Coronary artery stents
Summary
Percutaneous coronary interventions were revolutionised by the introduction of coronary stents, which were designed to prevent many of the shortcomings of balloon angioplasty. Despite their benefits in the early phase after PCI, the initial bare metal stent devices were associated with neointimal hyperplasia due to deep arterial injury giving rise to in-stent restenosis in 20-30% of cases. The latter was one of the primary driving forces behind the development of drug-eluting stents with controlled release of anti-proliferative agents released from polymers directly immobilised on the stent surface. Early generation drug-eluting stents releasing sirolimus or paclitaxel successfully addressed the problem of neointimal hyperplasia by reducing the risk of restenosis and subsequent need of repeat target lesion revascularisation by 50-70% compared with bare metal stents in nearly all patient and lesion subsets. However, safety concerns were raised in relation to their potential to delay arterial healing and to increase the risk of very late stent thrombosis. These concerns have led to significant modifications in stent design, resulting in a broad spectrum of new-generation drug-eluting stents. These stents feature novel anti-proliferative agents with lower drug loads, modified stent platforms, and a variety of polymers - ranging from biodegradable and durable to polymer-free options - in order to improve biocompatibility and clinical outcomes. Representing the current state-of-the-art, new-generation drug-eluting stents are now used in over 90% of PCI procedures. This chapter reviews the data supporting the use of current and newly developed metallic drug-eluting coronary stents. An overview on bioresorbable scaffolds is found in chapter Bioresorbable scaffolds.
Introduction
The safety and efficacy of percutaneous coronary interventions (PCI) has improved continuously over the past 45 years. The worldwide number of PCI procedures particularly among patients with acute coronary syndromes (ACS) reflects its widespread acceptance related to its clinical benefits as well as its emergence as the preferred revascularisation strategy surpassing coronary artery bypass surgery (CABG). The advent of stents has considerably improved the safety of PCI by minimizing peri-procedural vessel closure due to dissections and the need for emergency CABG. The basic mechanism of actions of coronary artery stents are common to all platforms:
- Enlargement of arterial lumen by scaffolding of the arterial wall.
- Tagging of intimal flaps between stent surface and vessel wall.
- Sealing of dissections.
Historical perspective
The term "stent" was coined in 1916 by Johannes F. Esser, a Dutch plastic surgeon referring to a dental impression compound formerly invented by the English dentist Charles T. Stent. The first vascular stent was developed and implanted in 1968 by Charles T. Dotter in a canine popliteal artery. The first coronary stent was the result of discussions between two Swedish expatriates in Switzerland: Hans Wallsten, a paper engineer, and Ake Senning, the chief cardiac surgeon collaborating with Andreas Grüntzig during the first coronary angioplasties in Zurich.
The very first coronary stent, called the Wallstent, was self-expanding and developed by Medinvent in cooperation with Ulrich Sigwart. It was implanted by Jacques Puel (Toulouse, France) in March 1986 in a 63 year old male presenting with restenosis after plain balloon angioplasty of the left anterior descending artery (Figure 1). The first bail-out coronary stenting was performed by Ulrich Sigwart during a live course in June 1986 in a 50-year-old female suffering from occlusive dissection of the left anterior descending artery after balloon angioplasty. The use of bare metal stents increased continuously, however in-stent restenosis was frequent, and limited the indications for their use. Further research led to the development of the combination of a metallic platform, a polymer and an antiproliferative drug released from the polymer, which showed a remarkable inhibition of smooth muscle cells proliferation, effectively reducing of the risk of restenosis and improving long-term clinical outcomes., The description and in-depth discussion of historical stent designs (Gianturco-Roubin and Palmaz-Schatz stents), infrequently used bare metal stents and commercially no longer available early generation DES can be found in the Supplementary Appendix.
Figure 1
First human coronary stent implantation in March 1986. (a) Restenosis post balloon angioplasty (b) Self-expanding WALLSTENT (c) Immediate results post stent (d) Angiographic results at 11-year follow-up.
