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Original research
Predictors of incomplete aneurysm occlusion after treatment with the Pipeline Embolization Device: PREMIER trial 1 year analysis
  1. Ricardo A Hanel1,
  2. Andre Monteiro1,
  3. Peter K Nelson2,
  4. Demetrius K Lopes3,
  5. David F Kallmes4
  1. 1 Cerebrovascular and Endovascular Surgery, Lyerly Neurosurgery and Baptist Medical Center, Jacksonville, FL, USA
  2. 2 Radiology, NYU Langone Medical Center Neuroradiology Section, New York, New York, USA
  3. 3 Brain and Spine Institute, Advocate Aurora Health, Park Ridge, Illinois, USA
  4. 4 Interventional Neuroradiology, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Ricardo A Hanel, Lyerly Neurosurgery, Baptist Medical Center Downtown, Jacksonville, FL 32207, USA; rhanel{at}


Background Flow diverters have revolutionized the treatment of intracranial aneurysms. Nevertheless, some aneurysms fail to occlude with flow diversion. The Prospective Study on Embolization of Intracranial Aneurysms with the Pipeline Device (PREMIER) was a prospective, multicenter and single-arm trial of small and medium wide-necked unruptured aneurysms. In the current study, we evaluate the predictors of treatment failure in the PREMIER cohort.

Methods We analyzed PREMIER patients who had incomplete occlusion (Raymond-Roy >1) at 1 year angiographic follow-up and compared them with those who achieved Raymond-Roy 1, aiming to identify predictors of treatment failure.

Results 25 aneurysms demonstrated incomplete occlusion at 1 year. There was a median reduction of 0.9 mm (IQR 0.41–2.43) in maximum diameter between pre-procedure and 1 year measurements, with no aneurysmal hemorrhage. Patients with incomplete occlusion were significantly older than those with complete occlusion (p=0.011). Smoking (p=0.045) and C6 segment location (p=0.005) were significantly associated with complete occlusion, while location at V4 (p=0.01) and C7 (p=0.007) and involvement of a side branch (p<0.001) were significantly associated with incomplete occlusion. In multivariable logistic regression, significant predictors of incomplete occlusion were non-smoker status (adjusted OR 4.49, 95% CI 1.11 to 18.09; p=0.03) and side branch involvement (adjusted OR 11.68, 95% CI 3.84 to 35.50; p<0.0001), while C6 location had reduced odds of incomplete occlusion (adjusted OR 0.29, 95% CI 0.10 to 0.84; p=0.02).

Conclusions The results of our study are consistent with previous retrospective series and warrant consideration for technique adaptations to achieve higher occlusion rates. Further follow-up is needed to assess progression of aneurysm occlusion and clinical behavior in these cases.

  • aneurysm
  • flow diverter
  • intervention
  • hemorrhage

Data availability statement

Data are available upon reasonable request.

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Since the publication of the Pipeline for Uncoilable or Failed aneurysms Study (PUFS), flow diversion has become a widely accepted endovascular modality for the treatment of intracranial aneurysms.1 The concept of higher metal coverage deviates the flow away from the aneurysm, inducing blood stasis and subsequent thrombosis within the aneurysmal sac. Also, it allows for better endothelialization of the mesh along the stented parent artery sealing the neck of the aneurysm and excludes it from the circulation. Once the aneurysm is occluded, the odds of recurrence are extremely low.2 Despite revolutionary results, some aneurysms still do not occlude after treatment with flow diverters, with rates of incomplete occlusion reported in the literature ranging from 16.1% to 24.6% at 1 year angiographic follow-up.2–5 Several studies have been assessing features that could predict failure of flow diversion, such as age, smoking status, aneurysm size, morphology and involvement of vessel branches, with inconclusive and sometimes conflicting findings.2 3 5 6

The Pipeline Embolization Device (PED) is currently the most commonly used flow diverter in the USA. PED was proven to be effective and safe in multiple large retrospective series and prospective trials.1 7–10 Among these, the Prospective Study on Embolization of Intracranial Aneurysms with the Pipeline Device (PREMIER) assessed the efficacy and safety of PED in wide-necked small and medium unruptured aneurysms located along the internal carotid (ICA) and vertebral arteries (VA), and obtained a high rate of Raymond-Roy (RR) 1 (81.9%) with very low morbidity (2.1%).7 We performed an analysis of aneurysms that were considered failure of treatment based on pre-specified criteria (incomplete occlusion and/or parent vessel stenosis >50%) at 1 year angiographic PREMIER follow-up, aiming to contribute to the ongoing field of investigation of predictors for flow diversion failure.


