Safety and Efficacy of Flow Diverter Therapy for Unruptured Intracranial Aneurysm Compared to Traditional Endovascular Strategy : A Multi-Center, Randomized, Open-Label Trial

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J Korean Neurosurg Soc. 2022;65(6):772-778

Publication date (electronic) : 2022 June 24

doi : https://doi.org/10.3340/jkns.2022.0043

Junhyung Kim¹, Gyojun Hwang², Bum-Tae Kim³, Sukh Que Park⁴, Jae Sang Oh⁵, Seung Pil Ban⁶, O-Ki Kwon^,6, Joonho Chung^,1, Committee of Multicenter Research, Korean Neuroendovascular Society

¹Department of Neurosurgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

²Department of Neurosurgery, Bundang Jesaeng General Hospital, Seongnam, Korea

³Department of Neurosurgery, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea

⁴Department of Neurosurgery, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea

⁵Department of Neurosurgery, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea

⁶Department of Neurosurgery, Seoul National University Bundang Hospital, Seongnam, Korea

Address for correspondence : Joonho Chung Department of Neurosurgery, Severance Hospital , Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel : +82-2-2228-2150, Fax : +82-2-393-9979, E-mail : ns.joonho.chung@gmail.com

O-Ki Kwon Department of Neurosurgery, Seoul National University Bundan Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea Tel : +82-31-787-7163, Fax : +82-31-787-4097, E-mail : meurokwonoki@gmail.com

Received 2022 February 25; Revised 2022 May 19; Accepted 2022 June 20.

Abstract

INTRODUCTION

The prevalence of intracranial aneurysms is 0.4–3.0% [25,28], and aneurysmal rupture results in subarachnoid hemorrhage that has a decimal prognosis with substantial mortality and morbidity [4,28,29]. Advances in non-invasive brain imaging methods such as magnetic resonance angiography have facilitated the diagnosis of unruptured intracranial aneurysms [24], and the preventive treatment of unruptured intracranial aneurysm is generally recommended for an aneurysm with a diameter ≥7 mm [25].

Microsurgical clipping and endovascular coil embolization are two major treatment modalities for intracranial aneurysms [5]. Equipped with the advantage of non-invasiveness and advances in devices and techniques, coil embolization has become the dominant treatment choice with lower procedural morbidity and mortality [3,12,18]. However, coil embolization of wide-necked aneurysms is still difficult; even with adjunct use of stent, recurrence and retreatment rates are approximately 12% and 6%, respectively [7,15]. Furthermore, larger aneurysms are associated with higher rates of recurrence even when complete or near-complete occlusion has been initially achieved, due to coil compaction leading to recanalization [10,11,17]. A study revealed that large aneurysms (≥7 mm) were more likely to recur than smaller aneurysms (<7 mm) after coil embolization [26].

Flow diversion has been developed to address the challenges faced during traditional coil embolization. Flow diverters are designed to exert lower radial force to improve conformability and provide increased metal surface coverage for improved flow diversion, compared to conventional intracranial stents [27]. They elicit remodeling of the parent artery primarily through the following mechanisms : 1) exclusion of blood flow into the aneurysmal sac, resulting in thrombus formation inside the sac and 2) provision of a scaffold for endothelialization [23]. A clinical trial using the Pipeline embolization device (Medtronic, Minneapolis, MN, USA), the first commercially available flow diverter, revealed that flow diversion of large aneurysms (>10 mm) in the internal carotid artery with wide neck (>4 mm) showed a complete occlusion rate of 86% at 12 months, and major morbidity and mortality rate of 5.6% [1], and the device was approved by the United States Food and Drug Administration (FDA) for use in large aneurysms (>10 mm) with wide neck (>4 mm). Subsequently, a recent clinical trial using the Pipeline Flex embolization device for unruptured wide-necked aneurysms ≤12 mm demonstrated complete occlusion rate of 76.8% at 12 months with a major morbidity and mortality rate of 2.1% [13]. The U.S. FDA has expanded the instructions for its use in wide-necked aneurysms with a small- and medium-sized aneurysms.

In Korea, the flow diverter was initially approved for use in the treatment of unruptured aneurysms ≥15 mm, and only recently was it approved for aneurysms ≥10 mm. Currently, endovascular treatment options for wide-necked aneurysms <10 mm are limited to traditional procedures such as parent artery occlusion, coil embolization by multiple-catheter technique, or balloon or stent-assist technique.