Drug-Eluting Stents
Drug-eluting stents (DES) enable site-specific, controlled delivery of therapeutic agents into the coronary artery wall. The three components of DES and their main targets for modification are summarised in Figure 2. Heparin was used initially as a coating material on stents in an attempt to reduce their thrombogenic potential and thus reduce the risk of early stent thrombosis (ST). When used in the setting of acute myocardial infarction (AMI), one study showed a reduced rate of ST and recurrent myocardial infarction (MI). Although heparin has proven anti-inflammatory effects in addition to its anticoagulant properties, no benefit was observed in terms of restenosis. Sirolimus-eluting stents (SES, Cypher, Cordis/Johnson & Johnson, U.S.) were first implanted in humans in 2001 and subsequently became the first Food and Drug Administration (FDA) approved DES that significantly reduced the risk of restenosis compared with bare metal stents (BMS). This was followed by a polymer-based, paclitaxel-eluting stent (PES, Taxus, Boston Scientific, Natick, MA, U.S.), which was also shown to consistently reduce restenosis and the need for repeat revascularisation procedures compared with BMS.
Figure 2
Main components of newer-generation drug-eluting sents, and their options for modification.
Coronary Scaffolds
Since both shortcomings, acute recoil and neointimal hyperplasia, are relatively short-lived phenomena, coronary artery stents do not provide additional long-term benefit, but may be the source of late adverse events including very late ST, restenosis and elimination of physiological vasomotion. Moreover, coronary artery stents may impede subsequent surgical revascularisation and impact non-invasive imaging quality. Fully bioresorbable scaffolds have been developed with the aim of the overcoming these drawbacks (Figure 3). An important limitation in the past has been the polymer-mediated occurrence of severe local inflammation. A full discussion of biodegradable vascular scaffolds is found in chapter Bioresorbable scaffolds.
Figure 3
A summary of the biodegradation process of polymer-based and metallic-based bioresorbable scaffolds.
Reproduced with permission from the publisher under the Creative Commons Attribution-NonCommercial-NoDerivatives License
(https://doi.org/10.1080/17434440.2021.1904894)
Drug-coated Balloons
Drug-coated balloons (DCB) have been developed to release antiproliferative substances to the vessel wall during balloon inflation without leaving permanent material behind. DCBs have been shown to reduce the risk of restenosis compared with balloon angioplasty alone while eliminating the risk for early and late stent-related events, and allowing for less intensive antiplatelet strategies. The ability to perform bypass-graft surgery in the vicinity of the target lesion is another benefit. The safety and efficacy of DCB compared to DES have been largely explored in the treatment of in-stent restenosis, small vessels disease and diffuse long lesions. Evidence is growing for de-novo large vessel lesions, bifurcations, calcified lesions and treatment of ACS patients., , , A full discussion of DCB is found in chapter Drug-coated balloons.
Types and Components of Newer-generation Drug-Eluting Stent Platforms
Components of metallic newer-generation DES are presented in Figure 2.
The key prerequisites for coronary artery stent platforms are as follows:
- Good deliverability with a small and flexible profile.
- Appropriate radial and longitudinal strength to prevent elastic recoil and limit foreshortening.
- Sufficient plaque coverage to avoid tissue prolapse.
- Sufficient side branch access
Metallic Backbone
Metal Composition
Stainless steel (316L SS) was the most frequently used component of early coronary stent designs due to its excellent processing characteristics, durability, corrosion resistance, biocompatibility, sufficient radial force and low elastic recoil (<5%). Defects in the regular crystalline arrangements typical for pure metals account for its brittleness and deformability in general, requiring alloying and other metallurgic techniques to affect electromagnetic and mechanical behaviour. Clinical limitations included moderate radio-opacity (density 8.0g/cm3), reduced flexibility, and a relatively high (10-15%) nickel content which has been linked to allergic reactions resulting in restenosis.
Cobalt chrome (L605 CoCr) alloys constitute the most frequently used stent backbone material today. The increased strength, wear resistance, elasticity and density of CoCr alloys can be tied to the specific effects of cobalt, chromium, tungsten, and molybdenum on the crystal structure during fabrication, while this type of unit cell rearrangement is not observed with SS. From a clinical perspective, CoCr allows for thinner struts without compromising radial strength and is somewhat more radio-opaque compared to SS (density 8.4-9.1g/cm3), and despite containing a comparable amount of nickel (~10% for L605 CoCr), oxide stability prevents nickel release.,
Platinum (Pt) has been introduced as another promising alloy with adequate biocompatibility, corrosion resistance, fracture resistance and twice the density of iron or cobalt. Alloys with 33% Pt are suited best to balance mechanical properties, processability, and radiopacity (density 9.9 g/cm3), while allowing low strut profiles with maintained radial strength. ,
Among currently marketed DES in Europe and the United States, the Promus and Synergy stent platforms (Boston Scientific, Natick, MA, U.S.) are using PtCr backbones, while the Onyx DES (Medtronic, Minneapolis, MN , U.S.) incorporates a platinum-iridium core with the purpose of improving visibility.
