Intracranial aneurysms (IAs) can be treated by microsurgical or endovascular means. In both cases, many different techniques have been designed to get a stable obliteration of the IA while ensuring the safety of the parent arteries. Since the introduction of Serbinenko's intravascular balloons1 and, overall, after Guglielmi detachable coils,2 endovascular coil embolization has emerged as an established therapy for both ruptured and unruptured IA. The ISAT (International Subarachnoid Aneurysm Trial)3-5 and, more recently, the BRAT (Barrow Ruptured Aneurysm Trial)6 have provided evidence that endovascular therapy may be superior to neurosurgical clipping in appropriately selected patients. Despite the ongoing discussion provoked by these trials,7 they both have design limitations and are focused only on ruptured IAs, whereas the proportion of unruptured IAs diagnosed and treated in clinical settings is increasing.8
The major concern with endovascular treatment of complex and giant aneurysms is that it may result in incomplete aneurysm occlusion or recanalization. In this setting, flow-diverter devices (FDDs) have emerged as a new generation of endoluminal implants that are designed to treat aneurysms by reconstructing the diseased parent artery.9 Its design focuses on diverting flow from the aneurysm and thus creating an environment prone to its thrombosis. However, although great enthusiasm has been aroused during the past years with FDDs,10 the level of evidence on which its use is based has not yet been systematically evaluated. Only 1 randomized trial is ongoing, and its estimated completion date is 2017.11
Here we report the results of a systematic review of the medical literature up to May 15, 2012. Our aims were as follows: (a) to assess the neurological morbidity and case-fatality rate of FDDs for IAs; (b) to estimate the efficacy of FDDs by using digital subtraction angiographic results and clinical follow-up events that have been reported; and (c) to evaluate the quality of the studies and whether the results are affected by bias.
MATERIAL AND METHODS
We developed a detailed protocol including objectives and plans for collecting and analyzing data. This article was prepared in accordance with the MOOSE12 and the PRISMA13 guidelines. The study was designed, conducted, analyzed, and written independently of industry or any other financial support.
Search Strategy
The medical literature on FDDs for IAs was reviewed up to May 15, 2012, by using MEDLINE, Embase, and all Evidence-Based Medicine reviews (including Cochrane DSR, ACP Journal Club, DARE, CCTR, CMR, HTA, and NHSEED) using the OVID database, with no limits on languages. The key words and free text searches used in combination (by using the Boolean operators OR and AND) were the following: “intracranial aneurysm(s),” “brain aneurysm(s),” “flow diverter,” “flow diverting,” “pipeline” and “silk.” Also, the references from the publications obtained were checked for additional studies.
In case of overlapping study populations, we tried to exclude the possibility of patients being described twice. If a single-center study was included in another multicenter one, we made efforts to contact the respective authors by e-mail to exclude the duplicate cases. If there was no response or it was inadequate, the report with the highest number of patients and/or the longest follow-up was selected. To perform the selection, 3 authors (I.A., R.S., and R.P.) discussed, one by one, each paper until reaching agreement. In case of doubt, those series of cases were excluded from the analysis. Contact by e-mail was also used to compile patient data from congress abstracts by using a standardized questionnaire. These studies were excluded if there was no author response.
Selection Criteria
The inclusion criteria for the studies were (a) series of at least 10 patients undergoing IA treatment with an FDD, (b) reporting on the duration of follow-up and number of patients lost to follow-up, (c) documenting in some way the rate of angiographic aneurysm occlusion, and (d) documenting death and neurological complications during follow-up.
The exclusion criteria for the studies were if it was not a consecutively reported case series and if only a subset of patients was analyzed of the total number of patients treated with FDDs.
Quality Analysis
Two authors (R.S., R.P.) separately graded the quality of the studies using the STROBE checklist (22 items).14 This analysis was carried out with the articles published in journals. The studies from conferences included in the review, with data sent by the authors, were not quality graded. When there was disagreement in the grading score given by the reviewers, the first author acted as referee.
Data Extraction
Epidemiologic data included the number, sex, age, and clinical presentation (incidental, hemorrhagic, or symptomatic) of the patients. Patients with headache were included in the incidental group. If other aneurysms were found in the context of a ruptured or symptomatic one, they were considered incidental.
Aneurysm features were the number, location (anterior or posterior circulation), shape (saccular or nonsaccular), and size (small aneurysms were <10 mm, large aneurysms were 10-24 mm, and giant aneurysms were ≥25 mm).
Stent features were the number and type of device.
Endpoints
- Angiographic success: complete or nearly complete occlusion of the treated aneurysm with a patent parent artery.
- Early procedural adverse events: (a) early procedural mortality, defined as any death during the first month after the procedure; b) early procedural neurological morbidity defined as any neurological deterioration at 1 month. We also categorized procedural adverse events as follows: symptomatic ischemic events, hemorrhagic events, and symptoms derived from mass effect.
