THEMED ARTICLE y Vascular Disease

Review

Bioresorbable scaffolds in peripheral arterial disease Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by University of Pennsylvania on 01/19/15 For personal use only.

Expert Rev. Cardiovasc. Ther. 12(4), 443–450 (2014)

George Kassimis1, Stavros Spiliopoulos2, Konstantinos Katsanos3, Dimitrios Tsetis4 and Miltiadis E Krokidis*5 1 Oxford Heart Centre, Oxford University Hospitals NHS Trust, Oxford, UK 2 Departmentof Radiology, Patras University Hospital, Rio, Greece 3 Department of Radiology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK 4 Department of Radiology, Heraklion University Hospital, Medical School of Crete, Heraklion, Greece 5 Department of Radiology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, CB2 0QQ, Cambridge, UK *Author for correspondence: Tel.: +44 122 334 8920 Fax: +44 122 321 7847 [email protected]

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The risk of in-stent restenosis has been dramatically reduced with the use of thin-strut nitinol and balloon-expandable drug-eluting stents in the peripheral arterial territory. However, the presence of a permanent endovascular device is linked to a series of events that can lead to restenosis and stent thrombosis. Significant advances in the technology of bioresorbable materials have delivered the potential for fully bioresorbable scaffolds (BRS), which are able to mechanically support the artery wall and elute an anti-restenotic drug for a predetermined time period after which the scaffold becomes fully absorbed into the vascular wall. Currently, several vascular BRS are available, undergoing evaluation either in clinical trials or in preclinical settings. The aim of this review is to present the new developments in BRS technology, describe the mechanisms involved in the resorption process, and discuss the current and potential future prospects of this innovative treatment option for peripheral arterial disease. KEYWORDS: below-the-knee arteries • bioresorbable vascular scaffold • design, femoropopliteal axis • peripheral arterial disease

Endovascular treatment of obstructive coronary and peripheral arterial disease (PAD) has dramatically evolved in the last years to include the use of various innovative balloon and stent technologies in order to achieve superior clinical outcomes. Bare metal stents, commonly used both as primary and as bailout options for the management of PAD, are permanent devices, which offer high technical success rates. In order to improve long-term outcomes, drug-eluting stents (DES) using various types of cytostatic (-olimus family) or cytotoxic (paclitaxel) agents have been also used in the peripheral arterial bed [1]. However, recent evidence suggests that the permanent presence of a metallic prosthesis within the vascular wall promotes inflammation, alters flow dynamics, abolishes vascular reactivity and limits the potential for maximal vasodilation [2,3], possibly contributing to malapposition of stent struts, accelerated neo-atherogenesis within the stented segment and perhaps stent thrombosis (ST) [4–6]. When combined with optimal medical therapy, bioresorbable scaffolds (BRS) could provide an alternative treatment modality to traditional metallic stents. Bioresorbable vascular scaffold (BVS) provide the necessary structural support to the diseased arterial segment for the first year after implantation and are 10.1586/14779072.2014.897226

then fully resorbed within 18–24 months into the vascular wall. This could permit the ‘restoration’ of vasomotor function, and physiological responses to stress/exercise and completion of the vascular response to stenting, without the hazard of subsequent inflammation, accelerated atherosclerosis and/or thrombosis [7]. Currently, many different scaffolds have been or are being developed by various manufacturers. This review summarizes the rationale for development of BRS, the available clinical and research data and describes the potential future prospects of this innovative therapy for PAD. What is the reason for vascular stenting in PAD?

Plain old balloon angioplasty (POBA) can be effective in a variety of lesions but is unpredictable, due to its tendency to create eccentric, potentially occlusive, dissection flaps and the impact of early elastic vessel recoil immediately or within the first few hours following the procedure. As a result, immediate technical success is not always guaranteed, while suboptimal angioplasty requires bailout stenting. Moreover, mid-term restenosis after POBA is frequent due to adverse constrictive vessel remodeling occurring over the first few