Strut Geometry
Previously, stent metallic platforms were categorised into coil or tube designs. Coils crafted from a continuously wound wire or flat sheet coils have been used in Gianturco-Roubin stents (Figure 4). Coil designs have become obsolete due to strut properties ultimately resulting in poor radial strength. Current devices have modular or slotted tube designs, fabricated by perforating a semi-finished metallic tube into a mesh-shaped tube with a laser beam (“laser-cut design”)., These platforms can be further categorised into open-cell and closed-cell designs, with the main difference that in stents with a closed-cell design all deflections between two contiguous hoops are connected, whereas in an open-cell design some of the internal deflection points of the hoops are not connected by bridges or welds (Figure 5). As a result, a closed-cell design provides better coverage of the luminal surface and conveys greater radial strength. Cell size is minimally affected when a closed-cell stent is deployed in a tortuous site, however, they are less flexible and may be more difficult to deliver in tortuous and calcified vessels. In addition, side-branch access may be more challenging. The open-cell design allows for greater stent flexibility and easier side branch access. Possible drawbacks are weaker radial strength, changes in cell size in tortuous anatomy, and less coverage of the vessel wall particularly on the outer curvature. To further improve flexibility, the number of crowns has been increased accompanied by a decrease in strut length and thickness (Figure 6). Finally, the strut’s cross-sectional geometry has also been improved, with most struts now rounded to limit edge dissections and perforations. The vast majority of available newer-generation DES therefore have open-cell designs., Examples of contemporary ultra-thin strut DES cell designs are depicted in Figure 7.
Figure 4
Prior and contemporary manufacturing techniques of metallic stents: Obsolete coil design devices were braided or knitted from a continuously wound wires. Newer-generation drug-eluting stents are laser-cut from metallic tubes into the desired mesh-shape. Powder metallurgy is based on compaction of powdered materials, a possible method for fabricating porous iron-based biodegradable stents. Reproduced with permission from the publisher
Figure 5
Design characteristics of balloon-expandable coronary stents.
Figure 6
Stent structure and design. A, B, C: Struts, rings, cells, crowns and connectors form the backbone of a stent. Strut: single element that forms larger structural entities (cells, rings and crowns). Cell: small but regularly repetitive structure of a stent, delimited by 2 layers of rings and the connectors and might be open or closed. Connectors: attach the adjacent rings and can be straight or curved or can be direct welds that link the rings directly. Rings and crowns: (1 crown = 2 struts) comprise a cluster of cells and are held together by connectors. D: Orientation of the stent (in-phase or out-of-phase) and connectors (offset peak-to-peak; mid-shaft; peak-to-peak–out-of-phase; peak-to-valley–in-phase). Design and geometry of these components define the mechanical performance of a stent: crowns and rings determine radial support and expansion capacity; the number of connectors is responsible for the longitudinal stability, flexibility, deliverability, side branch access and longitudinal integrity. Open cell designs with a reduced number of connectors provide greater stent flexibility with reduced arterial injury and decreased neointimal response.
Reproduced with permission from the publisher
(https://doi.org/10.1016/j.rec.2017.11.022)
Figure 7
Open-cell strut designs of four contemporary ultrathin-strut drug-eluting stents and their comparator in clinical trials, the Xience stent. Reproduced with permission from the publisher
Strut Thickness
In addition to material composition and architecture, reducing strut thickness has become a major strategy to improve deliverability, safety and efficacy of newer-generation DES. The first bare metal and early-generation DES had a strut thickness in the range of 80-140 μm. Despite the lack of a standardised definition, the terms “thin-strut” and “ultrathin-strut” generally refer to DES with strut thicknesses, excluding the polymer coating, of <100 μm and <70 μm, respectively. , The physiological and clinical advantages of thinner strut architectures include a reduction in shear-stress induced platelet aggregation (thrombogenicity), reduced arterial injury resulting in reduced neointimal proliferation, and improved vessel healing related at least in part to faster endothelialisation. ,
The impact of strut thickness on flow patterns and shear rates are illustrated in Figure 8. The theoretical advantages of thinner struts also correlate with clinical benefits. A meta-analysis of 80,885 patients included in 69 randomised trials reported lower rates of ST and MI with incrementally decreasing strut thickness dimensions of 60-80 μm, 81-100 μm, 101-120 μm and ≥120 μm. In a more recent meta-analysis of 22,766 patients included in 16 randomised trials, the use of ultrathin-strut DES vs. thicker-strut DES was associated with a 15% lower risk of target lesion failure (TLF), largely due to a lower risk of clinically-indicated TLR. Similarly, a pooled analysis of 10 randomised controlled trials (RCT) of 11,658 patients randomly assigned to ultrathin-strut DES (Orsiro [Biotronik,Bülach,Switzerland] 60 μm, MiStent [MicellTechnologies,Durham,NC,USA] 64μm, BioMime [MerilLifeSciences,Gujarat,India] 65μm) or new-generation thin-strut DES (≈81 μm), reported a 16% relative reduction in TLF which was largely driven by a 20% lower risk of MI, and a trend towards a lower risk of ST (relative risk 0.72, 95% CI 0.51–1.01).