The aim of this study is to assess the safety and efficacy of flow diversion treatment of unruptured intracranial aneurysms ≥7 mm by evaluating complication rates and complete occlusion rates at 12 months compared to traditional endovascular treatment in patients who are either to receive the first treatment or retreatments for recurrent aneurysms after initial endovascular treatment.

MATERIALS AND METHODS

Study population

The study population will include patients aged between 19 and 75 years diagnosed with unruptured intracranial aneurysms or with recurrent aneurysms after initial endovascular treatments with a maximum diameter ≥7 mm arising from the internal carotid artery, anterior cerebral artery, middle cerebral artery, or vertebrobasilar arteries. Recurrent aneurysms are defined as grade 2 (70% to 89% aneurysm occlusion in orthogonal images of catheter cerebral angiography from optimal projection) or higher according to the aneurysm occlusion grading system for endovascular aneurysm occlusion suggested by Meyers et al. [16] (Table 1). Detailed inclusion and exclusion criteria of the study are described in Table 2.

Table 1.

Aneurysm occlusion grading system

Table 2.

Inclusion and exclusion criteria of the study

Clinical and radiologic outcome measures

The primary endpoint will be complete occlusion (grade 0 or 1 confirmed by catheter cerebral angiography according to the Aneurysm occlusion grading system) at 12 months after the treatment. Secondary endpoints will evaluate the short-term and the longer-term safety of the trial, and include the following : 1) any procedure-related complications defined as thromboembolic or hemorrhagic complications that occur within 30 days after the treatment, 2) severity of hemorrhage evaluated by Thrombolysis in Myocardial Infarction bleeding criteria [8], 3) delayed intracranial hemorrhage defined as spontaneous intracranial hemorrhage that occurs within 12 months after treatment, 4) delayed cerebral infarction defined as cerebral infarction due to thromboembolism within 12 months after treatment, and 5) neurologic status evaluated using the modified Rankin scale score at 1 month and 12 months. A summary of the scheduled visits is shown in Table 3.

Table 3.

Study visits

RESULTS

The trial will begin enrollment in 2022, and clinical data will be available after enrollment and follow-up.

DISCUSSION

This study aims to provide definitive data on the safety and efficacy of flow diversion with devices available in Korea in comparison to traditional endovascular treatment for unruptured cerebral aneurysms ≥7 mm.

Previously, several studies have compared the treatment outcomes of flow diversion and coil embolization, but they were retrospective studies. A systematic review and metaanalysis by Zhou et al. [32] reported that flow diversion showed a significantly higher complete occlusion rate than coil embolization and a subgroup of stent-assisted coil embolization. A recent meta-analysis comparing flow diversion treatment with conventional endovascular treatment revealed that flow diversion was associated with higher 6-month complete occlusion rate for large or giant aneurysms, but no such difference was observed for non-large or giant aneurysms [30]. The current randomized trial is expected to minimize selection bias and confounding factors due to unequal distribution of significant factors, and to warrant direct comparison of the two treatment methods.

The off-label use of flow diverters for aneurysms <10 mm has already been prevalent, and its efficacy and safety have also been reported for different flow diverters such as FRED (MicroVention) [2,21] and SILK (Balt Extrusion, Montmorency, France) [22]. A meta-analysis of flow diversion treatment for intracranial aneurysms <10 mm revealed the complete occlusion rate of 84.2%, and procedure-related mortality and morbidity of 0.9% and 5.2%, respectively [31]. A matched-cohort study by Chalouhi et al. [6] demonstrated that flow diversion was associated with a significantly higher complete occlusion rate than coil embolization (70% and 47.5%, respectively, p=0.04) without additional morbidity in the treatment of small aneurysms <10 mm. To date, no study has directly compared the treatment outcomes of flow diversion and traditional endovascular coiling for treatment of aneurysms <10 mm.

CONCLUSION

This article describes the design of a multi-center, randomized, open-label trial to compare the safety and efficacy of the treatment of unruptured cerebral aneurysms with maximum diameter ≥7 mm by flow diversion versus traditional endovascular treatment. This trial is expected to warrant direct comparison of the two treatment methods with minimal bias.

Supplementary materials

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