Population and data

PREMIER was a prospective, multicenter and single-arm interventional trial of patients with unruptured aneurysms arising from the ICA (up to the terminus) and VA (up to and including the posterior inferior cerebellar artery), measuring ≤12 mm in diameter with neck ≥4 mm or dome to neck ratio ≤1.5. Patients were prospectively consented and enrolled between July 2014 to November 2015 from 22 US centers and one Canadian center. All patients were planned to receive mandatory 1 year angiographic follow-up. Detailed information about this study’s methodology (angiographic measurements and other baseline aneurysm characteristics) is described elsewhere.7

Present study

We retrospectively analyzed the PREMIER study’s database to assess patients who failed to achieve this study’s primary efficacy endpoint: complete occlusion (RR scale 1) of the target aneurysm without significant parent artery stenosis (≤50%) or retreatment through 1 year follow-up. A total of 32 patients matched these criteria, accounting for 23.2% (32/138) of the patients who completed 1 year angiographic follow-up. Assessment of the patients’ images was done by an independent core laboratory, which evaluated the degree of aneurysm occlusion according to the RR scale and the presence and degree of parent vessel stenosis.11 12

Statistical analysis

Summary statistics were calculated for the following variables: age, gender, smoking status, maximum diameter (mm), location, morphology, side branch involvement, and dual antiplatelet therapy (DAPT) compliance. Frequency distributions were used for categorical variables and means and standard deviations for continuous variables. For categorical measures, χ2 tests or Fisher’s exact tests (as appropriate) were used to assess comparisons between cohorts. Continuous measures were compared between cohorts using two-sample t-tests.

Multivariable logistic regression was performed using a stepwise selection process. The outcome model was incomplete occlusion (vs complete occlusion). All variables listed above were included as possible explanatory variables. The significance level for entry into the stepwise model was set at 0.10. The significance level required to stay in the model was set at 0.05. Statistical significance was set at an α level of 0.05. Statistical analyses were performed with SAS software version 9.4 (SAS Institute, Inc).


Failure to achieve primary effectiveness endpoint

Thirty-two patients with 32 treated aneurysms failed to achieve the primary efficacy endpoint. Four patients presented with stenosis of the parent artery >50% within 1 year but had complete occlusion of the aneurysm. Two patients required retreatment at 6 months but had complete occlusion of the aneurysm at 1 year, with one of these so-called retreated patients only being treated on the second attempt; this was due to a technical failure of the device during the first procedure when two PEDs were used to treat the aneurysm, and complete occlusion of the aneurysm was achieved at 1 year follow-up. One patient had the target aneurysm retreated at 6 months, and remained incompletely occluded at 1 year. Twenty-four patients did not undergo retreatment and their aneurysms remained incompletely occluded at 1 year follow-up. These findings are summarized in figure 1.

Figure 1

Flowchart of reasons for failure to achieve the primary effectiveness endpoint.

Aneurysms incompletely occluded at 1 year angiographic follow-up

A total of 25 aneurysms did not achieve complete occlusion at 1 year angiographic follow-up. Their characteristics, in comparison to those completely occluded, are summarized in table 1. Adequate coverage of the aneurysm neck and adequate wall apposition of the device were achieved in 88% (22/25). Device migration was seen in three patients: one during deployment, one at 6 months, and one at 1 year. Twenty-two patients had residual aneurysm (RR 3) and three had a residual neck (RR 2). Overall, there was a median reduction of 0.9 mm (IQR 0.41–2.43) in maximum diameter between pre-procedure and 1 year-follow-up measurements. None of the aneurysms suffered re-rupture. Nineteen of the 25 aneurysms had involvement of a side branch. Of these 19 aneurysms, six had the branch arising from the dome, seven arising from the neck, and six had the branch adjacent to the neck. Details on each involved branch are summarized in table 1.

Table 1

Univariate analysis of features associated with incomplete aneurysm occlusion

Predictors of incomplete occlusion

In the univariable analysis (table 1), the mean±SD age of patients with incomplete occlusion was significantly higher than those with complete occlusion (59.9±10.4 vs 53.6±11.2 years, p=0.011). Smoking (p=0.045) and C6 segment location (p=0.005) were significantly associated with complete occlusion, while location at V4 (p=0.01) and C7 (p=0.007) segments and involvement of a side branch (p<0.001) were significantly associated with incomplete occlusion. Based on the multivariable logistic regression, significant predictors of incomplete occlusion were non-smoker status (adjusted OR 4.49, 95% CI 1.11 to 18.09; p=0.03) and side branch involvement (adjusted OR 11.68, 95% CI 3.84 to 35.50; p<0.0001). The model also included the C6 location as a predictor, where those with a C6 segment location had reduced odds of incomplete occlusion versus those at other segment locations (adjusted OR 0.29, 95% CI 0.10 to 0.84; p=0.02).


