John Wainwright

Thrombogenicity of flow diverters in an ex vivo shunt model: effect of phosphorylcholine surface modification

Background Flow diverters offer a promising treatment for cerebral aneurysms. However, they have associated thromboembolic risks, mandating chronic dual antiplatelet therapy (DAPT). Shield Technology is a phosphorylcholine surface modification of the Pipeline Embolization Device (PED) flow diverter, which has shown significant reductions in material thrombogenicity in vitro. Objective To compare the thrombogenicity of PED, PED with Shield Technology (PED+Shield), and the Flow-Redirection Endoluminal Device (FRED)—with and without single antiplatelet therapy and DAPT—under physiological flow. Methods An established non-human primate ex vivo arteriovenous shunt model of stent thrombosis was used. PED, PED+Shield, and FRED were tested without antiplatelet therapy, with acetylsalicylic acid (ASA) monotherapy, and with DAPT. Radiolabeled platelet deposition was quantified over 1 hour for each device and total fibrin deposition was also quantified. Results Cumulative statistical analysis showed significantly lower platelet deposition on PED compared with FRED. The same statistical model showed significant decreases in platelet deposition when ASA, clopidogrel, or Shield Technology was used. Direct comparisons of device performances within antiplatelet conditions showed consistent significant decreases in platelet accumulation on PED+Shield relative to FRED. PED+Shield showed significant reductions in platelet deposition compared with unmodified PED without antiplatelet therapy and with DAPT. PED accumulated minimal fibrin with and without Shield Technology. Conclusions In this preclinical model, we have shown that the Shield Technology phosphorylcholine modification reduces the platelet-specific thrombogenicity of a flow diverter under physiologically relevant flow with and without DAPT. We have further identified increased fibrin-driven thrombogenicity associated with FRED relative to PED.

Acute thrombus formation on phosphorilcholine surface modified flow diverters

Purpose Thromboembolic complications remain a limitation of flow diverting stents. We hypothesize that phosphorilcholine surface modified flow diverters (Pipeline Flex with Shield Technology, sPED) would have less acute thrombus formation on the device surface compared with the classic Pipeline Embolization device (cPED). Methods Elastase-induced aneurysms were created in 40 rabbits and randomly assigned to receive cPED or sPED devices with and without dual antiplatelet therapy (DAPT) (four groups, n=10/group). Angioplasty was performed to enhance apposition and create intimal injury for a pro-thrombotic environment. Both before and after angioplasty, the flow diverter was imaged with intravascular optical coherence tomography. The outcome measure was the number of predefined segments along the implant relative to the location of the aneurysm with a minimum of 0 (no clot formation) and maximum of 3 (all segments with thrombus). Clot formation over the device at ostia of branch arteries was assessed as either present or absent. Results Following angioplasty, the number of flow diverter segments with clots was significantly associated with the flow diverter (p<0.0001), but not with DAPT (p=0.3872) or aneurysm neck size (p=0.8555). The incidence rate for clots with cPED was 1.72 times more than with sPED. The clots on the flow diverter at the location corresponding to side branch ostia was significantly lower with sPED than with cPED (OR 0.180; 95% CI 0.044 to 0.734; p=0.0168), but was not associated with DAPT (p=0.3198). Conclusion In the rabbit model, phosphorilcholine surface modified flow diverters are associated with less thrombus formation on the surface of the device.

Solitaire FR revascularization device 4×40: safety study and effectiveness in preclinical models

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.

