- Saturday, February 03, :56:12 PM - IP Address:

Transcription

1 446 Original communication Multiple stent delivery system Multi-LOC, a new technology for spot-stenting of the femoropopliteal artery proof of concept study in a preclinical large animal model Martin Sigl 1, Oliver Dudeck 2, Johannes Jung 3, Heinz Koelble 4, and Klaus Amendt 1 1 Diakonissenkrankenhaus Mannheim, Mannheim, Germany 2 Hirslanden Private Hospital Group, Radiology Clinic, Zurich, Switzerland 3 Medicut Stent Technology GmbH, Pforzheim, Germany 4 Endoscout GmbH, Freiburg, Germany Summary: Background: A new stent system was studied in a porcine model to evaluate its feasibility for spot-stenting of the femoropopliteal artery. Materials and methods: In a preliminary study in a single pig, handling and mechanical features of the novel multiple stent delivery system were tested. The Multi-LOC system demonstrated great feasibility regarding its pushability, trackability, and crossability. Excellent visibility of the individual stents allowed exact anatomically controlled implantation. In our main study, four to five short Multi-LOC stents (13 mm long) were implanted into the femoropopliteal arteries of six domestic pigs and long (60 to 100 mm) self-expandable nitinol stents were implanted into the same target vessel contralaterally to allow for intraindividual comparison. After four weeks survival under dual antiplatelet treatment, control angiography was performed. The animals were euthanized, stented vessels were explanted, and histologic sections were examined for the presence of neointimal formation. Results: Multi-LOC stents demonstrated no occlusion of the femoropopliteal axis (0 vs. 1 occlusion distal to a control stent), no stent fractures (0 out of 26 vs. 2 out of 6 control stents), and lower percentage diameter stenosis (0.564 ± vs ± 0.089; p = 0.008) and length of stenosis ( ± vs ± ; p = 0.007) compared to a standard control stent, which was similar in total length to the multiple stented artery segment. Histological examination confirmed myointimal hyperplasia underlying in-stent stenosis. Conclusions: The multiple stent delivery system was studied in a porcine model, which demonstrated its feasibility. Preclinical experience revealed favourable results concerning stent fracture, restenosis, and patency of spot-stented femoropopliteal arteries. Keywords: Peripheral artery disease, femoropopliteal artery, spot stenting, multiple stent delivery system Introduction In femoropopliteal lesions of peripheral artery disease, current guidelines recommend an endovascular therapy as the first-line revascularization method for all femoropopliteal TASC A C lesions with high evidence, and percutaneous intervention can also be considered in TASC D lesions [1 3]. Advancing techniques and devices have led to very high procedural success rates at low risk. Despite the many endovascular treatment options for femoropopliteal lesions, little consensus exists regarding the best treatment strategy [4] and optimal endovascular treatment of the superficial femoral and the popliteal artery remains controversial. In case of suboptimal or failed results from balloon dilation with or without drug elution (e.g., residual diameter stenosis > 50 %, flow-limiting dissection, or persistent translesional gradient) bailout stenting is widely accepted. However, unlike any other lower extremity artery, the femoropopliteal artery is exposed to biomechanical stressors including elongation, torsion, flexion, and extension. Also, stents in this segment have created challenges including restenosis and fracture, which are associated with reduction of patency rates [5]. Reduction in restenosis rates after angioplasty remains to be of high interest for the peripheral intervention commu- Vasa (2017), 46 (6), Hogrefe

