Abstract
Background
Neuroendovascular procedures, especially those involving significant vessel tortuosity, giant intracranial aneurysms, or distally located lesions, frequently necessitate exchange methods. However, exchange maneuvers pose a risk of inadvertent vessel injury. To address these challenges, a Stabilizer device was developed and evaluated for its efficacy and safety. This clinical trial aimed to assess the efficacy and safety of the Stabilizer device in facilitating the navigation of neuroendovascular devices to target lesions in cases where the exchange technique was necessary.
Methods
This was a single-arm, prospective, open-label, multicenter clinical trial performed at nine different sites. It focused on investigating the use of the Stabilizer device for treating intracranial aneurysms and atherosclerosis.
Results
A total of 31 patients were enrolled across nine centers in Japan from July 21, 2022, to March 10, 2023. The study enrolled 24 (77.4%) patients with intracranial aneurysms and seven (22.6%) patients with intracranial artery stenosis. Majority of the target lesions were in the middle cerebral artery territory (83.9%). The Stabilizer device was used to exchange for 0.027-inch catheters, intermediate catheters, PTA balloons, and Wingspan stent system. The Stabilizer device demonstrated 100% technical success rate. While three complications related to the treatment were noted, there were no complications related to the device, including any vascular damage.
Conclusions
This is the first multicenter clinical trial that investigated and demonstrated technical efficacy as well as overall safety profile of the Stabilizer device in neuroendovascular procedures where the use of an exchange method was necessary.
Keywords: Clinical trial, device navigation, exchange method, anchor technique, stent
Introduction
Recent advancements in neuroendovascular treatments have markedly progressed with the development of diverse, revolutionary devices. For example, development of neck bridge stents and flow diverter stents introduced great advancements in the treatment of intracranial aneurysms. In addition, angioplasty balloon and stent systems specifically designed for intracranial arteries have been used to treat intracranial arteriosclerosis. The employment of these advanced devices often requires the use of access tools or treatment devices that are relatively large and stiff. However, this often poses challenges particularly in situations of severe vessel tortuosity or when targeting distal lesions. Exchange technique is useful when direct delivery of these neuroendovascular devices is not feasible. The exchange method serves to initially secure the distal access to the target lesion using a small, flexible microcatheter and microguidewire, then replace the wire with a long, supportive guidewire to track the desired device. Nonetheless, the exchange technique carries inherent risks, including the potential for the supportive guidewire to move unexpectedly, leading to vessel perforation and severe hemorrhagic complications.
According to a national survey by the Japanese Society for Neuroendovascular Therapy, there were a total of 264 accidents involving guidewire perforations between 2012 and 2016, of which 26 (9.9%) resulted in patient mortality. The data reveal that 15 (5.7%) of the guidewire perforations occurred during exchange maneuvers, highlighting their notable risk.1,2 Additionally, in the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, which compared the safety and efficacy of angioplasty and stenting with maximal medical treatment for intracranial atherosclerotic disease (ICAD), perioperative complications from endovascular treatment were 14.2%, significantly more compared to the medical treatment group. The SAMMPRIS trial reported that one-third of the complications occurred while navigating the stent system using the exchange method. 3 Although the literature describes the use of anchor techniques using compliant balloons4–8 and stent retrievers,8–10 there are no medical devices specifically approved specifically for the anchor technique to avoid complications related to the exchange method.
Recently, a novel Stabilizer device (Bolt Medical Co., Ltd, Tokyo, Japan) is introduced featuring an exchange-length microguidewire with a self-expanding stent on the distal end, designed to act as a distal anchor. The first in-human trial of the use of the Stabilizer device has been conducted in 2021 in Japan, which demonstrated the technical success of the Stabilizer device without adverse events in the five cerebral aneurysm cases. 11 The objective of this multicenter clinical trial was to evaluate the performance of the Stabilizer device in neuroendovascular therapy.
Material and methods
Study device
The Stabilizer device has a self-expanding retrievable stent mounted on the distal end of a 320-cm exchange-length microguidewire (Figure 1). It is compatible with 0.0165″ inner diameter microcatheters. In this clinical trial, we evaluated the performance of the Stabilizer device which has a self-expanding retrievable stent mounted on the distal end of a 320-cm exchange-length microguidewire (Figure 1). It is compatible with 0.0165″ inner diameter microcatheters. This feature not only prevents the tip of the exchange wire from moving and causing perforation but also allows the outer endovascular device to be safely advanced over the wire. Therefore, exchange technique using the Stabilizer device may potentially reduce hemorrhagic complications especially in cases with severe vascular tortuosity or distal lesions.
Figure 1.
Stabilizer device with a 320-cm exchange-length wire with a self-expanding retrievable stent at the distal end, compatible with 0.0165″ microcatheter.