Figure 8
The impact of stent designs with different strut crossections and heights on flow patterns and shear rates. Reproduced with permission from the publisher
Polymeric Drug Release
Polymer Technology
Polymeric materials applied to the metallic stent surface can store and modulate anti-proliferative drug release into the coronary artery wall. These polymer coatings are applied to the stent struts either circumferentially or abluminally, while the drug itself may be dissolved either in a reservoir surrounded by the polymer film or within the polymeric matrix (Figure 9)., , Polymers of newer generation DES are either durable (permanent) with improved biocompatibility or biodegradable, of low thickness in the range of 2-15μm, and have the theoretical advantage of avoiding life-long persistence within the coronary artery wall, which may trigger prolonged inflammatory responses., , A histological study of inflammatory responses to first- and new generation DES polymers is depicted in Figure 10.
Figure 9
Schematic drawing of the components of a drug-eluting stent with durable polymer (A) and a drug-eluting stent with bioresorbable polymer limited to the abluminal side (B).
Figure 10
Histological study of the inflammatory reaction to first- and newer-generation drug-eluting stents. Representative histological images of the Cypher sirolimus-eluting stent (SES), Xience everolimus-eluting stent (EES) and Synergy EES in human coronary arteries. Note the excessive inflammation associated with the Cypher SES, whereas the inflammatory reaction with the Xience EES and Synergy EES is minimal. Reproduced with permission from the publisher
Supplemental layers are found in most DES and consist of either top coatings to delay drug release (e.g. poly[butylmethacrylate] PBMA) or base coatings to increase polymer adhesion to the stent struts (e.g. Parylene C). Coatings are typically spray coated or dip coated, and some stent manufacturers use sophisticated auto-pipetting procedures to ensure highly reproducible coatings. The drug may be dissolved either in a reservoir surrounded by a polymer film or within a polymeric matrix. Controlled drug release can occur by diffusion, chemical reaction, or solvent activation. Biodegradable polymers allow drug release by both passive diffusion and matrix degradation, whereas non-degradable polymers enable drug release by particle dissolution.
Durable Polymers
The EluNIR (Medinol, Tel Aviv, Israel), Promus (Boston Scientific, Natick, MA, U.S.), Resolute Onyx (Medtronic, Minneapolis, MN, U.S.) and Xience (Abbott, Santa Clara, CA, U.S.) stent platforms are newer-generation devices with a durable polymer coating. The Promus and Xience stents use a blend of poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) and PBMA applied circumferentially. PBMA is used as a thin primer adhesion layer, whereas PVDF-HFP acts as the surface drug reservoir carrying everolimus. PBMA has favourable biocompatibility and the ability to adhere to metallic surfaces as well as to PVDF-HPF. Such highly fluorinated polymers have been found to be suitable for drug delivery due to their stability. , Fluorocarbons are the most chemically inert organic compounds, with a high electronegativity, forming the strongest carbon-fluorine bonds that carbon can form with any element. Fluoropolymers provide remarkable resistance to oxidative and hydrolytic stress while having good thermal stability and reduce platelet adhesion and activation compared with non-fluoropolymer-coated metallic stents. ,
The Resolute DES family (Medtronic, Minneapolis, MN, U.S.) uses the proprietary durable BioLinx polymer, consisting of a hydrophobic C10 drug reservoir, hydrophilic polyvinyl-pyrrolidinone (PVP), and both hydrophobic and hydrophilic C19 polyvinyl-pyrrolidinone groups for drug release kinetics and biocompatibility. The EluNIR uses a PBMA and CarboSil polymer, the latter being a silicone-modified polyurethane with elastomeric and biocompatible properties, more resistant to cracking, flaking, and peeling.
