J (2013) Safety and occlusion rates of surgical treatment of unruptured intracranial aneurysms: a systematic review and metaanalysis of the literature from 1990 to 2011. J Neurol Neurosurg Psychiatry 84:42–48 Lebedev V, Kuksova N, Krylov V, Miatchin M (1988) The information value of the EEG in the acute period of subarachnoid hemorrhage as a consequence of rupture of intracranial aneurysms. Zhurnal voprosy neirokhirurgii imeni NN Burdenko: 44–49 Leonardi M, Cirillo L, Toni F, Dall’Olio M, Princiotta C, Stafa A, Simonetti L, Agati R (2011) Treatment of intracranial aneurysms using flow-diverting silk stents (BALT): a single centre experience. Interv Neuroradiol 17:306–315 Lin L-M, Colby GP, Kim JE, Huang J, Tamargo RJ, Coon AL (2013) Immediate and follow-up results for 44 consecutive cases of small (<10 mm) internal carotid artery aneurysms treated with the pipeline embolization device. Surgical Neurology International 4

Lubicz B, Collignon L, Raphaeli G, De Witte O (2011) Pipeline flowdiverter stent for endovascular treatment of intracranial aneurysms: preliminary experience in 20 patients with 27 aneurysms. World Neurosurg 76:114–119 Malatesta E, Nuzzi NP, Divenuto I, Fossaceca R, Lombardi M, Cerini P, Guzzardi G, Stecco A, Andreula C, Carriero A (2013) Endovascular treatment of intracranial aneurysms with flow-diverter stents: preliminary single-centre experience. Radiol Med 118:971–983 McLaughlin N, McArthur DL, Martin NA (2013) Use of stent-assisted coil embolization for the treatment of wide-necked aneurysms: a systematic review. Surgical Neurology International 4 Olivo SA, Macedo LG, Gadotti IC, Fuentes J, Stanton T, Magee DJ (2008) Scales to assess the quality of randomized controlled trials: a systematic review. Phys Ther 88:156–175 Pandit S, Biswas TK, Debnath PK, Saha AV, Chowdhury U, Shaw BP, Sen S, Mukherjee B (1999) Chemical and pharmacological evaluation of different ayurvedic preparations of iron. J Ethnopharmacol 65:149–156 Shapiro M, Becske T, Sahlein D, Babb J, Nelson PK (2012) Stentsupported aneurysm coiling: a literature survey of treatment and follow-up. Am J Neuroradiol 33:159–163 Skukalek SL, Winkler AM, Kang J, Dion JE, Cawley CM, Webb A, Dannenbaum MJ, Schuette AJ, Asbury B, Tong FC (2014) Effect of antiplatelet therapy and platelet function testing on hemorrhagic and thrombotic complications in patients with cerebral aneurysms treated with the pipeline embolization device: a review and metaanalysis. J Neurointerv Surg Sundram-Novelend SY, Appleton DS, Screaton NJ, Davies RJ, Chilvers ER (2008) Spontaneous rupture of an intercostal artery aneurysm during air flight. Thorax 63:294 Tahtinen OI, Manninen HI, Vanninen RL, Seppanen J, Niskakangas T, Rinne J, Keski-Nisula L (2012) The silk flow-diverting stent in the endovascular treatment of complex intracranial aneurysms: technical aspects and midterm results in 24 consecutive patients. Neurosurgery 70:617–624 Toma AK, Robertson F, Wong K, Joshi Y, Haridas A, Grieve J, Watkins LD, Kitchen ND, Brew S (2013) Early single centre experience of flow diverting stents for the treatment of cerebral aneurysms. Br J Neurosurg 27:622–628 Woo D, Hornung R, Sauerbeck L, Brown R, Meissner I, Huston J, Foroud T, Broderick J, Invest F (2009) Age at intracranial aneurysm rupture among generations Familial Intracranial Aneurysm Study. Neurology 72:695–698 Zanaty M, Chalouhi N, Starke RM, Barros G, Saigh MP, Schwartz EW, Ajiboye N, Tjoumakaris SI, Hasan D, Rosenwasser RH, Jabbour P (2014) Flow diversion versus conventional treatment for carotid cavernous aneurysms. Stroke 45:2656–2661 Zhou Y, Yang PF, Fang YB, Xu Y, Hong B, Zhao WY, Li Q, Zhao R, Huang QH, Liu JM (2014) A novel flow-diverting device (Tubridge) for the treatment of 28 large or giant intracranial aneurysms: a single-center experience. Am J Neuroradiol 35:2326–2333 Zhou G, Su M, Zhu YQ, Li MH (2015) Efficacy of flow-diverting devices for cerebral aneurysms: a systematic review and meta-analysis. World Neurosurgery