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months following the procedure. Implantation of a permanent stent offers the opportunity to optimize acute lumen gain by preventing early recoil and also to restrain dissection flaps, creating a regular tubular vessel lumen. The permanent mechanical properties of metal stents also prevented the constrictive effect of negative vessel remodeling. However, an increased neointimal hyperplastic reaction attributed to the presence of the metallic scaffold within the vessel is noted, while the period after stent implantation (before the completion of the healing process) is associated with an increased acute thrombotic risk and clinically significant mid-term restenosis requiring reintervention [8]. The use of anti-proliferative drugs applied directly or through polymers to the stent mesh, which is the basis of DES technology, has significantly improved the longterm gains of stenting, by reducing the volume of neointima generated by the continuous vessel-wall stimulation of the metallic stent [9,10]. However, despite the proven efficacy in reducing restenosis and the need for clinically driven target lesion re-interventions, DES implantation necessarily attenuates the vessel’s healing processes, resulting in delayed and sometimes incomplete endothelialization, with an increased risk of neo-atherosclerosis and possibly late restenosis or occlusion leading to clinical relapse [11–16]. One possible fate of the dilated but caged lesion is an intra-stent lumen reduction by intra-stent neointimal tissue growth, even if the immunosuppressive drug slows down or actually postpones the phenomenon. This neointimal tissue may in turn degenerate and become atherosclerotic, up to the point where it will develop its own vulnerable plaque and rupture inside the cage of the stent [11,17,18]. In the ambit of coronary disease, recent advances in DES technology with the use of either a bioresorbable or compatible polymer reduced the occurrence of ST but still failed to address other limitations of permanent metallic DES, namely the potential risk of neo-atherosclerosis and late ST, preclusion of surgical revascularization and the distorted vessel-wall physiology caused by the presence of a foreign body within the artery [19,20]. Bioresorbable scaffolds: the evolution of endovascular treatment in PAD?

From the very early days, the ‘interventionalists’ have been envisaging of a transient scaffold that would disappear ‘after the job has been done’ [21]. Percutaneous intervention with BRS has potential advantages over the current generation metallic bare metal stents/DES technology. These mainly include reduction of the potential clinical relapse because after bioresorption there is expected to be no further stimulus for instent restenosis (ISR), such as uncovered stent struts or durable polymer. The absence of these foreign materials may also reduce the requirements for long-term dual antiplatelet therapy, resulting in the potential reduction in associated bleeding complications [22,23]. BRS are particularly suitable for peripheral vascular anatomy where metallic stents are prone to deformation, crushing and 444

fractures, frequently seen in the femoropopliteal axis and the infrapopliteal arteries [24,25]. Furthermore, BVS can obviate some of the other problems associated with the use of permanent metallic stents such as the covering of side branches and the presence of allergy to metal [26,27]. More importantly, these scaffolds permit future percutaneous and surgical revascularization strategies without the hindrance of previous permanent metal prostheses. Finally, BRS offer the possibility for radiation-free, non-invasive magnetic resonance angiography imaging follow-up due to the absence of artifacts caused by the metallic stent mesh [28,29]. There are other more complex biological interferences resulting from metallic caging. In the infrapopliteal arteries, stiff metallic stents alter vessel geometry and these long-term flow disturbances and chronic irritation contribute to restenosis, without mentioning strut fractures or deformations, related to ISR [25,30]. From that point of view, the initial superior conformability and flexibility of the newly developed drug-eluting BVS can, at an early stage, contribute to less change in vessel geometry and biomechanics [31]. Furthermore, these scaffolds provide all the benefits of drug elution (e.g., less restenosis leading to superior clinical results), and could contribute in less late stent fractures since at late time points, the struts will have disappeared and permit a future surgical by-pass treatment necessary in case disease relapses. There is increasing recognition that neo-atherosclerosis occurring within contemporary metallic stents [11] may be responsible for the continuing requirement for long-term repeat revascularization reported 2–5 years after device implantation [32–34]. The ultimate therapeutic goal is that after scaffold resorption, biologically active atheromatous plaque may be ‘healed’, permitting truly normal vascular function after percutaneous intervention. It is shown that the scaffolding properties of the bioresorbable polymer offer the advantages of gradual load transfer of mechanical strain to the healing tissue so that the healthy compliance of the vessel can be progressively restored long term [34]. Gradual exposure of cellular structures within the vessel wall to normal physiological stress conditions has a positive effect on cellular organization and function. After bioresorption of the polylactide, the void previously occupied by the struts is filled progressively by proteoglycan and collagen. The full disappearance of the struts, which has been documented by ultrasound, optical coherence tomography, histology and pharmacologically induced dynamic vasomotion, suggested that the vessel wall will ultimately sense again the mechanical strains of pulsatile blood flow, which is an important stimulus for the cell biology of the vessel wall [20,22]. Limitations & challenges Flexibility & radial strength