- Late adverse events: (a) mortality and (b) neurological complications (defined as any neurological deterioration).
Data Analysis
The different outcomes (eg, morbidity, mortality) were pooled using a fixed-effect model only taking into account the weight of each study according to the number of patients in the pooled estimate. Studies with no outcomes in any of the branches were excluded using conventional pooling procedures. We applied a correction procedure to studies with zero outcomes by adding to both the numerator and denominator the result from dividing the number of patients of the study by the total studies to be pooled.15
The heterogeneity between studies was assessed by the Q test and the calculation of I2, which can be interpreted as the percentage of the total variability in a set of effect sizes due to true heterogeneity, that is, between-studies variability.16,17 We assessed publication bias by using funnel plots, representing the estimate (proportion of an event) in the x axis vs its precision (inverse of the standard error of the estimate) in the y axis, and applying the test of Egger et al.18 All analyses were performed with the STATA 12 statistical package (StataCorp, College Station, Texas).
RESULTS
Study Characteristics
Eighteen studies, 7 multicenter and 11 single center, were initially included (Figure 1). No new studies were found in the reference lists. One of the multicenter studies was eliminated from the analysis because later published single-center studies were found to report updated data. Two of the single-center studies were removed: one of them because most of the data included were duplicated in a multicenter study and the other because the authors did not respond to us regarding whether they had participated in an included anonymous multicenter study. As a result, 15 studies were included in the analysis, totaling 897 patients with 1018 aneurysms (Figure 2).19-33
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FIGURE 1: Flowchart of information through the different phases of the systematic review.
FIGURE 2: The 15 studies included in the analysis (after excluding overlapping or possible overlapping populations). The baseline characteristics of the patients and of the aneurysms are shown.
Quality Analysis
The mean value of the methodological quality score was 14.4 (median, 15; mode, 15; range, 11-18). None of the studies received a favorable score on all items. In most studies (14 of 15), 1 of the authors was the physician performing the treatment, and in all the studies, physicians involved in the treatment judged the outcome. The median year of publication was 2011 (mode, 2012; range, 2008-2012).
Baseline characteristics of patients and aneurysms are summarized in Figure 2.
Adverse Events
The early mortality rate was 2.8% (95% confidence interval [CI]: 1.7-3.8; I² = 93.4%). The high grade of heterogeneity could not be justified by subgroup analysis. The results categorizing the case mortality rate were hemorrhage (1.7%; 95% CI: 0.9-2.5; I² = 88.1%) and ischemia (0.9%; 95% CI: 0.3-1.6; I² = 62.2%)
The early neurological morbidity rate was 7.3% (95% CI: 5.7-9; I² = 91.8). Specific causes were hemorrhage (0.9%; 95% CI: 0.2-1.6; I² = 45.5%), ischemia (3.6%; 95% CI: 2.3-4.9; I² = 93.3%), and mass effect (1.1%; 95% CI: 0.3-1.8; I² = 79.6%).
During the clinical follow-up (mean, 8.5 months; SD, 7.8 months), the late mortality rate was 1.3% (95% CI: 0.2-2.3; I² = 36.9%) and the late neurological complication rate was 2.6% (95% CI: 1.1-4; I² = 81.3%).
Aneurysm Occlusion
The mean angiographic follow-up was 9.0 months (SD, 6.6 months).
At the final follow-up, the mean rate of aneurysm occlusion was 76.2% (95% CI: 72.1-80.2; I² = 99.2%). In the subgroup analysis, we found differences when stratifying by the type of FDD (Figure 3). The studies using the SILK device had a mean occlusion rate of 68% (95% CI: 62-74), compared with a mean occlusion rate of 88% (95% CI: 84-92) with the Pipeline device, which is a significant statistical difference (test for the comparison of 2 proportions, P < .01). Otherwise, we did not find any other significant statistical differences between the groups of the 2 types of device. The mean angiographic follow-up of the SILK group was 9.1 months and 9.4 months in the pipeline group (P = .944)
FIGURE 3: Meta-analysis of the occlusion rate of aneurysms stratified by the type of flow-diverter device. The mean occlusion rate obtained with the SILK device is significantly lower than that obtained with Pipeline. CI, confidence interval; ES, effect sizes.
Analysis of Publication Bias
The Egger test of early and late morbidity (P < .001) and the funnel plot graphics (Figure 4) are suggestive of important publication biases: studies with large numbers of patients (in the upper part of the figure) are symmetrical around the vertical axis (the pooled estimate of overall morbidity), whereas small studies are all of them on the right side of the vertical axis. With regard to aneurysm occlusion, the Egger test also shows P < .001, and the funnel plot (Figure 5) is again suggestive of publication bias, with the worst results corresponding to the studies with a smaller sample size.