Biodegradable Polymers
A variety of biocompatible polymers have been developed as alternative to durable polymers for drug release on DES. Some biodegradable polymer DES (BP-DES) feature an abluminal or asymmetric polymer coating, reducing polymer volume applied to stent surfaces. Biodegradable polymers allow drug release by both passive diffusion and matrix degradation, and their biodegradation occurs through a hydrolytic process. , Early efforts to identify suitable polymers were characterised by exuberant inflammatory and thrombotic responses, potentially through inappropriate polymer degradation and the molecular weight of the compounds (Figure 10). , The majority of contemporary biodegradable polymers are synthetic polyesters from the poly (α-hydroxy acid) family, such as polylactic acid (PLA), polyglycolic acid and their co-polymer polylactic-co-glycolic acid (PLGA).
A study exposing umbilical vein endothelial cells and human coronary arterial smooth muscle cells to polymer surfaces suggested that material-dependent differences exist in the response of both endothelial and smooth muscle cells. Of note, improved neo-intimal coverage with a BP-DES (Figure 11) has been shown on scanning electron microscopy. , On the other hand, confocal microscopy studies of the thrombogenicity of different platforms found visually heterogeneous results, implying greater ex-vivo thrombogenicity of some BP-DES and polymer-free DES compared to DP-DES (Figure 12). , , Therefore it is difficult, if not impossible, to disentangle the long-term clinical effects of polymer composition, degradation time, and eluted drug on top of the backbone of stent design considerations and anti-thrombotic strategies.
Figure 11
Neointimal coverage of a biodegradable polymer and durable polymer DES, implanted in pig coronary arteries. a) and a Xience EES (part b) at 3 days after implantation in rabbit iliac arteries. c | The percentage of neointimal coverage is significantly higher with the Synergy EES than with the Xience EES. Reproduced with permission of the publisher
Figure 12
Confocal microscopy images showing thrombogenicity of stents. hunt study 1 shows the thrombogenicity of a bare-metal stent (BMS), a fluoropolymer-only stent, a Xience everolimus-eluting stent (EES), an Ultimaster sirolimus- eluting stent (SES) and a BioFreedom Biolimus A9-coated stent (BCS). The low-power confocal microscopy images show very small thrombus-occupied areas in stents with fluoropolymers (that is, the fluoropolymer-only stent and the Xience EES) compared with the other stents (that is, the BMS, Ultimaster SES and BioFreedom BCS), using antibodies against dual platelet markers CD61–CD42b (shown in red). Shunt study 2 shows immunofluorescent staining against dual platelet markers (CD61–CD42b, shown in green) in a pig shunt model with the use of Xience EES, Synergy EES, Orsiro SES, BioMatrix Flex Biolimus A9-eluting stent (BES) and Nobori BES.
Reproduced with permission of the publisher
The complex process of degradation varies between 3 to 12 months for most contemporary devices, which must also be taken into account when comparing outcome data to durable-polymer DES (DP-DES). Additionally, the return of healing also depends on drug levels falling below biologically active levels. , . Polymers of contemporary BP-DES and their principal clinical properties, as well as clinical outcomes of DP-DES vs. BP-DES vs. polymer-free
DES are discussed later.
Polymer-free Stent Platforms
Polymer-free DES offer the potential advantages of avoiding the long-term adverse effects of polymers. Several technologies have been developed to deploy anti-proliferative drugs directly from the metallic stent surface (Figure 13). The absence of any polymeric coating means the controlled release kinetics of applied drugs are not available, therefore polymer-free stents rely on the physicochemical properties and water solubility of the applied coatings to achieve sufficient arterial wall drug retention.
Figure 13
Techniques for polymer-free stent coatings. Reproduced with permission from the publisher.
The YUKON SES (Translumia, Hechingen, Germany) was the first polymer-free DES with a micro-porous surface 2μm in depth. With respect to contemporary polymer-free stent platforms, the Biofreedom Ultra drug-coated (DCS, Biosensors International PTE LTD, Singapore) stent uses a micro-structured surface eluting Biolimus A9 from drug wells and is the only currently FDA-approved platform, the Coroflex ISAR / ISAR VIVO ((B. Braun Melsungen, Berlin, Germany / Translumina Therapeutics, Dehradoon, India) uses a sirolimus-probucol coating applied to a microporous stent surface, and the Cre8 (CiD / Alvimedica, Saluggia, Italy) stent uses an abluminal reservoir technology eluting Amphilimus, a sirolimus and fatty acid formulation. , , ,
Antiproliferative Agents
The drug aims to limit neointimal proliferation, with its ideal profile characterised by:
- A wide therapeutic window.