The evolution of metallic stent design has resulted in the current generation of high performance devices, which vascular scaffolds may struggle to compete with, at least initially. Lowprofile new-generation nitinol stents dedicated for femoropopliteal artery lesions are highly flexible; a requisite for the specific Expert Rev. Cardiovasc. Ther. 12(4), (2014)

Bioresorbable scaffolds in peripheral artery disease

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anatomical location susceptible to a variety of mechanical forces, while infrapopliteal balloon expandable metallic stents can be dilated to a range of diameters without losing radial strength. Moreover, PAD usually affects elderly and diabetic patients with hard calcified stenoses, which challenge current BVS devices. It is unlikely that the early generations of scaffolds will be efficient in treating challenging ‘real-life’ lesions and therefore every effort has to be made to produce a BVS that could address these problems. Preparation of the lesion

With the current BVS technology, appropriate and intense lesion preparation is paramount, with proper balloon predilation and if calcified blocks have to be treated then the use of atherectomy or high-pressure or cutting balloons is obligatory. Proper vessel sizing & scaffold apposition

As the expansive possibilities of BVS material are more limited compared with the standard metal stents, proper vessel sizing with the use of quantitative vessel analysis or more accurate intravascular imaging and especially frequency domain optical coherence tomography, before and after scaffold apposition, should be considered [35]. Stent fracture

Another potential challenge of this new technology is strut/ stent fracture. Unlike metal stents, the polymeric devices have inherent limits of expansion and can break as a result of overdilatation, which practically should be avoided by respecting the nominal size of the scaffold. However, metallic stents are also prone to deformation and fractures particularly in the femoropopliteal axis, infrapopliteal arteries and BRS and are expected to respond better than polymeric devices. No fracture of BRS is reported in the published clinical trials and restenosis rate is not related to scaffold fractures. Nevertheless, there are no fatigability preclinical studies with BRS and in the clinical trials the scaffolds were used for less challenging lesions, therefore, their behavior in the fatigue of the abductor canal is still unknown. Initial biomechanical performance

Current stents have evolved to provide deliverability, sustained luminal area gain with minimal recoil, good wall coverage minimizing plaque prolapse and minimal longitudinal shortening. Stainless steel has been replaced by a variety of alloys such as nitinol, cobalt chromium and platinum chromium. This change has allowed thinner struts with enhanced flexibility. It is illustrative to note that in order to have the same mechanical strength as existing metal stents, magnesium scaffolds need to be 150% larger in cross-section and poly-L-lactic acid (PLLA) 240% that of cobalt chromium, as a consequence of their relative mechanical properties [36]. Thus, providing sufficient mechanical strength in a deliverable device is a significant challenge. This issue was illustrated by the initial iteration of informahealthcare.com

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the ABSORB BVS (Abbott Vascular, Santa Clara, CA, USA), which showed insufficient radial strength with evidence of acute recoil of 16.6% [37]. Changes in scaffold design have demonstrated a significant improvement in acute performance characteristics. Beneficial modification of the vascular healing process

As outlined, the process of healing and stabilization of the plaque after DES placement takes months to be completed. Therefore, the ideal scaffold must exhibit preserved mechanical properties for some months following implantation, before beginning degradation. Sustained device performance during resorption allowing restoration of normal vascular function

Ideally, the process of resorption should be completed without strut fracture or embolization, ultimately leaving no evidence of the scaffold. The process must also be non-toxic and as biologically ‘inert’ as possible to prevent additional late vascular inflammation. As the device starts to degrade, it begins to lose radial strength; however, the mechanical strength of a bioresorbable material and its in vivo resorption do not have a linear relationship. Therefore, for scaffolds to be clinically valuable, the initiation of the loss of mechanical performance must be predictable, particularly as changes in the mechanical properties of the device will occur with minimal change in mass, and as a result not even intravascular imaging will be able to depict any possible change in its mechanical properties. Cost

