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Abstract
Recent randomized clinical trials have shown the benefit of stent retrievers for endovascular intervention in patients with acute ischemic stroke. The Solitaire 2 FR 4×40 device was developed to address longer clots as well as procedural difficulties. This study was undertaken to evaluate the safety of the new device in a swine model at 0, 30, and 90 days as well as its in vitro effectiveness. There were no significant differences in the overall animal health, tissue injury, hemorrhagic or thrombogenic events related to device usage. Based on the comparison at multiple time points, the Solitaire 2 4×40 device was similar in safety and usability to the Solitaire 2 4×20 device. Due to the additional length of the device, the Solitaire 2 4×40 device may in fact provide a number of additional technical benefits in the neurothrombectomy treatment of ischemic stroke.
- Stent
- Thrombectomy
- Stroke
- Device
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Introduction
Recent randomized clinical trials have shown the benefit of endovascular intervention in patients with acute ischemic stroke.1–5 The majority of these studies used stent retrievers and high rates of good recanalization were demonstrated. Technical challenges remain, however, and improvements in devices to address these are desirable. It has been shown that clot burden is predictive of a poor response to intravenous thrombolysis.6 Furthermore, patients with proximal occlusions have a greater clot burden leading to a poor response to intravenous thrombolysis and hence the benefit of added endovascular intervention in this group.7 The Solitaire 2 FR 4×40 device was developed to address longer clots as well as procedural difficulties. This study evaluated the safety of the new device in a swine model at 0, 30, and 90 days as well as its in vitro effectiveness.
Methods
Animal experimentation was performed in accordance with FDA Good Laboratory Practices (GLP) Regulations (21 CFR Part 58) and policies set by the National Institutes of Health and the Institutional Animal Care and Use Committee.
Solitaire 2 FR 4×40 mm device
The design of the Solitaire 2 FR 4×40 mm test device is identical to the Solitaire 2 FR 4×20 mm control device with 40 mm of working length rather than 20 mm. The push wire, attachment method, and cell dimensions all have the same design as the Solitaire 2 4×20 mm device.
Animal studies
Six Yorkshire cross swine were used at 0, 30, and 90 day time points. The swine model was chosen because the vessel sizes of the model allow for insertion and navigation of standard-sized devices used in humans and have diameters that are comparable with those of human neurovascular vessels. The coagulation and vasculature systems of swine are also similar to those of humans.8
Study procedure
The Solitaire thrombectomy device was deployed using a standard technique, making a total of three passes and six resheathings across the selected section of the vessel. A pass is defined as deployment and full retraction of the device and the Rebar 18 microcatheter (Medtronic, Irvine, California, USA) through the Envoy 6 F guide catheter (Cordis, Fremont, California, USA). A resheathing is defined as deployment and retraction of the device until it is fully constrained by the microcatheter. A total of four vessels per animal were treated, including the bilateral internal thoracic, vertebral, and/or costocervical arteries. In each animal, two vessels were treated with the control device and two vessels with the test device, with the test and control devices placed in paired vessels when anatomically feasible. A total of six animals were used for each time point, which resulted in 12 vessels being treated by the test device and 12 by the control device per time point.
Angiography was performed at baseline and after final device retrieval. The interventionalist ranked the usability of the device based on delivery through the catheter, ability to position the stent retriever at the intended target zone, ability to deploy the stent retriever, ability to resheath and reposition, ability to retrieve the device through the guide catheter, and device condition. The post-procedure angiograms were evaluated for the presence of emboli, vessel wall damage, thrombus formation, and vasospasm.
The animals were killed at 0, 30, or 90 days after the procedure. For the 30 and 90 day time points, follow-up angiography was performed before they were killed to assess dissection, stenosis, thrombosis, and vessel narrowing. Percent stenosis was calculated at termination based on the angiography measurements by the following formula due to the taper of the vessel: (vessel mean diameter (0 day) − termination mean diameter)/vessel mean diameter (0 day)× 100, such that negative values indicate no stenosis.
