The FRED Flow-Diverter Stent for Intracranial Aneurysms: Clinical Study to Assess Safety and Efficacy

Discussion

In this single-center prospective clinical study, the FRED was evaluated for the treatment of otherwise untreatable or difficult-to-treat intracranial aneurysms (ie, wide-neck, fusiform, dissecting, blisterlike, or giant). This new generation of intracranial FD appeared to be a promising safe and effective alternative treatment to other FDs for these complex aneurysms. The primary end point for clinical safety (ie, absence of death and major or minor stroke and absence of transient ischemic attack) was reached in 26/29 (90%) treated patients.

The observed overall permanent morbidity of 3.4% and mortality of 0% in our study was low. In other prospective clinical studies on different intracranial FDs (Pipeline Embolization Device; Covidien, Irvine, California; Silk+, Balt Extrusion; Surpass stent; Stryker Neurovascular, Fremont, California), similar end points occurred with 0%–15% permanent neurologic deficits and 0%–8% mortality.^{7⇓⇓⇓⇓⇓⇓⇓⇓–16}

Altogether, we report in this study that the end point of clinical safety was not achieved in 2 patients with minor ischemic stroke, in whom complete resolution of symptoms was observed after 3-month follow-up and in 1 patient with major ischemic stroke. In the latter patient, the only one with a permanent neurologic deficit, an exceptionally rare and difficult-to-treat aneurysm was targeted. Only repeat DSA but not initial DSA revealed a ruptured aneurysm of a perforator branch of the trunk of the basilar artery. In the literature, only 13 cases were reported with this type of aneurysm.^18,19 Because this aneurysm was not amenable to any coiling or neck-clipping technique, we decided in favor of treatment with flow diversion by using the FRED. Despite sufficiently effective antiplatelet therapy according to platelet function tests, however, the patient's symptoms, consistent with a delayed perforator stroke 9 hours after FRED deployment, were confirmed by DWI. The exact location and anatomic extension of the ischemic pontine DWI lesion was consistent with delayed occlusion of the perforator branch harboring the aneurysm and was likely the inevitable effect of decreased flow in this vessel.²⁰

In one patient who had microembolic infarcts in the superior cerebellar artery territory, from which she recovered completely at 3-month follow-up, a similar flow-related pathogenesis seems most plausible. In a larger series, only observing 32 posterior circulation aneurysms treated with FDs, Phillips et al¹² reported a permanent neurologic complication rate of 9.4%, with perforator territory infarctions occurring in 14% of the subgroup of patients with basilar artery aneurysms. These authors concluded that treatment with an FD is safe and effective but should be reserved for cases not easily or effectively treatable with conventional endovascular techniques, owing to the high rate of ischemic perforator infarcts following FD use in the posterior circulation and the basilar artery trunk in particular.¹²

Two cases (2/29 patients, 6.9%) of in-stent thrombosis occurred in our study: one appositional clot formation in the acute stage of SAH, which was fully reversible on angiography and without clinical consequences under controlled hypertension together with weight-adapted tirofiban and heparin; and the other at 2 months after termination of prasugrel because of infection of his ventriculoperitoneal shunt requiring surgical intervention for conversion into a ventriculoatrial shunt. No further delayed thromboembolic events after the procedure were detected in any other patient by occurrence of clinical symptoms or by follow-up MR imaging.

In the present trial, FD deployment was technically successful in all cases. Insufficient opening of the FD, which is reported for other available FDs to occur in up to 10% of cases, was not observed in any case for the FRED in our study.^8,9,16 We elected to perform in-stent PTA of the FRED if the slightest suspicion of incomplete wall apposition arose on the immediate postdeployment control angiograms (5/29 patients, 17%). This operation standard was chosen because we consider the risk of thrombus formation and subsequent parent artery occlusion to be high if suboptimal wall apposition is tolerated.^11,15 In those 5 cases in which we performed PTA within the FD stent (all were paraophthalmic or supraclinoid ICA aneurysms with sharp angulation of the carotid siphon), opening of the stent before PTA was still near-complete with at least 90% of the stent diameter and was further improved to 100% after PTA. To ensure proper opening and full deployment of the FRED, we ensured that unsheathing and release of the FRED occurred in a slow and controlled fashion during several minutes by gentle application of the push/pull technique with the delivery microcatheter tip properly held in a central position within the central vessel lumen. However, the operator should be aware that even if these precautions are taken, incomplete opening still may occur, which should prompt complete retrieval of the device by simply resheathing it into the delivery microcatheter.