2 M. Sigl et al., Multiple stent delivery system 447 nity. Furthermore, no stent fractures and less or no disturbance of the overall biomechanical properties in the stented segment seem to be of paramount importance. It appears that this can be accomplished with the leave nothing or little behind strategy combined with a minimized chronic outward force. Therefore, it seems reasonable to limit stent implantation to segments where scaffolding properties are needed after balloon dilatation. As a consequence, less acute and chronic trauma, due to less foreign material in the vessel wall, might have less negative influence on biomechanical properties of the arteries, especially near joints, and better maintain natural vessel movement. In the field of spot-stenting of peripheral arteries, a new multiple stent delivery system is an innovation aiming to achieve a reducing of stent-related complications in femoropopliteal arteries. The idea behind Multi-LOC spotstenting is: 1. to enable stent implantation where scaffolding properties are needed, due to radial stent force similar to other nitinol stents. 2. to minimize damage of biomechanical properties of stented arterial segments by limiting short stent implantation (spot-stenting) to these segments. 3. to enable an exact anatomically-controlled release of single short stents with this new device. 4. to try to achieve a reduction of fractures and lumen loss in the stented segment by myointimal hyperplasia. 5. to optimize procedural device handling and cost-effectiveness, as multiple femoropopliteal segments can be stented with only one device. In this study, the Multi-LOC angioplasty was evaluated in a preclinical in vivo model. Materials and methods Stent device description The multiple stent delivery system (Multi-LOC, medicut Stent Technology GmbH Pforzheim, Germany) is a 6-French coaxial stent delivery system, designed for the treatment of femoropopliteal arteries. With six short stents mounted on one wire-guided catheter, Multi-LOC enables spot-stenting, without changing the delivery system. The 13 mm long self-expandable nitinol stents have a closedcell design, whose radial force and crush resistance is comparable to standard length nitinol stents. Stents used in this study measured 5 mm in diameter. By turning a wheel on the handle at the end of the device, the outer sheath is withdrawn, releasing the stent. A radiopaque tantalum marker at the proximal end of each stent prevents stent jumping and enables exact angiographically controlled stent positioning (Figure 1, Figure 2). Animal study Animal investigations were conducted at the Institute of Medical Technology and Research, Rottmersleben, Germany. All studies were conducted in accordance with the principles of Good Laboratory Practice as specified by national (German Chemicals Act, July 25, 1994, last amendment May 08, 2001) and international (OECD, Paris, 1998) legislation, as well as in substantial compliance with applicable Good Laboratory Practices consistent with the U.S. Code of Federal Regulations, Title 21 Part 58 (21 CFR 58) and in accordance with the guidelines for animal experiments set forth by the competent local animal protection committee of the Sachsen-Anhalt government, Germany. The study was performed in a total of seven healthy domestic pigs, about six weeks old, which were maintained on a standard laboratory diet. After an overnight fast, the swine were premedicated with intramuscular ketamine (20 mg/kg). After endotracheal intubation, general anaesthesia was maintained with mechanical ventilation and inhalation of 0.5 % to 1.5 % halothane. Fentanyl (0.025 mg/kg/h) was administered for analgesia. The six pigs in our main study were scheduled for follow-up angiography and dual antiplatelet therapy, consisting of 100 mg of acetylsalicylic acid and clopidogrel 75 mg per day, which was administered throughout the study, starting two days prior to the procedure. Endovascular procedure and medication regimens In a preliminary study in a single pig, handling and mechanical features of the Multi-LOC stent system were tested. Therefore, we advanced the stent delivery system through diverse kinking arteries of the swine, e.g. from the common femoral artery into the arteries of the forelegs or crossover into the contralateral leg with and without crossover-sheath. Excellent pushability was subsequently confirmed through passage of the system through prior delivered stents into some extremely kinking arteries without any mechanical problems. Passive bending of the legs did not show obvious changes in biomechanical properties of Figure 1. Drawing to illustrate the multiple stent delivery system. The Multi-LOC device is a 6-French multiple stent delivery system with six selfexpanding nitinol stents mounted on one central wire-guiding (0.035 inch) catheter. Each stent is 13 mm in length and developed for spot-stenting of the femoropopliteal artery after balloon dilatation. A proximal radiopaque tantalum marker prevents stent jumping at withdrawal and enables exact stent positioning Hogrefe Vasa (2017), 46 (6),