FIGURE 4: Funnel plot of the overall morbidity reported in the series. Publication biases are evident. Studies with small series of patients may be published more frequently if they report any adverse event, whereas large studies, although reporting no adverse events, are usually published. s.e., standard error.
FIGURE 5: Funnel plot of the reported proportion of aneurysms closed. Publication biases are evident. The small series studies show a trend to report more adverse outcomes. s.e., standard error.
DISCUSSION
With the available data revised, our analysis shows that this technique might be relatively safe and effective, with more than 70% complete or nearly complete aneurysmal occlusion and a morbimortality of approximately 10%. These results seem to compare favorably with other alternatives, assuming that its use is restricted to complex and giant aneurysms, which is not always the case. The major concerns from our analysis derive from the heterogeneity and publication biases observed in these studies, which preclude any confident conclusion to help inform clinical decisions about the use of FDDs. In the presence of other more conventional alternatives such as surgical clipping or nonassisted endovascular coiling, the introduction of new neurovascular devices should be based on stronger evidence than solely enthusiasm for a new intervention that is conceptually appealing. There are problems derived from the technical skills required (learning curve), evidence of possible serious complications in the early and late follow-up, and a lack of clear-cut indications that should motivate the performance of a well-conducted randomized, controlled trial to obtain scientific proof of the potential benefits and risks of treating IAs with FDDs. In this regard, the FIAT (Flow Diversion in Intracranial Aneurysm Treatment) trial is ongoing, and its estimated completion date is 2017.11 Before the end of that study, both open and endovascular neurosurgeons should use these devices with caution and when other conventional treatments are ruled out.
We tried to explain the high heterogeneity obtained in our analysis by performing subgroup analysis, but we could only find differences in the rate of aneurysm occlusion related to the type of device used. For that reason, the fixed-effects model was chosen: it detects differences more easily than the random-effects model (ie, heterogeneity by the type of device). In relation to morbidity, the heterogeneity might be due to the differences in the severity thresholds assumed by the authors. Nevertheless, we are aware that, in general, excessive heterogeneity can only be interpreted as a default quality of the current literature.
In relation to the lower rate of aneurysm occlusion with the SILK device compared with the Pipeline device found in this review, we did not find any other statistical differences between SILK and Pipeline groups according to several variables (characteristics of patients or aneurysms, length of follow-up). Some authors have reported that the hemorrhage risk with the use of the SILK device may persist in aneurysms angiographically occluded.34,35 The SILK distribution company in the United Kingdom in fact reported a medical alert regarding the potential death of the patient if the device is used to treat intracranial aneurysms without concomitant coiling. Other authors have also pointed out the risk of hemorrhage with Pipeline devices and recommend the placement of coils in addition to the device in an attempt to protect the dome.36 However, there is no evidence that the use of coils in association with FDDs will effectively avoid the risk of aneurysm rupture after treatment, as there is no general agreement about the reason for the rupture. With regard to our results, it is interesting to note that the lower IA occlusion rates in the SILK group do not correlate with a higher rate of hemorrhagic adverse events. Nevertheless, the mean follow-up in both groups is short, so the evolution of the IAs treated with any FDD in a longer period is still unpredictable.
According to the publication bias analysis, small studies have reported more adverse outcomes than large studies. The most plausible explanation for this is that studies with a small number of patients may be more easily accepted for publication if they alert for any adverse event, whereas large studies are almost always published independently of reporting or not adverse events.
Because of the necessity of antiaggregation for patients undergoing treatment with an FDD, the majority of treatments are performed in patients with unruptured IAs. In treating this particular type of IA, there is still a lot of controversy about the use of more standardized techniques like clipping and coiling,37-41 making it even more difficult to define the role of FDD in this set. Regarding our review, the results of treatment with FDDs are worse than those reported in some clipping or coiling series.41-44 However, these results can be biased if FDDs have been used in more difficult cases in which standard treatments have been ruled out. In fact, in some studies, the authors do specify that both clipping and unassisted coiling were previously ruled out for the patients treated with FDDs.
The rate of asymptomatic arterial stenosis and occlusions during the follow-up was not analyzed in our meta-analysis because of a lack of information on some studies. The studies reporting this angiographic finding report it in approximately 5% to 10% of cases, although resolution of the parent artery stenosis after prolonged antiplatelet therapy has also been reported. Nonetheless, we consider that using FDD in arteries beyond the level of the circle of Willis should be indicated with extreme caution, even though some authors advocate this use.45
Limitations
We are aware that several limitations may have affected our results. First, there were inherent limitations related to the observational nature of the studies analyzed. Second, the literature available shows a highly variable quality, and many reports had to be ignored. Third, due to the disparity of criteria and scales used by the different authors, we could not use severity thresholds for analyzing the complications. Moreover, after contacting authors requesting additional information on the case series presented in congresses, only 2 of them answered us satisfactorily. When we made inquiries for doubts related to articles published in journals, only 1 author answered us to clarify which patients had been included in some other study. Fourth, the lack of detailed baseline information precluded multivariate analyses. Hence, none of our results could be corrected for confounders. We must keep in mind that all analyses remain exploratory, and clinicians should be extremely cautious about using these data for decision making.