Histopathologic examination
After the animals were killed, the treated vessels were dissected and processed for histopathologic examination. An independent blinded histopathologist evaluated the following parameters based on a 0–4 point ranking scale (table 1): thrombus, endothelialization, acute and chronic inflammatory cells, fibrin, inner elastic lamina (IEL) disruption, smooth muscle cell (SMC) loss, medial inflammation, medial fibrosis, external elastic lamina (EEL) disruption, adventitial inflammation, adventitial fibrosis, neovascularization, hemosiderin/vessel wall hemorrhage, mineralization, and arterial branch thrombus.
Histological parameter ranking scales
In vitro studies
An in vitro silicon model based on a three-dimensional angiogram of a patient with tortuous anatomy was set up. Blood mimicking solution was circulated through the model at 37°C. The device was tested with an additional pass (3 passes and 6 resheathings) to that indicated in the instructions for use; the instructions for use were followed for all other parameters. For two of the passes an approximately 40 mm proprietary synthetic clot made with xenogeneic blood components was retrieved through a balloon guide catheter. The clot was made in both soft and firm stiffness to simulate clinical variability. The device durability as well as the performance was assessed. For performance, both the immediate flow reperfusion and clot retrieval were recorded.
Results
Angiographic evaluation
Procedure
No procedural adverse events were noted. In particular, there were no embolic events, thrombus formation, or vasospasm. No vessel wall damage was noted angiographically, including no dissections or extravasations. The segments of the vessel proximal and distal to the treatment site were also free of visible injury by angiography.
Follow-up
At day 30, three test samples and four control samples had mild luminal narrowing within the treated segment and two test samples and one control sample had luminal narrowing proximal to this. The proximal luminal narrowing occurred at the precise location of placement of the guide catheter. No luminal narrowing was noted in any of the samples at day 90. Furthermore, at day 30 and day 90 the average vessel diameter had increased for all groups in this juvenile porcine model. Percent stenosis was calculated for the treatment areas for all animals (table 2).
Percent stenosis calculated for the treatment areas for all animals
Device usability
For all passes the test device was rated as equivalent to the control device for delivery through the microcatheter, ability to position the device at the intended target zone, ability to deploy, resheath, reposition, and retrieve through the guide catheter. Additionally, for all passes the device condition showed no visible damage.
Animal health
The animals were in good clinical health after the procedure and throughout the duration of the study, with no device-related or procedural adverse events noted.
Histopathologic evaluation
At 0, 30, and 90 day time points, histopathologic evaluation of treated vessels showed no intraluminal thrombi or vessel wall hemosiderin or hemorrhage. There was no inflammation in the wall of the blood vessels and the IEL and EEL were well preserved in all samples examined.
There was no SMC loss in the animals killed on the day of the index procedure. At 30 days, SMC loss was absent or minimal in all the samples examined. At day 90, SMC loss was absent. Overall there was no difference between devices (figure 1).
Representative Movat Pentachrome images of treated internal thoracic arteries on days 0, 30, and 90 for test samples (A–C) and control samples (D–F).
Endothelial denudation was noted at day 0 in most test and control subjects. This was not associated with hemorrhage, dissection or thrombus formation. At day 30, 64% of the test devices and 56% of the control devices had complete endothelialization and, by day 90, endothelialization continued to increase such that 86% of the test devices and 89% of the control devices had complete endothelialization (table 3). Although neointimal hyperplasia was seen in both test and control subjects, in none of the subjects did this lead to significant cross-sectional narrowing (table 3).
Blinded histopathological scoring
In vitro evaluation
For all of the passes, both the Solitaire 2 4×40 and the Solitaire 2 4×20 devices retrieved the clot into the balloon guide and the devices had no damage. The Solitaire 2 4×40 device had better immediate flow restoration (57/58 attempts) than the Solitaire 2 4×20 device (18/58) with the 40 mm long clot.