3 448 M. Sigl et al., Multiple stent delivery system Histology the multiple stented extremity arteries. At the end of the procedure, the animal was euthanized in deep anaesthesia. In our main study, in a total of six domestic pigs, the endovascular procedure (Artis zee, SIEMENS, Erlangen, Germany) was performed by sonographically guided placement of a 6-French (F) sheath into the right common carotid artery, which was attached to pressurized saline infusion, to which 5000 IU of heparin had been given. A 5F multipurpose catheter (Cordis, Warren, USA) was used for catheterisation of the lower limb vessels. In each pig, stents of both types were deployed bilaterally into the femoropopliteal vessels which allowed for an intraindividual comparison. Four to five short Multi-LOC stents (13 mm long) were implanted into the left femoropopliteal arteries with a distance of at least 5 mm between the stents (as mounted on the device). As a control, long (60 to 100 mm) commercially available self-expandable helical nitinol stents (mc-peripheral 6F, medicut Stent Technology Pforzheim, Germany) were implanted into the artery of the contralateral side. All stents were oversized (at least 2 mm) to induce inflammatory vessel wall reaction, due to chronic outward force of the implants. During the intervention, the multiple stent delivery system was evaluated. The technical feasibility endpoint was the deliverability of the Multi-LOC stent system by two experienced interventionalists. Furthermore, the ability of a precise and controlled deployment of the short stents was evaluated. Technical success was defined as acute, haemodynamically uncompromised luminal patency immediately after stent placement as assessed by angiography. For the documentation of the interventional procedure, the following parameters were recorded: catheterization success, rupture/perforation of the artery, thrombosis, or dissection of the artery. Follow-up angiographies After 27 days of survival under medication and free mobility of the pigs, control angiography was performed. For followup angiographies, animals were anesthetized and angiography was performed as described before. The following parameters were evaluated: patency of femoropopliteal arteries at the site of stent implantation and distal to the stented segment, presence of stent fracture, vessel dissection, and in-stent stenosis. Minimal lumen diameter and reference diameter were measured at follow-up angiographies and degrees of diameter stenosis were calculated. Vasa (2017), 46 (6), Figure 2. Stent dimensions: stent-length 13 mm, stent-diameter 5 mm (available from 5 to 8 mm); Stent materials and design: nitinol, self-expanding, closed-cell-design, radiopaque tantalum marker. Animals were euthanized in deep anaesthesia, the vessels were rapidly explanted, and prepared for haematoxylin and eosin staining. Histologic sections were examined for the presence of neointimal formation. Data analysis Categorical variables were expressed as counts and percentages, continuous data were expressed as means with standard deviations. Angiographic continuous variables were compared using paired two-tailed Student s t-tests. Statistical significance was defined at p < Analyses were performed using SPSS software, version 23.0 (SPSS, Chicago, Illinois). Results The Multi-LOC system demonstrated excellent feasibility in a preliminary pig study concerning the following aspects: trackability, crossability, pushability, and visibility of the delivery system. Excellent visibility of the individual stents allowed exact anatomically controlled implantation. The six animals planned for follow-up examination survived the entire study duration of 27 days. At the time of follow-up angiography, occlusion of the femoropopliteal axis was observed in one control limb, distal to the stented segment, while no occlusions were seen in the spot-stented limbs. There was no fracture of Multi-LOC stents (0 out of 26 stents) compared to two out of