Canadian Experience with the Pipeline Embolization Device for Repair of Unruptured Intracranial Aneurysms

Discussion

Review of the initial Canadian experience with the PED demonstrates effective angiographic closure of the treated aneurysms, with 84.2% complete or near-complete occlusion through an average of 1.25 years follow-up. Survival analysis indicates progressive aneurysm closure over time. These results are comparable with other studies in the literature reporting angiographic aneurysm occlusion rates in between 74% and 94% of cases.^{2,3,6⇓⇓⇓⇓–11} In the current study, multivariate analysis suggested female sex and previous aneurysm treatment as predictors of persistent aneurysm filling. Many studies do not comment on predictors of aneurysm occlusion after flow-diverting stent placement. Although small numbers precluded statistical analysis, McAuliffe et al⁸ identified fusiform aneurysms, smaller aneurysm size, and previous aneurysm treatment as predictors of persistent angiographic filling in follow-up. Further study is required to better predict successful aneurysm occlusion with flow-diverting stents. The most favorable results in this initial Canadian experience came from the subset of cavernous segment aneurysms, with all cavernous aneurysms closed by 1 year. There were no deaths and significant morbidity was uncommon. Most patients presenting with cranial nerve deficits were resolved or improved in follow-up. Flow-diverting stents may represent an important treatment option for patients with large cavernous aneurysms; however, one must consider that proximal occlusion is a safe and effective treatment in appropriately selected patients.¹²

There were 2 general sources of morbidity after PED treatment of the aneurysms in this series: failure to alter the natural history or complications related to placement of the device. The natural history of unruptured aneurysms has never been clearly defined. Nevertheless, most studies have shown that large aneurysms, such as those treated in this study, have a high risk of rupture and neurologic morbidity due to progressive growth.¹³ In many cases, the PED appears to avert this natural history by leading to aneurysm occlusion and even regression of the aneurysm mass. However, there are important exceptions. Despite successful PED placement, aneurysm rupture occurred in 3.2% of cases in this series. One of the cases occurred over 1 year after the initial treatment in an aneurysm that demonstrated persistent filling despite the successful PED placement. Before presenting with rehemorrhage, the patient had declined further intervention. The other cases bled relatively early after partial thrombosis of the treated aneurysms. This pattern is similar to other reports in the literature and has been postulated by others to relate to thrombus-mediated weakening of the aneurysm wall.^5,14 In this manner, it is possible that the flow diversion may actually increase the risk of rupture after treatment. The true incidence of aneurysm rupture after flow-diverting stent placement remains unknown. Kulcsár et al¹⁴ reported a series of 13 similar cases pooled from multiple institutions; however, the appropriate denominator could not be established. In other series, this delayed aneurysm rupture is a relatively rare occurrence, observed in 0%,^3,9 1%,⁶ and 1.4%⁶ of cases depending on the report. In the absence of aneurysm rupture, failure to alter the natural history can manifest as progressive aneurysm growth. In the Canadian experience, there were 3 cases of progressive aneurysm enlargement despite the flow-diverting stent. Importantly, this progression in size corresponded to adverse neurologic outcomes.

The second source of morbidity after placement of a flow-diverting stent is procedure-related complication. As with any endovascular procedure, periprocedural stroke is an important potential risk. In our series, symptomatic periprocedural ischemic stroke was relatively rare, occurring in 4% of cases, with persistent, but improving, deficit in 2%. This study did not consider new silent ischemic events, as postprocedural MR imaging scans were not available for all patients. Embolic events may occur at increased frequency, given the size of the delivery devices and the complexity of cranial vascular access seen in typical flow-diversion cases. On the other hand, dual antiplatelet therapy has been associated with a reduction in thromboembolic events in series using conventional coiling^15,16 and with stent-assisted coiling techniques.¹⁷ Distal ipsilateral hemorrhage has emerged as a more specific complication related to flow diversion. In our Canadian experience, distal hemorrhage occurred in 4% of cases, resulting in significant morbidity and mortality. The incidence of these hemorrhages varies in the literature, with no occurrences in most series.^3,6,8,9,11 Fischer et al² reported 3 cases in their experience (101 cases) with the PED. The putative mechanism is unknown, but hemorrhagic conversion of ischemic embolic events, due to antiplatelet medication, combined with altered pressure dynamics, due to redirected flow, have been postulated.¹⁸ Although the phenomenon appears to be relatively specific to flow diversion, it has been described with conventional stent-assisted coiling procedures.¹⁹ Finally, aneurysms may undergo an increase in size after treatment due to acute thrombosis and perianeurysmal edema. In cavernous aneurysms, this manifested as new cranial neuropathy. Most of these resolved over time; however, certain patients had persistent deficits. This acute increase in aneurysm mass effect also resulted in hydrocephalus, necessitating a surgical intervention (third ventriculostomy). If hydrocephalus is a potential concern on the basis of the preoperative imaging, prophylactic intervention before initiation of antiplatelet medication may be beneficial.