Study design
This study was designed as a single-arm, prospective, open-label, multicenter clinical trial, performed at nine sites in Japan. Its primary objective was to investigate the safety and efficacy of the Stabilizer device in the treatment of intracranial aneurysms and ICAD. This investigator-led trial was performed in compliance with Japanese Good Clinical Practice regulation and registered with the Japan Registry of Clinical Trials under the identifier jRCT2052220056. Approval was obtained from local internal review boards at all participating sites. The inclusion and exclusion criteria for this multicenter clinical trial are described in Table 1.
Table 1.
Enrollment criteria.
| Inclusion criteria |
|---|
| 1. age 20–80 at obtain consent |
| 2. modified Rankin Score 3 or less |
| 3. impossible to navigate treatment device to target position (detail is described in procedure) |
| 4. obtain documented consent from patient |
| Exclusion criteria |
| 1. impossible for 7 days follow uo after treatment |
| 2. impossible to administrate heparin during procedure |
| 3. history of severe allergic reaction |
| 4. out of indication under IFU |
| 1) allergy for trial device material |
| 2) arterial dissection, occlusion or active vasculitis on related artery |
| 5. other trial |
| 6. pregnant or during |
| 7. ineligible patient for trial, decided by investigator |
Patient enrollment
Treatment protocol for intracranial aneurysms
The treatment protocol for patients who underwent intracranial aneurysm embolization was as follows:
A small diameter microcatheter was delivered distal to the aneurysm through the aneurysm lumen using a microguidewire.
The microguidewire was then removed, and the Stabilizer device was delivered and deployed in target vessel using a small diameter microcatheter.
The small diameter microcatheter was then removed, and the therapeutic medical device was delivered over the Stabilizer wire.
The Stabilizer device was then retrieved and removed.
The intracranial aneurysm was embolized using the therapeutic medical device.
Treatment protocol for ICAD
The treatment protocol for patients who underwent balloon angioplasty and/or stenting for ICAD was as follows:
A microguidewire was used to deliver the small diameter microcatheter to the appropriate site.
The microguidewire was removed, and the Stabilizer device was advanced and deployed using a small diameter microcatheter.
The small diameter microcatheter was withdrawn, and the therapeutic medical device was delivered over the Stabilizer wire.
Study endpoints
The primary efficacy endpoint was the success of endovascular treatment, utilizing the Stabilizer device. Success was defined as the successful embolization of an aneurysm or the successful placement of a stent and/or execution of balloon angioplasty for ICAD. The primary safety endpoint was the occurrence of any severe adverse events (SAEs) related to the endovascular treatment or the Stabilizer device during the procedure and within seven days after the procedure. Severe adverse events included conditions such as symptomatic intracranial hemorrhage, vessel dissection, vasospasm, or thrombotic occlusion that led to a worsening of the National Institutes of Health Stroke Scale score by four or more points and required additional treatment. The secondary efficacy endpoint was the technical success in the navigation and deployment of the treatment device using the Stabilizer device. Secondary safety endpoints included other adverse events associated with the use of the Stabilizer device, as detailed in Table 2.
Table 2.
Secondary endpoints.
| Efficacy |
|---|
| Successful navigation of treatment device |
| Safety |
| 1. hemorrhagic stroke required additional treatment within 7 days after procedure or before discharge |
| 2. ischemic stroke required additional treatment within 7 days after procedure or before discharge |
| 3. arterial dissection required additional treatment related to trial device |
| 4. symptomatic vasospasm required additional treatment related to trial device |
| 5. other severe adverse event related to trial device |
Results
A total of 31 patients were enrolled from nine centers in Japan between July 21, 2022, and March 10, 2023, with the final follow-up completed on March 13, 2023. All 31 patients met the enrollment criteria for the clinical trial, and efficacy and safety results were analyzed. Patient demographics are presented in Table 3.
Table 3.
Background and procedure.