six control stents. The percent of diameter stenosis was reduced in the Multi-LOC group compared with the stent group and the cumulative length of stenosis in the spot-stented arterial segments were significantly lower compared to control (Figure 3, Table I). Histological examination confirmed myointimal hyperplasia underlying in-stent stenosis. Discussion This preclinical study demonstrates technical feasibility and safety of the multi stent delivery system Multi-LOC. Following the concept of spot-stenting, a major advantage over other commercially available (single-) stent delivery systems lies in the possibility to release up to six stents without changing the delivery system. This is of particular interest, whenever several lesions, due to strong recoil or flow limiting dissection, need (focal) scaffolding (e.g. after balloon angioplasty). The study further demonstrated that exact anatomically controlled implantation of short stents is possible. Advancing techniques have led to very high procedural success rates in short and middle-long femoropopliteal 2017 Hogrefe

4 M. Sigl et al., Multiple stent delivery system 449 lesions. Up to date, it is the long lesions and chronic total occlusions of the femoropopliteal artery that continue to represent a major challenge for currently available endovascular treatment approaches. In case of intermediate and long femoropopliteal lesions, stenting with conventional or drug-eluting (long) nitinol stents ( full metal jackets ) did not show convincing patency rates, but was associated with relevant in-stent-restenosis rates [6 8]. Therefore, on the one hand, non-stent-based approaches ( leave nothing behind strategy) would be particularly Table I. Comparison of Multi-LOC spot-stenting and single long nitinol stent in six domestic pigs Multi-LOC stents single nitinol stent p-value Number of implanted legs of domestic pigs 6 6 Implantation site left femoropopliteal artery right femoropopliteal artery Mean number of stents per leg Stent diameter, mm 5 (oversized) 5 (oversized) Mean total length of stented segment, mm Technical success, % Number of fractured stents (%) 0 of 26 (0) 2 of 6 (33.3) Target vessel occlusion at 27-day follow-up 0 1 (distal to stent) Angiographic restenosis at 27-day follow-up diameter stenosis (%, mean ±SD) cumulative length of stenosis (mm, mean ± SD) 56.4 ± ± ± ± Figure 3. Left: Acute angiographic result after implantation of five Multi-LOC individual short stents (13 mm long each) into the left superficial femoral artery (SFA) of one of six domestic pigs. As a control, a long (80 mm) commercially available helical stent was implanted into the artery of contralateral side. Right: After 27 days survival under dual antiplatelet treatment, control angiography was performed showing stent fracture and high-grade stenosis of the long-stented SFA, not in the spot-stented SFA. The animals underwent histological (staining with haematoxylin-eosin) evaluation of the stented arterial segments (red arrow) Hogrefe Vasa (2017), 46 (6),

5 450 M. Sigl et al., Multiple stent delivery system desirable for long lesions. On the other hand, after balloon treatment, it seems that, with increasing complexity of the lesion, the need for a (at least segmental) mechanical stabilization as a bailout ( spot- ) stenting might become necessary. In primary plain old balloon angioplasty versus drugcoated balloon studies bailout, stenting rate varied from 4 to 34 % for short lesions (mean lesion length 6.1 to 8.1 cm [9 12]); however, real-world registry data trend towards 23 % as a bailout-stenting rate in longer lesions [8]. As one of the largest randomized controlled trials of an endovascular device to treat patients with femoropopliteal lesions of up to 14 cm, Zilver PTX RCT even had a bailout-stenting rate of 50 % in the PTA arm, due to 30 % residual stenosis or a 5 mm Hg mean transstenotic pressure gradient, despite repeated two- to threeminute balloon inflation [13]. Consequently, we assume that particularly the subgroup of patients with complex and strongly calcified lesions and dissections, will often need mechanical treatment modalities, including stent placement, as a bailout. We hypothesize that the combination of balloon dilatation (plain old balloon or drug-coated-balloon angioplasty) and/or