Phosphorylcholine surface modified flow diverter associated with reduced intimal hyperplasia

Background Optical coherence tomography (OCT) is a high-resolution, intra-vascular diagnostic technique widely used for the characterization of vascular pathologies and optimization of stent implantation during percutaneous coronary intervention. OCT was used to investigate the in vivo vascular response to a new phosphorylcholine surface modified flow diverter (sPED). Methods In an in vivo rabbit aneurysmal model, we used two different types of flow diverters (classic Pipeline – cPED; and sPED) with or without dual antiplatelet therapy (four groups, n=10 per group). OCT cross-sectional area measurements were compared with histology in all animals. Neointimal hyperplasia (NIH) ratio was compared between OCT and histology at five different levels for each stent. The severity of NIH was also compared between the different stents, antiplatelet protocols, and vessel locations. Results OCT was used to calculate in-stent hyperplasia in 227 different locations corresponding to histology sections. OCT measurement strongly correlated with gold standard histology (r2=0.83; slope=0.988; P<0.0001). sPED had significantly less in-stent NIH than non-treated flow diverters (mean percent of lumen reduction 5.7% for sPED versus 8.9% for cPED; P<0.0001). The NIH ratio was slightly higher with dual antiplatelet therapy (DAPT) (NIH ratio=7.9% with DAPT versus 6.8% without DAPT; P<0.05). Complete and near complete occlusion rates of the aneurysms were not different with the cPED or sPED. Conclusion OCT is a promising technique for immediate and long-term evaluation of flow diverter stent treatments. In an animal model, phosphorylcholine surface modified flow diverters induces less NIH after stent implant without reducing aneurysm occlusion rates.

Communicating malapposition of flow diverters assessed with optical coherence tomography correlates with delayed aneurysm occlusion

Background Optical coherence tomography (OCT) is a high resolution intravascular imaging method that allows visualization of flow diverter struts and the vessel wall. In this study, malapposition of the flow diverter that continues into the neck of the aneurysm, named communicating malapposition (CM), was investigated as a potential factor for delayed aneurysm healing. Methods 40 New Zealand White rabbits underwent elastase induced aneurysm creation, and were subsequently assigned to one of four treatment groups based on flow diverter type and administration of antiplatelet therapy. All animals underwent post device deployment balloon angioplasty and subsequent OCT to assess device/vessel apposition. The incidence of CM seen on OCT was assessed with a binary scoring system: 0–CM present; 1–CM absent. At 30 days, DSA was acquired to assess aneurysm healing. Aneurysm healing on terminal DSA was measured using a previously developed 5 point scale, with a score of 3 or 4 considered a positive outcome. Results All animals were grouped into a single cohort for analysis as no difference in the rate of CM or healing was seen in the four treatment groups. Significant interaction between the absence of CM and a positive outcome was confirmed by Fisher exact test (P=0.0034). Angioplasty was shown to treat 33% of the cases of CM seen at implant, and these treated cases overwhelmingly had a positive outcome (P<0.001). Conclusion The use of OCT to assess CM of flow diverters has been shown to be predictive of the 30 day healing rate of an animal model of aneurysms.

Preliminary outcomes of single antiplatelet therapy for surface-modified flow diverters in an animal model: analysis of neointimal development and thrombus formation using OCT

Objective To evaluate the rate of neointimal development and thrombus formation of surface-modified flow diverters in single antiplatelet therapy (SAPT) using optical coherence tomography (OCT) in a porcine model. Methods We divided 10 experimental pigs into two groups. One group (n=6) received dual antiplatelet therapy (DAPT) and the other group (n=4) received SAPT. Four stents (two per carotid artery) were implanted in both groups. The stents used were the Pipeline Flex embolization device (PED Flex), Pipeline Flex with Shield technology (PED Shield), and the Solitaire AB stent. All animals underwent weekly angiography and OCT. The OCT data were analyzed using the following measurements: neointimal ratio ((stent – lumen area)/stent area), stent-coverage ratio (number of stent struts covered by neointima/total stent struts), and the presence or absence of thrombus formation per 1 mm cross-section. Results PED Flex and Shield in the SAPT group had higher neointimal ratios than in the DAPT group (P<0.001, respectively). In the DAPT group, the speed of endothelial growth on day 7 in the PED Shield group was higher than that in the PED Flex group (P<0.001). In the SAPT group, PED Flex demonstrated significantly more thrombus formation on day 7 than PED Shield (P<0.001). Conclusions The PED Shield stent showed faster endothelial growth than the other devices and comparable neointimal volume. There was significantly less thrombus formation on PED Shield than PED Flex when using SAPT in a porcine model.

