The Pipeline Embolization Device for the Intracranial Treatment of Aneurysms Trial

Traditional Endosaccular Treatment of Cerebral Aneurysms

Endovascular therapy (eg, coil embolization) has been subject to criticism for a consistent failure to achieve the same level of durable and complete aneurysm exclusion that surgical aneurysm clipping typically provides. This is particularly true for large (> 10 mm) and wide-neck aneurysms, which have low rates of complete occlusion both initially and at angiographic follow-up as well as relatively high rates of recurrence with traditional endovascular endosaccular occlusion strategies.^5,6 In particular, very large and giant aneurysms are almost never completely “cured” with reconstructive endosaccular approaches and usually require numerous retreatments and lifelong imaging surveillance.⁷ Numerous iterations of endovascular coils, such as complex-shaped, 3D framing, and very soft packing coils, as well as bioactive and hydrogel-coated coils have been developed in an attempt to address these limitations. However, the results of many single-center series and industry-sponsored multicenter trials have failed to demonstrate that any of these technologies have produced a marked incremental improvement in either the safety of the procedure, rate of complete aneurysm occlusion, or likelihood of aneurysm recurrence after treatment.^8,9

The failure of endosaccular techniques to achieve a complete and durable occlusion of aneurysms has been attributed to several factors, including limitations with respect to the volumetric packing of the aneurysm sac with coils, inherent difficulties associated with achieving a continuous reconstruction of large complex aneurysm neck defects with coils, and finally a fundamental failure of the endosaccular strategy to address the underlying diseased parent vessel (Fig 1).²

Endoluminal Reconstruction of Cerebral Aneurysms with Flow Diverters: Putative Mechanism of Action

Endoluminal reconstruction with the PED represents a completely different approach to the endovascular treatment of intracranial aneurysms in that the parent artery defect is actually repaired by the device and the biologic response it elicits from the adjacent parent artery. The feasibility of the concept of primary endoluminal reconstruction (rather than endosaccular filling) to achieve aneurysm occlusion was demonstrated in the 1990s by the seminal work of several investigators who implanted stents, with and without endosaccular embolization coils or liquid polymers, across the necks of experimental aneurysms.^10–14 With the development of low-profile microcatheter-delivered self-expanding (eg, Neuroform, Boston Scientific; Enterprise, Cordis, Miami Lakes, Florida) and balloon-expandable intracranial stents, the concept of intracranial parent artery reconstruction became clinically feasible.^14–16 These initial self-expanding neurostents were engineered primarily for adjunctive use to support the coil embolization of cerebral aneurysms and, as such, had very low metal surface-area coverage and large cell sizes to permit traversal with a microcatheter. As such, the hemodynamic impact achieved with solitary use of these devices in most cases was minimal.^17,18

In contradistinction to the coil-assist stents, the low-porosity flow diverting constructs were designed specifically to redirect blood flow along the normal course of the parent artery, markedly altering dynamic fluid exchange across the aneurysm/parent vessel interface, thereby creating an intra-aneurysmal environment that is conducive to thrombosis. As important, however, following successful aneurysm thrombosis, the construct becomes progressively incorporated into the parent artery through a process of neointimal overgrowth. Once this has occurred, a continuous, homogeneous layer of tissue unites the normal parent artery segments proximal and distal to the aneurysm neck defect, completing the process of endoluminal reconstruction. The construct-induced neointimal overgrowth of the aneurysm neck ultimately results in the anatomic exclusion of the aneurysm from the circulation and promotes final involution of the aneurysmal mass as the intrasaccular thrombus is resorbed. Optimally, this anatomic restoration of the perivascular anatomy may lead to a resolution of any clinical sequelae related aneurysmal to mass effect and restoration of normal extravascular anatomy (Figs 1 and 3). This sequence of events has been observed clinically in individual human patients and has also been validated in a series of experimental aneurysms.^19–21

Parent Artery Reconstruction with the Pipeline Is Technically Feasible

Ultimately, successful placement of the desired number of PEDs across the aneurysm neck was achieved 98% of the time. During the PITA trial, the PED was deployed through approved microcatheters (Renegade Hi-Flo; Masstransit) that were not specifically designed for PED implantation. These microcatheters frequently “ovalized” or kinked around vascular turns and sometimes stretched during device delivery, making PED deployment challenging, particularly in tortuous segments of the cerebral vasculature. Since the completion of PITA, a microcatheter (Marksman, ev3/Chestnut Medical) has been specifically engineered for the delivery and deployment of the Pipeline. The availability of an optimized PED delivery catheter may significantly improve the ease of device placement and reduce the frequency of delivery-deployment failures.