This study evaluated the aneurysms that failed to achieve complete occlusion at 1 year angiographic follow-up of the PREMIER trial. Non-smoking status and side branch involvement were identified as significant predictors of incomplete occlusion on both univariable and multivariable analysis. Most studies that evaluated predictors of aneurysm persistence after flow diversion were retrospective series or multicenter experiences that, despite having a larger sample size, lack consistency in the follow-up or antiplatelet therapy regimen.6 The current study has advantages inherent to prospective trial data (PREMIER), such as consistent angiographic follow-up and standardized DAPT regimen. Further, our study is the first to present prospective data demonstrating that aneurysms incompletely occluded after treatment with a flow diverter do not grow in size or suffer re-rupture.

Involvement of vessel branches has been extensively described in the literature as perhaps the most relevant feature associated with incomplete aneurysm occlusion after treatment with PED.6 13–16 It is currently accepted that the persistence of aneurysm filling in these cases occurs when the involved branches are end arteries, such as an ophthalmic artery without collateralization from the external carotid artery (ECA), a posterior communicating artery (PComm) with fetal posterior cerebral artery origin, the anterior choroidal artery (AChoA), and the posterior inferior cerebellar artery (PICA). Due to absence of distal collateral flow and a high demand from the territories supplied by these vessels, the increased pressure gradient sustains continuous flow over the branching point, with insufficient stasis for thrombosis of the sac and endothelialization of the neck, resulting in persistent filling.

Given the higher odds of non-occlusion when a side branch is present, association of coils to PED or other techniques/modalities can be pursued.13 14 17 18 However, conventional coiling techniques and microsurgery carry significant morbidity and high recurrence in these cases.15 17 19 20 Retrospective studies with long-term follow-up of aneurysms treated with PED have suggested that even in the presence of an incorporated vessel, some aneurysms will eventually occlude in a delayed fashion, such as in the study by Chiu et al in which the mean time of closure was significantly higher in aneurysms that incorporate a vessel branch (16.7 months) than in those that do not (9.1 months).21 Furthermore, angiographic results are different depending on the involved branch. In our study, the rates of complete occlusion in aneurysms with ophthalmic artery involvement was 72.4%, while the rates for PComm, AChoA and PICA involvement were 62.5%, 20% and 20%, respectively. Collaterals from the ECA to the ophthalmic artery are often present, leading to sufficient stasis for aneurysm occlusion and, in some cases, asymptomatic obliteration of the branch as seen in previous series.22–24 This may have contributed to the significant associations between C6 location and complete occlusion found in our analysis, in addition to the fact that several paraophthalmic anatomical locations in the ICA wall do not directly involve the branching point of the ophthalmic artery, yielding good results when treated with PED.

Follow-up with MR angiography, CT angiography or digital subtraction angiography is certainly warranted in cases of incomplete aneurysm occlusion. Strategies for failure of occlusion, such as implantation of another flow diverter, were utilized in the PREMIER population. As demonstrated in the PUFS trial, aneurysm healing improves over time with flow diverters, so observation should be considered as a valid strategy for these aneurysm remnants.1

Even if complete occlusion does not occur, long-term stability of the aneurysm remnant has also being advocated as an acceptable result, under the concept of stable remodeling.25 Cerkige et al defined such a concept as persistent filling that remains unchanged or reduced in subsequent follow-ups, using two consecutive catheter-based angiographies with at least 6 months in between; they argue that, given the ultimate goal of the treatment is to secure the aneurysm from growing or re-rupturing, the angiographic appearance of complete occlusion could be of less importance than stability in these cases.25 Similarly, the incompletely occluded aneurysms analyzed in our study did not suffer re-rupture and had a reduction in size. In the case of aneurysms with an incorporated branch, stable remodeling was described as persistence of the neck region with contrast filling of the branch with an appearance different from the original, such as a different vessel course, more tortuosity or dilation.25 This description supports the proposal that incomplete occlusion may not express failure of the device, given that a different angiographic expectation is required when treating these cases with flow diverters.