The BVS are still significantly expensive for everyday clinical practice and much effort should be made to reduce the current price for being cost-effective in the near future. BRS design

The concept of a BRS is to provide equivalent performance to existing metallic stents but deliver complete resorption of the scaffold, facilitating complete vessel healing with restoration of vascular function. As a result of that, potential materials for scaffold manufacture must have acceptable acute biomechanical performance, provide beneficial modification of the vascular healing process and deliver sustained device performance during resorption. Currently, there are four materials used in BVS: lactide polymers, particularly PLLA, magnesium, polyanhydrides (salicylic acid and adipic acid) and polycarbonates (amino acids, e.g., tyrosine). • Most of the currently available BRS (e.g., Igaki-Tamai scaffold, ABSORB scaffold) are composed of PLLA. The catabolism of the PLLA incorporates several stages, with the resultant degradation of the polymer to carbon dioxide and water [38]. The first phase includes hydration of the polymer, which starts to absorb water from the surrounding tissue. The absorbed water catalyzes a chain scission at an ester bond, resulting in the degradation of the polymer. Gradually, 445

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the polymer loses its cohesive strength and fragments into segments with a lower molecular weight. Polymer chains become progressively hydrophilic through their hydrolysis to shorter lengths. The outcomes of the abovementioned process are hydrophilic monomers that can be phagocytized by macrophages. After phagocytosis, the soluble monomer (L-lactate) is catabolized to pyruvate and ultimately to carbon dioxide and water through the Krebs cycle [39]; • Another material used in BRS to date is magnesium, the only metal that has been implemented in BVS technology (absorbable metallic stent [AMS]). A limitation of magnesium is its fragility; thus, it has been mixed with several elements such as zirconium, yttrium and other rare earth metals to provide it with adequate radial strength. An advantage of the AMS is the fact that the degradation of the magnesium alloy to inorganic salts triggers only a minor inflammatory response, and creates an electronegative charge that has been shown to have an anti-thrombogenic effect [39]; • The IDEAL BVS is the only scaffold that incorporates salicylate directly into the polymer chain [39]; • Tyrosine polycarbonate is another polymer used in BRS technology (REVA BVS). Its catabolism includes hydrolysis of the polymer to carbon dioxide and iodinated-desaminotyrosyl-tyrosine ethyl esters, which are further hydrolyzed to ethanol and iodinated-desaminotyrosyl-tyrosine. Cleavage of the latter results in tyrosine molecules and iodinated-desaminotyrosine, which are finally catabolized into carbon dioxide and water through the Krebs cycle [39]. Initial clinical experience with BVS in PAD

Clinical experience with BRS in PAD is very limited as only few trials investigated this novel technology in the femoropopliteal and infrapopliteal arteries. The first dedicated superficial femoral artery (SFA) BVS was the balloon-expandable bare Igaki-Tamai stent (Remedy, Kyoto Medical Planning, Kyoto, Japan), a monofilament PLLA helical pattern coil, available in a maximum diameter of 5 mm, expandable to 7 mm and lengths of 36 and 78 mm compatible with a 7 Fr arterial sheath. Balloon dilatation was necessary to optimize vessel-wall apposition. The Igaki-Tamai stent was investigated in the PERSEUS trial, which included 45 patients with de novo SFA lesions less than 6 cm in length. [40]. The authors reported a 100% technical success rate with no serious adverse events. Angiographic binary restenosis was 30% at 6 months followup, while the primary-assisted patency rate was 91% at 9 months follow-up. However, these optimistic short-term results were not validated as larger cohorts suggested a less than 50% 1-year primary patency rate. [40,41]. Recently, the initial results of a multicenter, non-randomized registry [42] investigating the performance of the REMEDY PLLA semi-selfexpandable BRS (Kyoto Medical Planning) were reported [43]. The study is not completed and until today 100 patients with symptomatic Trans Atlantic Inter-Societal Consensus II A and B up to 8 cm lesions (20% occlusions) of the SFA have been TM