| Age | Mean 63.7, Median 63, Range 32–80 |
| Gender | Male = 8/31 (25.8%) |
| Disease | Aneurysm = 24 (77.4%), Intracranial Artery Stenosis = 7 (22.6%) |
| Target lesion | MCA = 26 (83.9%), ACA 1(3.2%), PCA 4 (12.9%) |
| Diameter of target lesion (mm) | Mean 2.1, Median 1.9, Range 1.1–3.1 |
| Microcatheter for navigate Stabilizer | Excelsior SL10 = 9, Headway17 = 18, Phenom17 = 2, Phenom27 = 2 |
| Device for withdraw Stabilizer | Excelsior SL10 = 3, Headway17 = 4, Prowler select Plus = 1, Headway27 = 2, Phenom27 = 19, Catalyst5 = 3 |
| Device for treatment | Prowler select Plus = 1, Headway27 = 2, Phenom27 = 18, Catalyst5 = 3, Gateway = 7, Wingspan = 1, |
Primary and secondary endpoints
The primary efficacy endpoint, which was the overall treatment success, was achieved in 96.8% of the cases, with successful outcomes observed in 30 out of 31 patients. The secondary efficacy endpoint, defined as the technical feasibility of successfully navigating the treatment device using the Stabilizer, was achieved in 100% of the cases (31 out of 31). In the one unsuccessful case, there was difficulty in accessing the distal parent artery of the aneurysm, which required formation of two loops within the partially thrombosed aneurysm to reach the target site. Although the Stabilizer was successfully deployed at the target site, and then microcatheter was exchanged to a larger Phenom27 microcatheter, an occlusion in the proximal middle cerebral artery (MCA) was identified. Adequate revascularization was achieved with a mechanical thrombectomy; however, the planned flow diversion was deferred due to concerns of a potential subarachnoid hemorrhage. Of note, the arterial occlusion site was not at the Stabilizer device deployment site, but rather in the proximal MCA. This suggested that clot migration may have been caused by manipulations of the microcatheter passing through the thrombosed aneurysm.
Regarding safety, there were no complications related to the testing device or incidences of vessel dissection, rupture, or vasospasm reported. Out of 31 cases, there were three complications related to the treatment, accounting for 9.7% (Table 4). These complications included: (1) MCA occlusion after device passage in the abovementioned partially thrombosed internal carotid artery (ICA) cavernous sinus aneurysm; (2) dysarthric speech due to focal epilepsy, which resolved within one week following the administration of antiepileptic medication; and (3) transient ischemic symptoms in a patient who responded poorly to Clopidogrel. The MCA occlusion in the case (1) occurred at the proximal part of the Stabilizer device and was presumed to be clot migration caused by the microcatheter. However, since the involvement of the Stabilizer cannot be completely ruled out, the relationship to the device was classified as possible in this clinical trial. Additionally, there were four SAEs reported (Tables 4 and 5), comprising the aforementioned three complications related to the treatment, and one case of worsening of abducens nerve palsy five days after the treatment probably due to aneurysm thrombosis following the flow diverter deployment, with subsequent gradual improvement of symptoms. These symptoms completely resolved one week after onset.
Table 4.
Results * 95%CI.
| Primary endpoint | ||||
|---|---|---|---|---|
| Efficacy | Treatment success with successful navigation of treatment device | 30/31 | 96.8% | 83.3–99.9 * |
| Safety | Severe adverse event within 7 days after treatment | 3/31 | 9.7% | 2.0–25.8 * |
| Secondary endpoints | ||||
| Efficacy | Successful navigation of treatment device | 31/31 | 100% | 88.8–100 * |
| Safety | hemorrhagic stroke required additional treatment within 7 days after procedure or before discharge | 0/31 | 0% | 0–11.2 * |
| ischemic stroke required additional treatment within 7 days after procedure or before discharge | 3/31 | 9.7% | 2.0–25.8 * | |
| arterial dissection required additional treatment related to trial device | 0/31 | 0% | 0–11.2 * | |
| symptomatic vasospasm required additional treatment related to trial device | 0/31 | 0% | 0–11.2 * | |
| other severe adverse event related to trial device | 0/31 | 0% | 0–11.2 * | |
Table 5.
Severe adverse event.
| Disease | Event | Relation to TX | Relation to D | |
|---|---|---|---|---|
| 1 | Aneurysm, cavernous giant | Delayed neurological symptom | possible | no |
| 2 | Aneurysm, cavernous giant | Delayed ischemic symptom | no | no |
| 3 | Aneurysm, cavernous giant, thrombotic | Arterial occlusion | related | possible |
| 4 | Aneurysm, cavernous giant, thrombotic | Mass effect | related | no |
TX: treatment; D: device.
Discussion
Neurointerventional therapies are inherently high-risk procedures. Vessel perforation due to wire movement during a device exchange technique may be fatal. It is reported that as high as three percent of the cases that involve exchange maneuvers have vessel perforation interprocedurally. 13 To avoid the possible risks associated with traditional wire exchange methods, the use of balloons, stents, and even stent retrievers has been reported; however, all of them are off-label, have limitations, and are costly.5,14–18 However, balloons carry risks of ischemia due to temporary occlusion of blood flow as well as vessel rupture and the wire length of these stents is about 200 cm, which is often inadequate for exchange methods. In response to these challenges, the Stabilizer device was developed to address the shortcomings of existing techniques. The distal basket-shaped retrievable stent of the Stabilizer device serves as a stable distal anchor while the exchange process occurs.