Thrombogenicity assessment of Pipeline Flex, Pipeline Shield, and FRED flow diverters in an in vitro human blood physiological flow loop model: In vitro thrombogenicity of flow diverters

Abstract Endovascular treatment of intracranial aneurysms with endoluminal flow diverters (single or multiple) has proven to be clinically safe and effective, but is associated with a risk of thromboembolic complications. Recently, a novel biomimetic surface modification with covalently bound phosphorylcholine (Shield Technology™) has shown to reduce the material thrombogenicity of the Pipeline flow diverter. Thrombogenicity of Pipeline Flex, Pipeline Shield, and Flow Redirection Endoluminal Device (FRED) in the presence of human blood under physiological flow conditions—in addition to relative increase in thrombogenicity with multiple devices—remains unknown and was investigated here. Thrombin generation (mean ± SD; μg/mL; thrombin–antithrombin complex or TAT) was measured as FRED (30.3 ± 2.9), Pipeline (13.9 ± 4.4), Pipeline Shield (0.4 ± 0.3), and negative control (no device; 0.1 ± 0.0). Platelet activation (mean ± SD; IU/μL; beta‐thromboglobulin or βTG) was measured as FRED (148 ± 45), Pipeline (92.8 ± 41), Pipeline Shield (16.2 ± 3.5), and negative control (2.70 ± 0.16). FRED was significantly more thrombogenic than Pipeline and Pipeline Shield (p < 0.05) for TAT. Additionally, Pipeline Shield had significantly lower TAT and βTG than the other devices tested (p < 0.05) and these were comparable to the negative control (p > 0.05). TAT and βTG scaled proportionately with multiple Pipeline devices (N = 6) but was unaffected by multiple Pipeline Shield (N = 6) devices—the latter being statistically similar to negative control (p > 0.05).

O-013 Communicating malapposition and its impact on aneurysm healing

Introduction/Purpose Malapposition has a negative correlation to aneurysm healing1. We examine the influence of malapposition communicating into the aneurysm, and the effect of malapposition incidence at any position along the parent artery on healing. We define communicating malapposition (CM) as any malapposition along the aneurysm neck (figure 1). We hypothesize that CM seen on optical coherence tomography (OCT) results in lower aneurysm occlusion rates after 30 days, and that malapposition at any other point along the parent artery has no effect. Materials and Methods Fifty New Zealand White rabbits underwent elastase-induced aneurysm creation.2 After 21 days, animals were randomly implanted with: Pipeline Embolization Device (PED; n=20); Pipeline Embolization Device with Shield technology (SHIELD; n=20); or, Flow Reduction Endoluminal Device (FRED; n=10). Five days prior to implantation, 10 animals from each group began dual antiplatelet therapy (DAPT; aspirin/clopidogrel 10 mg/kg each) which was continued daily until the 30 day terminal endpoint. All animals were used for statistical analysis in this study since the influence of DAPT yielded no significant impact on rates of aneurysm occlusion. All animals underwent post-deployment OCT to assess device/vessel apposition. At 30 days, DSA and OCT were acquired to assess aneurysm healing. The incidence of CM was assessed on a binary scoring system: 0 CM present; 1 CM absent. Aneurysm healing on DSA was measured using a previously developed 5-point scale3 – a score of 3 or 4 (neck remnant or complete occlusion) was considered a positive outcome. Separately, the presence of malapposition distal to the aneurysm neck was measured on a similar binary scale: 0- malapposition seen distal to aneurysm; 1 – no malapposition observed. A Fisher’s exact test was used to show significance. Abstract O-013 Figure 1 (A) OCT slice of aneurysm neck showing no communicating malapposition – final DSA occlusion score=4; (B) OCT slice of aneurysm neck showing communicating malapposition (arrow) – final occlusion score=1 Results Overall positive aneurysm outcome at 30 days was seen in 50% of cases (n=25), with no CM seen in 80% of those cases (n=20). Significant interaction between no CM and positive outcome was confirmed by a Fisher exact test, p=0.0014. When malapposition incidence along the parent artery distal to the aneurysm was compared to positive outcome, no significant interaction was found, p=0.776. Conclusion OCT shows potential in serving as an indicator of poor outcome in the presence of CM during device implant. From these data, absence of communicating malapposition is strongly associated with early aneurysm occlusion, whereas malapposition distal to the aneurysm showed no effect on rates of aneurysm healing. References . AJNR 2016;37(11):2087–91. 2. AJR. 2000;174:349–354. . AJNR 2012;33(10):2004–9. Disclosures R. King: None. O. Brooks: None. E. Langan: None. M. Marosfoi: None. F. Clarençon: None. T. Tamaura: None. J. Wainwright: 5; C; Medtronic Neurovascular. M. Gounis: 1; C; Medtronic Neurovascular. A. Puri: 1; C; Medtronic Neurovascular.