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enrolled. The mean lesion length was 35 mm (2–80 mm) and the investigators achieved immediate technical success in 98% of the cases. The reported 6 months primary patency and assisted primary patency rates were 70.2 and 88.5%, respectively using Doppler ultrasound, while clinically driven target lesion revascularization was performed in 17.9% of cases. Finally, the early 30-day outcomes of the ESPRIT I prospective, single-arm, multicenter trial were announced in LINC 2013, Leipzig, Germany, evaluating the Esprit BVS in symptomatic SFA or iliac atherosclerotic lesions. The study included seven cites in Europe, which enrolled 35 patients suffering from Rutherford 1–3 disease and lesions that can be treated with a single 6 mm  58 mm BRS. Initial results demonstrated 100% acute procedural success, no clinical end point events or BRS thrombosis. There was no acute scaffold recoil according to angiography and no binary restenosis was detected on duplex at 30 days follow-up, while patients with Rutherford 3 disease were reduced from 57 to 0% [40]. The only BRS used for the treatment of infrapopliteal arterial disease is the AMS balloon-expandable stent (Biotronik, Berlin, Germany), which is made of magnesium, zirconium, yttrium and rare earth elements. The AMS was investigated in the ambit of a randomized controlled trial (The AMS INSIGHT trial), which included 117 patients with critical limb ischemia (CLI) treated with either balloon angioplasty or AMS stenting in focal infrapopliteal lesions up to 15 mm [44]. However, the angiographic primary patency rates in the AMS group were significantly lower than in the angioplasty group (32 vs 58%; p = 0.013) at 6 months follow-up, as demonstrated by core lab quantitative vessel analysis. The authors reported that these disappointing outcomes should be attributed to very fast resorption (nearly fully resorbed after 4 months) leading both to elastic recoil and ISR and conclude that a second-generation AMS is under development, with optimization of the magnesium alloy and the stent design in order to result in a longer degradation time and increased radial force to improve outcomes. Moreover, the authors state that stent sizes should be better adapted to the characteristics of peripheral lesions [44]. BRS that have been used in clinical trials for the management of PAD are summarized in TABLE 1. The results of the ongoing STANCE trial [45] have not yet been reported. TM

Expert commentary

Dramatic advances in bioresorbable materials technology have delivered the potential for fully resorbable scaffolds, which are able to mechanically support the artery for a predetermined time period. This forward leap in technology is probably greater than the remaining challenge of fine-tuning the design of these scaffolds to match the initial performance and handling characteristics of conventional metal stents. Potential advantages of BRS compared with conventional balloonexpandable metallic stents are superior conformability and flexibility, which minimally modify the distribution of tissue biomechanics leading in preservation of the normal vessel Expert Rev. Cardiovasc. Ther. 12(4), (2014)

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2.5–3.5 mm/12, 18, 28 mm 150 mm

† ESPRIT bioresorbable vascular scaffold is neither approved nor available for sale. PLLA: Poly-L-lactic acid; OTW: Over the wire.

24 Abbott Vascular, CA, USA ABSORB biovascular scaffold

Poly-L-lactide/8.2 mg/mm everolimus on matrix of poly-D,L-lactide

4 Fr/0.014´/rapidexchange balloon expandable

3.0 and 3.5 mm/10, 15, 20 mm 5 Fr sheath/0.014´´/lowcompliance rapidexchange balloon expandable 4 Magnesium alloy/no Biotronik, Berlin, Germany Absorbable metallic stent -1 Biotronik magic stent

Infrapopliteal

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165 mm

6 /58 mm n/a 24 ESPRIT

TM



Abbott Vascular, CA, USA

Poly-L-lactide/100 mg/cm2 everolimus on matrix of poly-D,L-lactide

0.035´´ OTW/balloon expandable

5.0–8.0 mm/36 mm and 5.0–6.0 mm/78 mm 0.24 mm 7 Fr sheath/0.035´ OTW/ semi self-expandable ENDOCOR, Hamburg, Germany and Kyoto Medical Planning, Co Ltd, Kyoto, Japan REMEDYTM biodegradable peripheral stent