In 2021, Kaneko et al. reported the successful application of the Stabilizer device for exchange procedures in three complex realistic in-vitro models: a giant aneurysm, tortuous ICA, and intracranial arterial stenosis. 12 In a simulation of an ICA cavernous sinus giant aneurysm, the Stabilizer device provided stable advancement of an intermediate catheter, achieving significantly higher success rates of 80% compared to 20% for the conventional microguidewire (p < 0.001). Giant aneurysms frequently pose challenges in maintaining and securing distal access due to the acute angles between outflow and inflow tracts, the expansive nature of their necks, and the narrowing of the distal outlet artery compressed by the aneurysm.15,19,20 The Stabilizer device offers a distinct advantage by enabling the straightening of intra-aneurysmal loops, and stable exchanges for larger, intermediate treatment catheters. Additionally, the Stabilizer device showed significantly higher success rates in the delivery of Wingspan stent system in stenosis model compared to the exchange microguidewire. 12
Recently, in March of 2023, the first in-human clinical trial evaluating of the Stabilizer device in five cases in Japan was reported. 11 In this prospective single-arm study, the Stabilizer device was used to gain and secure distal access during the embolization of five complex intracranial aneurysms. The device achieved a 100% technical success in delivering the treatment device. No serious adverse events occurred related to the Stabilizer device, suggesting good safety profile of this investigational device. The success of this initial in-human study has laid the groundwork for this multicenter clinical trial.
In the present study, the authors similarly demonstrate excellent safety and technical success of the Stabilizer device during exchange maneuvers. There were no reports of vessel dissection, perforation or significant vasospasm requiring treatment. And the adverse events that did occur were within the expected range, suggesting the high safety profile of the device. In terms of efficacy, the success rate for therapeutic techniques exceeded 95%, and the technical delivery of therapeutic medical devices achieved 100%, indicating the exceptional effectiveness of the Stabilizer device. Given its ability to provide safe and effective treatment for high-risk patients, the advantages of the Stabilizer device significantly outweigh its potential risks.
In this clinical trial, there were no complications related to the device, including vascular damage, indicating its safety. A total of three treatment-related complications occurred; however, all patients demonstrated clinical improvement over time. In a case classified as an SAE, an occlusion in the MCA developed proximal to the deployment site of the Stabilizer device. Although the likely cause of the thrombus formation was due to the distal migration of thrombus within the aneurysm, the incident was assessed as “cannot exclude a relationship to the trial device.” Fortunately, this patient also experienced symptom improvement.
Conclusion
The findings from this trial showed a high technical success rate and an overall favorable safety profile for the Stabilizer device in these complex exchange procedures. This suggested that the Stabilizer device would be useful in complex neuroendovascular cases, particularly those involving severe vessel tortuosity, giant intracranial aneurysms, and distal location of a target lesion that require the use of exchange methods. To further validate these findings, additional studies are recommended.
In this clinical trial, there were no complications related to the device, including vascular damage, indicating its safety. The results of this multicenter clinical trial suggest not only a high technical success rate of the Stabilizer device in challenging neuroendovascular cases but also a reasonable safety profile. There was a total of three complications related to the treatment; however, all three patients showed clinical improvement over time. Specifically, in one case, the occlusion in the MCA occurred proximal to the Stabilizer device's deployment site. While the likely cause of the thrombus formation was the distal migration of the thrombus within the aneurysm, this incident was assessed as “cannot exclude a relationship to the trial device.” Notably, this patient also experienced symptom improvement.
Footnotes
Author contributors: All authors made a substantial contribution to the design and drafting of the manuscript. All authors contributed to and approved the final revisions of the manuscript.
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: This trial received trial devices and granted from Bolt Medical. The authors, NS, NK, and ST, were consultants of Bolt Medical at the treatment, but declare that this trial was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. NS received a research grant from Japan Lifeline, Kaneka, Medtronic, Terumo, and TG Medical; lecturer’s fees from Asahi-Intec, Kaneka, Medtronic, Stryker, and Terumo; membership on the advisory boards for Johnson & Johnson, Medtronic, and Terumo, outside of this article. HI received lecturer's fee from Medtronic. NK has been a consultant for Stryker and Medtronic, outside of this article. ST received research funds from Biomedical Solutions, Rapid Medical, and Medtronic, and a consultant for TG Medical, Irvine Neurovascular, Balt USA, Cerenovus, Medtronic, Phenox GmbH, MicroVention, Kaneka USA, Century Medical Inc., EnCompass, NVMedTech, and Stryker, outside of this article.
Ethics approval: The clinical trial was approved by the Certified Review Board agreement, registered on June 22, 2022 (https://jrct.niph.go.jp/en-latest-detail/jRCT2052220056). The approval was obtained from local internal review boards at all participating sites.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This trial received trial devices and granted from Bolt Medical Ltd, (grant number Grant).
ORCID iDs: Tsuyoshi Ohta https://orcid.org/0000-0001-9345-7701
Nobuyuki Sakai https://orcid.org/0000-0002-3289-1210
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