atherectomy with (bailout) spot-stenting might be a seminal concept as a treatment modality for long segment diseases. Short stents in actively bended arterial segments did not fracture (0 vs. 5). In former studies, evaluating longer nitinol stents, also with a closed-cell-design, the occurrence of stent fractures was related to the length of the stented segment and stent fracture was associated with a higher in-stent-restenosis and reocclusion rate [5, 14]. The stent fracture rate in TASC C and D femoropopliteal lesions, reported in a post-hoc analysis of the Durability I study, was 8.1 % after one year [15]. The 12-month results of the STELLA PTX registry, with TASC C and D femoropopliteal lesions (mean length 252 mm ± 90 mm) and paclitaxel eluting stents (mean number of stents 2.9), revealed a primary patency rate of 52.5 % with an incidence of 25 % in-stent re-stenosis and a stent fracture rate of 12,5 % on a limb basis and 9 % on a per stent basis [16]. It should also be mentioned that other data report the impact of stent fractures on long-time patency rates and clinical outcome remains less clear [17] or rather low [18]. With increasing complexity of the lesion, the need for a mechanical stabilization due to suboptimal results alter balloon dilation (bailout stenting) conflicts with the midand long-term effects of metal implants (in-stent-restenosis /-occlusion, stent fracture). In particular, concerning the femoropopliteal artery, it seems of central importance to reduce negative influence of metal implants on biomechanical properties of arterial segments. In this context, spot-stenting of the femoropopliteal axis realizes the demands of the community: to leave nothing or as little as possible behind. The Multi-LOC system enables stent implantation, where scaffolding properties are needed while maintaining biomechanical properties of Vasa (2017), 46 (6), the artery to the greatest possible extent. Avoiding full metal jacket lesion coverage in long femoropopliteal lesions might reduce late stent-associated problems. In a similar way, after subintimal recanalization of chronic total femoropopliteal occlusions, better patency rates of spot-stenting compared to long segment stenting point to that direction [19]. Finally, preclinical results of the new multiple stent delivery system showed a 100 % technical success rate without complications. Human studies will have to show its clinical safety and efficacy [20]. Limitations A substantial limitation of this preclinical study is the animal model itself with healthy arteries, as it does not reflect clinical settings. The classic atherosclerotic components with more or less calcified atherosclerotic plaques and stenosis or occlusions seen in humans, due to the underlying disease, are missing. A further limitation of this pilot study is the small sample size (six pigs); therefore, the statistical analysis must be interpreted accordingly. However, in every single swine, the percentage of diameter stenosis was lower in the Multi-LOC-stented legs compared with the long-stented control leg and statistical analysis of the two stent groups revealed significant differences. Histological examination confirmed this result. It was the aim of our study to explore the feasibility with respect to stent fracture, restenosis, and patency of spotstented femoropopliteal arteries in an animal model. The methods applied and the short follow-up period (27 days) do not primarily address safety. Human long-term studies are needed to ensure the safety. Conclusions Maintaining long-term patency after femoropopliteal endovascular intervention remains a challenge, particularly in terms of long lesions. The new multiple stent delivery system was studied in a porcine model, which demonstrated its feasibility. Preclinical experience revealed very favourable results concerning stent fracture, restenosis, and patency at 27 days, compared with longer standard helical nitinol stents. Acknowledgements The authors express gratitude to Dr. Dipl.Ing. Dirk Mahnkopf, Managing Director of the Institute of Medical Technology & Research (IMTR), Rottmersleben, Germany and the German Academy for Microtherapy ( DAfMT ) for angiographic data analysis (O. Dudeck) Hogrefe