CONCLUSION
Due to the absence of well-conducted studies comparing the efficacy and safety of FDD vs clipping or coiling, we can only recommend its use if the standard techniques are contraindicated. To establish the real value of FDD in the treatment of IAs, it is imperative to perform controlled trials comparing the safety and efficacy of FDD with those of more conventional treatment alternatives like surgical clipping and endovascular coiling. In this regard, the FIAT trial will perhaps clear up some of the current concerns in a few years. Until then, we should stress that there is still some uncertainty about the safety, benefits, and risks of the use of FDD and its long-term outcome. It is left to those clinicians involved in neurovascular therapies the cautious and judicious balance between innovation and patient safety.
Disclosure
The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
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COMMENTS
This paper points out the problems when we analyze the results of new therapy in the literature. We have much bias that influences the quality of conclusion. Thus, introduction of the flow-diverter device (FDD) in endovascular therapy of large neck aneurysms is encouraging in terms of “cure,” especially in the anterior circle. It is important to note that in the treatment of large-neck para- and supraclinoid aneurysms with FDDs, the complication rate is low, with a high percentage of cure (85%) at 3 months.1 In the posterior circle, we carefully evaluate this option case by case, like in the giant aneurysms. More studies are needed to evaluate the results during follow-up.
Francesco Briganti
Napoli, Italy
1. Briganti F. “Reply to comment of Dr. W-J van Rooij on: Italian multicenter experience with flow diverter devices for intracranial unruptured aneurysm treatment with periprocedural complications-a retrospective data analysis”. Neuroradiology, 2012;54(7):1181–1182.
Reviews are meant to synthesize and critically evaluate the state of current knowledge to help keep up with the constantly expanding body of data published in the medical literature. The systematic review methodology was meant to replace the more biased narrative or conventional reviews, in which authors could arbitrarily include those reports that support their opinions. One recurrent problem with the introduction of novel devices or treatments, is that the literature, which for the most part consists of case series from centers eager to win the “first to publish” race, can only offer a partial, biased, and immediately outdated view of the use of the new treatment. Inevitably, cases are unusual (otherwise a more conventional treatment option would have presumably been selected), and clinical follow-up is too short. In these circumstances, a review, no matter how systematic, is likely to provide unreliable data to inform clinical decisions. A meta-analysis, which may or may not follow a systematic review, is meant to enhance the precision of statistical estimates. When the quality of the publications is poor, such as when severe heterogeneity and publication biases exist, one may question the pertinence of the meta-analytic machinery, which can then only offer pseudo-precision in place of accuracy. The present article does have the merit of moderating the current enthusiasm for flow diverters by showing that this promising approach is not without risks.
The article also highlights our failure to safely introduce new devices or treatment options in the neurovascular field, an error we have relentlessly repeated over decades. Although the regulatory agencies and the industry may share some responsibility, ultimately clinicians must accept the blame for this failure, as we are the ones who either perform promising new interventions that carry unknown risks and benefits or suboptimal, more conventional alternatives, as if we knew what should be done. In the presence of such uncertainty, optimal medical care is to participate in a clinical trial designed to protect patients from medical enthusiasm, learning curves, and the unknown risks associated with promising new treatments, as much as from suboptimal conventional practices.
Jean Raymond
Montreal, Quebec, Canada
Tim E. Darsaut
Edmonton, Canada
I think this report needs a “health warning.” The authors' attempt to summarize the literature at this stage in the development of flow-diverter stents is laudable, but it is clear from their findings that the literature is not sufficiently mature for a systematic review. Currently, the main difficulty in comparing reports is the lack of consistency in indications and the heterogeneous nature of the material. The latter is best illustrated by the excellent response of extradural carotid cavernous aneurysms and poor outcomes of fusiform aneurysms of the vertebrobasilar arteries. Very different situations that are frequently combined in audit reports. So generalizations about the safety of the technology need caution, if patients are not to be denied an effective treatment in some situations. The authors emphasize the current lack of randomized, controlled data and incorrectly state that only 1 such trial is under way. I know of at least 1 other randomized, controlled study comparing stent and coil with flow diverter alone treatments, which has been recruiting for the past 3 years under the name Marco Polo. Assembling good-quality comparable data is a challenge that the community needs to embrace, and this report is a reminder of how it remains an aspiration rather than standard practice.
James Byrne
Oxford, United Kingdom