14–18

0.24 mm 7 Fr sheath/0.035´ OTW/ balloon expandable 24 PLLA/no Kyoto Medical Planning, Co Ltd, Kyoto, Japan Igaki-Tamai biodegradable peripheral stent

Iliac/femoropopliteal

PLLA/no

5.0–8.0 mm/36 mm

Available diameters/length Strut thickness Deployment Bioresorption time (months) Composition/drug elution Company Name

geometry. However, the treatment of challenging areas like the abductor canal or long lesions remains a challenge for all types of devices. Moreover, bioresorption could lead in late luminal gain and late positive remodeling, instead of late luminal loss detected after conventional permanent stenting. Additionally, resorption of the foreign material and restoration of endothelial function could reduce the risk of ISR or thrombosis, while other problems associated with permanent stenting can be overcome such as side branch ‘jailing’, stent protrusion/ coverage at bifurcation lesions and the inability to perform surgical by-pass at the stented segment [46]. However, it remains to be determined whether BRS can truly restore vascular integrity and function without compromising radial strength and deliverability. Specifically, in the SFA and popliteal arteries where the variety and intensity of the mechanical forces applied create a hostile environment for any endovascular implant metallic or not, BRS must perform equally with the highly effective newgeneration nitinol stents both in flexibility and radial strength, two features combined with the advantages of mid-term scaffold resorption might improve vessel patency and therefore clinical outcomes. Of note, scaffold resorption is a benefit for all cases of clinical relapse owned to chronic total occlusions as the absence of a metallic stent facilitates both endovascular subintimal re-intervention and leave room for surgical by-pass. Recently, the development of a self-expandable, drug-eluting BRS was driven by the results of large-scale trials reporting that nitinol DES and drug-coated balloons (DCB) produced less restenosis compared with plain balloon angioplasty [47,48]. Drug-eluting BRS is the hybrid of these promising technologies that could overcome their limitations in the management of femoropopliteal atherosclerotic disease. However, it is only the beginning of this interesting scientific quest as data regarding the clinical and angiographic findings following BVS use in the femoropopliteal axis are scarce and long-term results are missing. As a result, well-designed, multicenter, randomized controlled trials that will investigate the efficacy of BVS technology in this very demanding anatomical location are mandatory. Infrapopliteal artery disease is another challenging area for endovascular PAD treatment. Only recently, level A evidence emerged recommending DES implantation in below-the-knee (BTK) focal arterial atherosclerotic disease as they resulted in superior angiographic and clinical outcomes compared with balloon angioplasty or bare metal stenting [8,9]. However, several unresolved issues for permanent DES implants remain, mainly due to

Table 1. Characteristics of bioresorbable vascular scaffold used in peripheral arterial disease trials.

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A

Kassimis, Spiliopoulos, Katsanos, Tsetis & Krokidis

B

C

Figure 1. Example of absorbable stent insertion in the crural arteries in a 46-year-old diabetic male patient suffering from major tissue loss of the right foot. (A) Baseline angiogram showed long-segment occlusion of the anterior and posterior tibial arteries and a short nearly 5-cm occlusion of the distal third of the peroneal artery. (B) Due to suboptimal angioplasty result and the distal anatomical location predisposing to external mechanical compression and collapse of a metal stent, decision was made to treat the lesion with off-label primary placement of two overlapping 3.0  28 mm coronary absorbable everolimus-eluting stents (ABSORB, ABBOTT MEDICAL). Stents are only distinguishable from 2 radiopaque dots at the stent edges (white arrowheads). (C) Immediate angiographic result shows a widely patent peroneal artery immediately post-stent placement. Patient underwent a transmetatarsal amputation and had successful wound healing.