6 M. Sigl et al., Multiple stent delivery system 451 References 1. Tendera M, Aboyans V, Bartelink ML, et al. European Stroke Organisation; ESC Committee for Practice Guidelines. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2011;32: Lawall H, Huppert P, Espinola-Klein C, et al. German guideline on the diagnosis and treatment of peripheral artery disease a comprehensive update Vasa. 2017;46: Jaff MR, White CJ, Hiatt WR, et al. An update on methods for revascularization and expansion of the TASC lesion classification to include below- the-knee arteries: a supplement to the inter-society consensus for the management of peripheral arterial disease (TASC II): the TASC steering committee. Catheter Cardiovasc Interv. 2015;86: Shishehbor MH. Endovascular Treatment of Femoropopliteal Lesions: So Many Options, Little Consensus. J Am Coll Cardiol. 2015;66: Scheinert D, Scheinert S, Sax J, et al. Prevalence and clinical impact of stent fractures after femoropopliteal stenting. J Am Coll Cardiol. 2005;45: Dick P, Wallner H, Sabeti S, et al. Balloon angioplasty versus stenting with nitinol stents in intermediate length superficial femoral artery lesions. Catheter Cardiovasc Interv. 2009;74: Schillinger M, Sabeti S, Loewe C, et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. N Engl J Med. 2006;354: Schmidt A, Piorkowski M, Görner H, et al. Drug-Coated Balloons for Complex Femoropopliteal Lesions: 2-Year Results of a Real-World Registry. JACC Cardiovasc Interv. 2016;9: Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med. 2008;358: Scheinert D, Duda S, Zeller T, et al. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-inhuman randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv. 2014;7: Werk M, Albrecht T, Meyer D, et al. Paclitaxel coated balloons reduce restenosis after femoropopliteal angioplasty. Evidence from the randomized PACIFIER Trial. Circ Cardiovasc Interv. 2012;5: Werk M, Langner S, Reinkensmeier B, et al. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation. 2008;118: Dake MD, Ansel GM, Jaff MR, et al; Zilver PTX Investigators. Paclitaxel-eluting stents show superiority to balloon angioplasty and bare metal stents in femoropopliteal disease: twelve-month Zilver PTX randomized study results. Circ Cardiovasc Interv. 2011;4: Yang X, Lu X, Li W, et al. Endovascular treatment for symptomatic stent failures in long-segment chronic total occlusion of femoropopliteal arteries. J Vasc Surg. 2014;60: Bosiers M, Deloose K, Callaert J, et al. Results of the Protégé EverFlex 200-mm-long nitinol stent (ev3) in TASC C and D femoropopliteal lesions. J Vasc Surg. 2011;54: Davaine JM, Querat J, Kaladji A, et al. Treatment of TASC C and D Femoropoliteal Lesions with Paclitaxel eluting Stents: 12 month Results of the STELLA-PTX Registry. Eur J Vasc Endovasc Surg. 2015;50: Iida O, Nanto S, Uematsu M, et al. Influence of stent fracture on the long-term patency in the femoro-popliteal artery: experience of 4 years. JACC Cardiovasc Interv. 2009;2: Davaine JM, Quérat J, Guyomarch B, et al. Incidence and the clinical impact of stent fractures after primary stenting for TASC C and D femoropopliteal lesions at 1 year. Eur J Vasc Endovasc Surg. 2013;46: Hong SJ, Ko YG, Shin DH, et al. Outcomes of spot stenting versus long stenting after intentional subintimal approach for long chronic total occlusions of the femoropopliteal artery. JACC Cardiovasc Interv. 2015;8: Amendt K, Beschorner U, Waliszewski M, et al. First clinical experience with the Multi-LOC multiple stent delivery system for focal stenting in long femoro-popliteal lesions. Vasa 2017; 46: Submitted: Accepted after revision: Published online: Conflicts of interest: Klaus Amendt received lecture fees and travel support from B. Braun Melsungen AG and Biotronik SE & Co. KG. Johannes Jung is the managing director for the manufacture of the Multi-LOC device used. Heinz Kölble is the managing director of Endoscout GmbH, distribution partner of the manufacturer. Dr. Klaus Amendt, Johannes Jung and Heinz Kölble are co-inventors of a patent application for the Multi-LOC device used in this study. Oliver Dudeck and Martin Sigl have no conflicts of interest to declare. Correspondence address Martin Sigl, M.D. Innere Medizin 1 Diakonissenkrankenhaus Mannheim Speyererstr Mannheim Germany siglmartin.1@gmail.com 2017 Hogrefe Vasa (2017), 46 (6),