O-029 Acute Thrombus Formation on Flow Diverters Imaged In Vivo Using Optical Coherence Tomography

Introduction In vitro studies have shown that Pipeline Embolization Device+Shield Technology (Shield) with a surface modification of a 3 nm thick modified phosphorylcholine is less thrombogenic.1 We hypothesize that Shield has less thrombus formation in vivo as compared to Pipeline Embolization Devices (PED) regardless of dual antiplatelet therapy (DAPT). Methods Forty rabbits with elastase induced aneurysms were randomly assigned to receive a Shield or PED. For each device, half of the animals received DAPT. In each of the four groups, 10 animals were enrolled for a period of 30 days. Herein, we report on 32 animals that have reached the study endpoint to date. Animals that received DAPT (10 mg/kg each of aspirin and clopidogrel) were started a 5 days prior to implant and continued until the endpoint at 30 days. At the time of implant optical coherence tomography (OCT, Dragonfly, St Jude) was performed before and after angioplasty, and repeated at terminal follow-up. Thrombus formation was assessed at 4 locations along the implant (distal end, at the level of the vertebral artery, at the aneurysm neck, and at the proximal end) as present or absent. Aneurysm occlusion was assessed on digital subtraction angiography after 30 days and according to the scale of Darsaut et al.2 Results Baseline characteristics (e.g., aneurysm size, neck size, parent vessel diameter) were not different between the four groups (p > 0.1). Animals receiving DAPT had a significant reduction in PRU values (69 ± 28 vs 247 ± 41, p < 0.0001) and no change in ARU (649 ± 31 vs 659 ± 9, p > 0.05). The Shield was more likely to have no thrombus or thrombus only at one of the four locations as compared to PED (OR 0.10 95% CI 0.02–0.56, p = 0.01). There was no difference in thrombus at the four locations as a function of DAPT (p > 0.05). There was no dependence on aneurysm occlusion on the device used or PRU value; however, achieving complete or near complete occlusion was negatively and marginally correlated with the aneurysm neck size (Spearman’s rho = 0.314; p = 0.049). Conclusion The hypothesis that Shield technology reduces acute thrombus formation regardless of DAPT has been confirmed in vivo using OCT.Abstract O-029 Figure 1 Top panel shows thrombus formation on the PED surface (arrows) absent in the Shield device (bottom panel), after implantation. Left images taken at the origin of the vertebral artery, and right images are acquired proximal to the aneurysm References 1 G Girdhar et al. J Thromb Thrombolysis 2015;40:437–4432. 2 TE Darsaut, et al. AJNR. 2012;33:2004–2009 Disclosures M. Marosfoi: None. E. Langan: None. S. Vedantham: None. F. Clarençon: None. R. King: None. J. Wainwright: 5; C; Medtronic Neurovascular. M. Gounis: 1; C; Medtronic Neurovascular. A. Puri: 1; C; Medtronic Neurovascular. 2; C; Medtronic Neurovascular.