In the current study, non-smoking status was also significantly associated with incomplete occlusion on both univariable and multivariable analysis. The correlation between smoking and aneurysm occlusion has been previously described. In a multicenter series by Adeeb et al, smoking was significantly associated with higher rates of complete occlusion, while a more recent series by Maragkos et al found a trend in the association between non-smokers and incomplete occlusion.3 5 Adeeb et al hypothesized that the prothrombotic state induced by smoking could enhance intrasaccular thrombosis and subsequent aneurysm occlusion. Nevertheless, larger studies have found that smoking status does not affect the aneurysm occlusion rates.26 While smoking probably has an effect on vascular healing after implantation of endoluminal constructs, our findings are not sufficient to draw any hypothesis or conclusions regarding the mechanism behind this association.27 28

Older age is another predictor of incomplete occlusion which has been investigated and described in previous studies. Although the mean age of patients with incomplete occlusion was significantly higher on our univariable analysis, it did not reach statistical significance as a predictor on regression analysis. The lack of association in our study probably occurred because the overall PREMIER cohort is younger (median age 54 years) than many other series. According to Maragkos et al, the studies that found an independent association had an overall older population, with a median age of approximately 58 years.2 3 5 6 The influence of age on failure of aneurysm obliteration after flow diversion has been suggested to be caused by deficient endothelial repair in older patients, but further studies are needed to confirm this mechanism of failure.3 5

Although size and morphology have been suggested to influence aneurysm occlusion after treatment with PED, we cannot draw any discussion about these factors based on our study, given the inclusion criteria for size (≤12 mm) and very small sample size of fusiform aneurysms (n=4).5 7 16

Four patients in the PREMIER trial had aneurysm treatment considered to be a failure due to parent artery stenosis >50%. Parent artery stenosis has been reported to be most often asymptomatic, and many times reversible, with multiple proposed underlying biomechanisms.29 The use of long-term DAPT and statins has been proposed to manage this condition.30 The use of surface modification in newer devices has been shown to diminish thrombus formation and may lead to decreased cases of in-stent stenosis.31 32

Our study has limitations. This is an analysis of prospective core laboratory adjudicated data, with the advantage of consistent and standardized protocol for all subjects, but with generalizability limited to aneurysm populations similar to the PREMIER trial.


This analysis of the PREMIER trial demonstrates non-smoking status and involvement of a vessel branch as the strongest predictors for incomplete occlusion at 1 year angiographic follow-up. Although the association between smoking and aneurysm occlusion has an uncertain impact on clinical practice, the involvement of vessel branches certainly is extremely relevant, and it has been well described. The results from our prospective study is consistent with previous retrospective series and warrants considerations for technique adaptations to achieve higher occlusion rates. We are aiming for long-term follow-up to evaluate whether these aneurysms with an incorporated vessel will eventually achieve complete occlusion in a delayed fashion, as has been observed in the experience of others.

Data availability statement

Data are available upon reasonable request.

Ethics statements

Patient consent for publication

Ethics approval

The PREMIER study was performed in compliance with the World Medical Association’s Declaration of Helsinki and each institutional review board approved the protocol and the informed consent form.



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  • Contributors In addition to the guarantor of this work (RH), all authors were involved and made substantial contributions to the conception or design of the work, or the acquisition, analysis, or interpretation of the data; drafting the work or revising it critically for important intellectual content; final approval of the version published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

  • Funding The PREMIER study was supported by Medtronic, Inc.

  • Competing interests RAH is a consultant for Medtronic, Stryker, Cerenovous, Microvention, Balt, Phenox, Rapid Medical, and Q’Apel. He is on the advisory board for MiVI, eLum, Three Rivers, Shape Medical and Corindus. Unrestricted research grant from NIH, Interline Endowment, Microvention, Stryker, CNX. Ivestor/stockholder for InNeuroCo, Cerebrotech, eLum, Endostream, Three Rivers Medical Inc, Scientia, RisT, BlinkTBI, and Corindus. DKL reports conflicts of interest with Medtronic, being the national PI of the ADVANCE trial, receiving research grants and being part of their Advisory Board. All the other authors have no disclosure to report. PKN is a consultant for Phenox GmbH. DFK is president of Marblehead Medical and has patents pending in balloon catheter technologies. He has received research support from Medtronic, MicroVention, NeuroSave, Neurogami, Sequent Medical, NeuroSigma, and Insera, and also serves on the Scientific Advisory Board for Triticum and Boston Scientific. PKN is a consultant for Medtronic.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.