Parent Artery Reconstruction with the Pipeline Was Achieved with an Acceptable Procedural-Risk Profile

Two periprocedural neurologic complications were noted in the present series, both of which were major strokes. This rate of periprocedural complications (6.5%) is analogous to that reported for the endovascular treatment of aneurysms using other approved self-expanding intracranial microstents.^22–24 One of the complications related to the placement of multiple PEDs within the M1 segment of the MCA to support endosaccular coiling of a giant aneurysm was an infarction in the territory of a lateral lenticulostriate branch. This complication, to some degree, reflects an earlier stage of understanding of the device, its optimal application, and its limitations. Currently, we do not recommend overlapping multiple constructs in regions giving rise to eloquent perforators.

Pipeline Treatment Elicited a Very High Rate of Complete Aneurysm Occlusion

The rates of complete aneurysm occlusion achieved with the Pipeline surpass those reported in the literature for conventional endovascular endosaccular aneurysm treatments. In the present study, 93% of the aneurysms treated were occluded at 6-month follow-up. Moreover, 1 of the aneurysms that was incompletely occluded at 6 months progressed to complete occlusion by 12 months. These complete occlusion rates are even more impressive when considering that the types of aneurysms included in the present study—large, giant, wide-neck, and failed/recurrent—are those that are typically the most challenging for conventional coil-based endosaccular treatments. Because the efficacy of Pipeline reconstruction is not at all dependent upon the dense packing of the aneurysm fundus with embolic materials, the ability to achieve a complete and durable occlusion with the Pipeline is not dependent on the size or configuration of the aneurysm sac, the presence of intra-aneurysmal thrombus, or the width of the aneurysm neck. As such, wide-neck, fusiform, partially thrombosed, and very large-giant aneurysms may be particularly well-suited for endoluminal reconstruction.

One of the 2 aneurysms not initially occluded with the Pipeline had been previously treated with another intracranial stent. Indwelling SESs not only have the potential to complicate the delivery and deployment of flow diverters, but we hypothesize that these SESs impair effective apposition of lower porosity constructs (like the PED) to the parent artery, thus slowing or preventing the overgrowth of a contiguous and homogeneous neointimal and endothelial coverage of the aneurysm neck and potentially inhibiting complete aneurysm occlusion.¹

Delayed In-Construct Stenosis Was Not Observed in the Present Series

In the current series, 1 asymptomatic moderate-grade (25%–50%) stenosis was observed in the 30 patients presenting for angiographic follow-up. There were no cases of high-grade (>50%) or symptomatic stenosis observed during the 180-day follow-up after PED implantation. Because the Pipeline is a bare metal device, it would be expected that most in-construct stenoses would be observed within 3–6 months of implantation.²⁵ As such, the present series suggests that in-construct stenosis observed after PED placement is likely to occur at a relatively low rate.

Delayed Neurologic Events Were Not Observed in the Present Series

The absence of delayed neurologic events following treatment suggests that, as with conventional endovascular aneurysm therapies, most complications with endoluminal reconstruction should be expected to occur during the early periprocedural period. Given that PED reconstruction results in a very high rate of complete aneurysm occlusion (approaching 100% in the present series) and conceivably will be associated with minimal or no recurrences after treatment, the requirement for multiple retreatments (and perhaps at some point continual angiographic or cross-sectional imaging surveillance) is likely to be substantially reduced if not eliminated altogether in most cases. This possibility is particularly important for large, giant wide-neck aneurysms and those that have failed prior treatment, because these lesions are notorious for recurrence following endovascular treatment and require long-term follow-up.⁵ This potential reduction in the rate of follow-up angiography and re-intervention could conceivably translate directly to lower cumulative risks for patients, fewer procedures, lower levels of radiation exposure, fewer hospital admissions, fewer imaging studies, and lower overall health care costs.