Allowing for overlap of specific complications, the overall morbidity and mortality rate in this series is 10.7% (6.3% mortality, 4.4% morbidity). The observed morbidity in this series must be considered in the context of the existing therapeutic alternatives. Effective surgical treatment of large aneurysms can frequently be achieved, with acceptable morbidity and mortality. More elaborate surgical procedures, such as high-flow bypass and circulatory arrest, have elevated procedural risk. In a recent report from a high-volume center, surgery for giant aneurysms using bypass and proximal occlusion techniques has a reported mortality of 13% and permanent neurologic morbidity of 9%.²⁰ Similarly, in a series of 105 patients with hypothermic circulatory arrest at the Barrow Neurological Institute, the combined procedure-related morbidity and mortality was 32%.²¹ Conventional endovascular approaches such as coiling with balloon or stent assistance may have relatively lower procedural risk; however, these interventions have been shown to have diminished efficacy for large, complex aneurysms leading to an increased risk of recurrence and retreatment. In a systematic review of giant aneurysms treated with conventional endovascular approaches, the complete occlusion rate was 57%, with recanalization in 27%.²² The rates of morbidity and mortality were 17% and 8%, respectively.²²

Given that flow-diverting stents are a relatively recent innovation, their performance through long-term follow-up remains to be evaluated. Imaging protocols varied significantly between and within the participating centers. In our experience, CTA is preferred over MRA in cases where there are not additional coils or clips causing artifacts. Contrast-enhanced CTA and MRA appear to be sufficient to evaluate for residual aneurysm filling as well as the residual aneurysm mass. Neither technique is suited to evaluating in-stent stenosis. DSA can be used at 6 months to screen for in-stent stenosis, thereby allowing a decision to be made regarding continuation of dual antiplatelet therapy. The optimal use and need for DSA in long-term follow-up requires further analysis.

Significant in-stent stenosis is relatively rare, occurring in 2 cases in this series, with both patients remaining relatively stable or improving over time. Of greater concern are our 2 cases of delayed vessel occlusion. Fortunately, neither patient suffered lasting neurologic consequences because of aneurysm locations in the anterior circulation with intact collateral circulation. Fiorella et al²³ reported a case with delayed stent thrombosis in the posterior circulation, with significant morbidity. The timeframe for most studies in the literature precludes effective analysis of this phenomenon. As such, the relative uncertainty in long-term performance should be factored into clinical decision-making surrounding potential flow-diversion interventions.

This study suffers from a number of limitations, given its retrospective and nonrandomized nature. Outcomes were self-reported by the treating interventionalist, introducing potential measurement bias. Standardized outcome measures such as angiographic grading scales and clinical outcome scales were not uniformly applied and were not available for complete analysis. Due to the proctoring requirements, case selection and stent deployment were subject to expert supervision, limiting generalizability of the data. This study was not, however, intended to provide definitive answers. Rather, this study reports a nascent experience with a novel technology used to treat challenging intracranial aneurysms. The purpose of this review is to highlight areas for further research and study. Focused randomized trials are needed determine the relative efficacy of flow-diverting stents compared with standard aneurysm treatment. Further data are needed on long-term outcomes as well as predictors of aneurysm closure and procedural complications. Finally, even if flow-diverting stents can be established as a safe and effective treatment for intracranial aneurysms, it must be determined whether these expensive devices are cost-effective for health care systems. Of note, the cost of a single PED approaches 3–4 times that of a conventional intracranial stent. As a result, a case using a single PED may have a similar cost to stent-assisted coiling; however, the costs rise exponentially with multiple PED use. Whether cost savings are realized in prevention of recurrence or complications requires further analysis.