On follow-up DSA at 3 months, no in-stent stenosis or changes in stent morphology such as “fish mouth” (ie, inward crimping of 1 or both ends of FD) or “foreshortening“ phenomena were observed, which were described in an early series by Kocer et al²¹ in 5 cases with a FRED. In our series of 29 patients, we exclusively used the second-generation version of the FRED, which obtained approval for human clinical use within the European community by CE marking in December 2012. Evaluation of the efficacy of occlusion showed promising results for the FRED in otherwise untreatable or difficult-to-treat aneurysms during early follow-up until 3 and 6 months postoperatively. Diagnostic follow-up was achieved not only by invasive angiographic but also MR angiographic evaluation, including contrast-enhanced TOF-MR angiography considered to be sensitive for residual aneurysmal inflow, especially when nonenhanced TOF-MR angiography source images are used for subtraction. At 3-month follow-up, complete occlusion (OKM D) was achieved in 19/34 (56%) aneurysms. At 6-month follow-up, aneurysm occlusion was complete in 22/30 (73%) aneurysms defined as an OKM grade of “D” (complete occlusion), which, on the Raymond and Roy scale, would correspond to grade 1°.²²

Compared with other prospective clinical studies on different intracranial FDs (the Pipeline Embolization Device, SILK+, and Surpass), our efficacy rate of 86% in aneurysms of <10 mm was similar to the reported complete occlusion rate at 6 months of 49%–93%.^{7⇓⇓⇓⇓⇓⇓⇓⇓–16,23} However, in aneurysms of >10 mm, our occlusion rates were lower than the rates reported in the Pipeline Embolization Device for Uncoilable or Failed Aneurysms trial¹⁵ and in the recent meta-analysis from Brinjikji et al.²³ One possible explanation is that the low number of aneurysms of >10 mm in our study (n = 11) might have led to deviations from the population mean, which, due to the larger group size, might have been estimated more accurately in a larger study such as the Pipeline Embolization Device for Uncoilable or Failed Aneurysms trial, for example. Another possible explanation is that we required the 6-month follow-up to include TOF-MRA and applied rigorous aneurysm evaluation of nonenhanced TOF, contrast-enhanced TOF and, importantly, also on subtracted TOF images on which we rated any suspicion of residual inflow or very slow inflow as noncomplete occlusion.

In experimental aneurysm models and also in human studies, it could be regularly observed that FD stents can induce complete and stable occlusion of the aneurysm sac by stasis of flow and subsequent thrombosis, even without additional introduction of coils. In 10 patients, aneurysm occlusion was observed after adjunctive use of coils, introduced by a jailed microcatheter during the same treatment session before FD deployment. In our current practice, we use adjunctive coiling if aneurysms are large or giant, in the acute stage of SAH, or in cases of retreatment/recurrence of previously ruptured aneurysms pretreated by coiling. The primary rationale for adjunctive coiling in our view is to prevent aneurysm rupture and to enhance stable long-term occlusion.²⁴ Additional coiling may not only prevent early or delayed rupture but also, especially for extremely wide-neck aneurysms, provide good mechanical support and stabilization for FD deployment and a stable long-term position, in that (partial) herniation or bulging of the FD into the aneurysm sac can be avoided.

The recently introduced FRED may offer several potential advantages over other currently available intracranial FDs: 1) Due to its dual-layer design and availability in long sizes of up to 56 mm, the scaffolding effect of the stent for obtaining outward stability toward the wall of the parent vessel seems to be enhanced and, most important, is achievable in a single treatment session, which makes this device especially useful in fusiform or giant aneurysms, whereas 2 sequential procedures might have been necessary before (scaffolding stent first followed by FD implantation). 2) The outer stent is woven with 16 wires leading to lower friction within the delivery microcatheter, thus facilitating deployment especially of longer stents—other available FDs, for example, are composed of 48 wires (Silk+ and Pipeline Embolization Device) or 96 wires (Surpass). 3) The additive radial force vectors of the inner and outer stent provide a high degree of reliability of stent opening, a feature especially critical when deployment includes ICA segments around the carotid siphon. 4) There is improved lamination of blood flow through its dual-layer design and higher pore attenuation with 16 + 48 wires compared with 48 wires of the Pipeline Embolization Device and Silk.^16,25,26 5) There is lower vessel wall coverage in the longitudinal direction because of the shorter inner stent (shortest available on the market), which is designed to limit the working layer mainly to the neck of the aneurysm and to spare adjacent branches or perforator arteries, to maintain the patency of these vessels. 6) There is enhanced visibility of the central stent segment and of its distal and proximal ends.

We acknowledge that the major limitations of this prospective study include the limited number of 29 patients, a short follow-up period, MRA only after 6 months, and lack of randomized comparisons with other potentially efficacious therapies. Furthermore, most aneurysms were located at the paraophthalmic segment of the ICA, the mean aneurysm size was relatively small, and not all cases were treated solely by FDs but additional coiling was performed in some cases. However, recruitment followed clearly defined criteria of inclusion/exclusion, and clinical/radiologic follow-up was rigorous, including not only invasive angiography but also MR imaging to measure accurately the shrinkage of the aneurysm sac and also nonenhanced and contrast-enhanced TOF-MR angiography to detect even small amounts of slow residual inflow that may be silent on invasive angiography. Furthermore, our cohort is the largest so far in which the safety and efficacy profile of this new generation of intracranial FDs has been investigated and may serve as a basis for subsequent larger and multicenter studies.