Discussion
This in vivo study shows the safety of the Solitaire 2 4×40 device through usability, animal health, angiographic, and histological assessment. No serious adverse events were noted in either the test or control device with the maximum number of passes and resheathings allowed by the instructions for use. Also, no significant differences were noted in angiographic evaluation, device usability, or histopathology.
Endothelial denudation at day 0 was not unexpected and did not differ between the test and control devices. Re-endothelialization continued to progress through day 90 with no negative remodeling attributes observed. Previous animal studies have stated that the deployment of stent retrievers induces intimal injury that is comparable to that of catherization alone, although over a larger area and does not impact vessel integrity.9 Clinical evaluations using MRI have shown that disruption of vessel integrity after stent retriever use is rare.10 Further immunohistochemical analysis of thrombi showed that stent retrievers do not cause relevant intimal damage.11 The longer time points (30 and 90 days) showed almost complete vessel endothelialization and no negative remodeling, which confirms the previous preclinical and clinical evaluations showing the safety of the Solitaire devices.1–5 ,9–11
No significant luminal narrowing on long-term follow-up was noted in the segments of the vessel where the device was deployed and resheathed. There was luminal narrowing in some vessels at the location of the guide catheter tip at the origin of the treated artery. All of the proximal narrowings occurred in the internal thoracic artery (ITA), which had an acute sharp origin from its parent artery leading to difficulty in guide catheter access. We consider that manipulation of the guide catheter was the cause of the narrowing in this location.
The greater length of the Solitaire 2 4×40 device may provide multiple benefits to physicians in optimizing neurothrombectomy treatment of ischemic stroke. It may enable physicians to achieve recanalization with fewer passes, particularly for longer clots that would require more than one pass for complete removal with shorter devices. It may not be practical for most practitioners to determine the exact length of the clot prior to embolectomy, so the longer 40 mm device will be able to address the majority of ischemic strokes. In addition, the greater length of the Solitaire 2 4×40 device may mean that the clot or clot fragments are less likely to dislodge from the device and create distal emboli.
Another technical challenge is the precise placement of the device to ensure that the clot is captured within the working length of the device. This is particularly so in this setting, where patient movement may make precise placement difficult. With the 40 mm length this is likely to be less of a challenge, decreasing the chance of inaccurate deployment caused by patient movement. In vitro data using a blood derived clot substitute showed that the 4×40 device was more effective in immediate recanalization of a 40 mm clot than the shorter 20 mm device.
While preclinical studies provide a good insight into device usage, this study has some limitations. The porcine animal model does not replicate the tortuous intracranial vessels. Also, effectiveness was not assessed in vivo as introducing a xenogenic synthetic clot confounds the histopathology evaluation. Although, theoretically, the longer device should not affect the already well-established recanalization efficacy of the device, this was not proven in our in vivo studies. For these reasons, the in vivo model was paired with the in vitro model to establish the safety and effectiveness of the Solitaire 2 4×40 device.
Conclusion
There were no significant differences in the overall animal health, tissue injury, hemorrhagic or thrombogenic events related to device usage. Based on the comparison at multiple time points, the Solitaire 2 4×40 device is similar in safety and usability to the Solitaire 2 4×20 device. Due to the additional length of the device, the Solitaire 2 4×40 device may in fact provide a number of additional technical benefits in the neurothrombectomy treatment of ischemic stroke.
References
Footnotes
Collaborators Dr Igor Polyakov.
Contributors All authors met the ICMJE guidelines for authorship. JMW conceptualized the project and developed the research plan, wrote the rough draft and edited the manuscript. RJ developed the research plan, assisted in analysis, and contributed and edited the drafts and final manuscript.
Competing interests JMW is an employee of Medtronic plc. RJ is a consultant for Medtronic plc, Medina Medical, and Cerevatech Medical.
Provenance and peer review Not commissioned; externally peer reviewed.