the unnecessary long-term arterial irritation caused by the metallic mesh that constitutes a continuous inflammatory stimulus for the vessel wall that is the basis of ISR pathophysiology. The utilization of BTK drug-eluting BRS aims in supporting the vessel during the initial post-angioplasty remodeling period, homogenously elute the anti-proliferative drug in the vessel wall to reduce restenosis and then gradually resorb eliminating any foreign body presence and promote vessel healing [40,49]. BVS placement in the infrapopliteal arteries can offer the immediate optimal result and acute luminal gain necessary for small caliber BTK vessels, a major drawback of balloon angioplasty, and can also be used in bifurcation lesions without compromising a possible future endovascular or surgical treatment (FIGURE 1). Unfortunately, the ABSORB BTK multicenter, single-arm, trial, which was initiated in 2011 for the clinical evaluation of the everolimus-eluting BVS system in patients suffering from CLI due to infrapopliteal lesions, was recently discontinued due to poor enrolment [50]. Until today, there are no data available regarding the safety and effectiveness of this novel BRS technology in infrapopliteal lesions. Of note, the major drawback of current drug-eluting BRS technology for BTK 448

use is the lack of long scaffolds with adequate radial force that would correspond to the ‘real-life’ needs for the management of multilevel, calcified, infrapopliteal disease. In terms of biochemical and physical properties in BRS that are required for treatment of PAD, we believe that platform that will be gaining ground will be the polyanhydride ester based on salicylic acid and adipic acid anhydride with -olimus group coating that would potentially offer a double anti-inflammatory and anti-proliferative effect. However, the various materials have not been investigated in terms of inflammatory response in PAD. The ideal modality in our view for ISR is computed tomography angiography considering that the artifact from the metallic stents is no more present and inflammation may be monitored with POBA. The strut of the BRS is larger than the metallic stents; however, in peripheral vascular disease this is not likely to be a problem. Five-year view

BVS technology has evolved since the last failed attempts to replace permanent metal stents in the management of PAD. In the immediate future, clinical trials investigating the optimal endovascular treatment options for PAD will provide data from the comparison between drug-eluting and bare BVS versus nitinol stents or DCB in femoropopliteal lesions and drugeluting BVS versus DES or plain balloon angioplasty or DCB in infrapopliteal lesions. As PAD patients suffer from multilevel, long, calcified lesions involving various anatomical locations with different histological and mechanical properties, dedicated peripheral BVS technology should continuously evolve to offer the optimal scaffold for each arterial territory. Several ongoing trials will provide in the next few years evidence supporting the use of new drug-eluting and bare BVS for the management of PAD. For example, the ESPRIT I, a safety/efficacy single group, open-label study for the clinical evaluation of the Abbott vascular ESPRIT BVS System [51], has already reported the first very encouraging results. Taking into account the special advantages of BVS technology, demonstrating their non-inferiority compared with permanent stents would be enough to justify their use in PAD patients, especially those with CLI. Considering their current limitations and the scarce clinical experience, initial trials of BVS will include noncomplex, short, non-calcified lesions. Nonetheless, as initial encouraging data will continue to emerge, dedicated peripheral BVS technology will further improve so as to deal with more complex, real-world lesions and gradually become a part of everyday clinical practice. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript. Expert Rev. Cardiovasc. Ther. 12(4), (2014)

Bioresorbable scaffolds in peripheral artery disease

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Key issues • Stents are used in a variety of peripheral arterial disease (PAD) lesions as a bailout method of suboptimal angioplasty or as a primary treatment to reduce restenosis, which commonly occurs within the first few months. After this period, there is no proven need for stent scaffolding. • Permanent metal stents are obstacles to additional endovascular or surgical treatments. • Novel bioresorbable vascular scaffold (BVS) technology may be an ideal alternative, as it offers the acute and mid-term advantages of a conventional or drug-eluting stent combined with late luminal gain and late positive remodeling, which are detected only after Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by University of Pennsylvania on 01/19/15 For personal use only.

balloon angioplasty. • Dedicated peripheral BVS should be developed to address the needs of the different arterial and lesion characteristics encountered in PAD patients. • Ongoing trials investigating BVS in PAD will soon set the first indications for their use in everyday clinical practice.

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Expert Rev. Cardiovasc. Ther. 12(4), (2014)

Bioresorbable scaffolds in peripheral arterial disease.

The risk of in-stent restenosis has been dramatically reduced with the use of thin-strut nitinol and balloon-expandable drug-eluting stents in the per...
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