- A low inflammatory potential.
- A selectivity for suppression of smooth muscle cell proliferation without toxicity to the medial and adventitial cell layers.
- Promotion of re-endothelialisation.
The efficacy of candidate drugs is not only reliant on biological activity in vitro, but is also determined by local pharmacokinetics and physicochemical drug properties. Drug distribution is mediated by stent strut configuration and the balance between convective and diffusive forces. Hydrophilic drugs such as heparin readily permeate into tissue, but are also rapidly cleared. In contrast, lipophilic agents such as paclitaxel or limus analogues are water-insoluble and bind to hydrophobic sites in the arterial wall. Although both hydrophilic and lipophilic drugs show large spatial concentration gradients in the arterial wall, the latter is better and more homogenously distributed. Currently, immunosuppressive/antiproliferative (limus family) but not cytotoxic (paclitaxel) drugs are preferentially used for release in coronary arteries. More recently, asymmetric application of anti-proliferative agents (sirolimus) by means of abluminal stent coating in conjunction with anti-CD34 antibody surface modification has been shown to result in potent suppression of neoinitimal hyperplasia while promoting re-endothelialisation more effectively than circumferential stent strut coatings.
Paclitaxel
Paclitaxel stabilizes polymerized microtubules and enhances microtubule assembly, forming numerous unorganized and decentralized microtubules inside the cytoplasm (Figure 14). As a result, cell replication is inhibited, and this effect is seen predominantly in the G0/G1 and G2/M phases of the cell cycle . Paclitaxel was shown to effectively inhibit vascular smooth muscle cell migration and proliferation. In addition, it has several favorable characteristics for stent-based local drug delivery, such as a high degree of lipophilicity and a long-lasting anti-proliferative effect following a single-dose application at low concentrations. In a porcine restenosis model, implantation of stents dip-coated with paclitaxel at increasing doses resulted in a dose-dependent inhibition of neointimal formation at 28 days. However, the beneficial effects of paclitaxel on neointimal formation were counterbalanced by local cytotoxic effects that manifested as a decrease in medial wall thickness, focal neointimal and medial wall hemorrhage, cell necrosis, and pro-apoptotic mRNA transcription (e.g., FAS, BAX, caspase 3).,
Figure 14
The chemical structure of the macrocyclic lactone group of antiproliferative drugs of the limus family as compared to the chemical structure of paclitaxel, and their mechanism of action. Reproduced with permission of the publisher (https://doi.org/10.1056/nejmra1210816)
The most used devices for stent-based paclitaxel delivery were the TAXUS® Express2® stent and TAXUS Liberté™ (Boston Scientific, Natick, Mass, USA), both made of SS and manufactured with the same polymer and dose of paclitaxel. Paclitaxel has lost its role in new generation DES but is commonly used as an anti-proliferative agent released from drug-coated balloons.
Limus Analogues
Most of the currently available DES use drugs that are analogues of the limus family. The principal therapeutic agents encompass: sirolimus, zotarolimus, everolimus, biolimus-A9 (also known as umirolimus), novolimus, myolimus, and ridaforolimus (Figure 14). These agents bind to the intracellular receptor FKBP-12 and inhibit a phosphoinositide 3-kinase termed mammalian target of rapamycin (mTOR), thereby reversibly inhibiting the growth factor- and cytokine-stimulated cell proliferation in the G1 phase of the cell cycle. Vascular smooth muscle cells are usually quiescent, proliferate at low indices (<0.05%), and remain in the G0 phase of the cell cycle; however, stimulated by vascular injury or growth factors, vascular smooth muscle cells re-enter the cell cycle at G1 and advance into the S phase. Tacrolimus and pimecrolimus also belong to the limus family but have immunosuppressive rather than anti-proliferative activity. Both drugs bind to FKBP-506 rather than FKBP-12. The tacrolimus/pimecrolimus FKBP506 complex subsequently inhibits the calcineurin receptor, which leads to decreased cytokine expression on the cell surface membrane and results in inhibition of T-cell activation and lower smooth muscle cell selectivity (Figure 15).
Figure 15
Cellular effects of antiproliferative drugs of the limus family. Reproduced with permission of the publisher
Sirolimus
Sirolimus (C51H79NO13, molecular weight 914 Da), a highly lipophilic drug previously known as rapamycin, was the first member of the limus family to be used for prevention of restenosis following PCI. Following experimental studies showing potent suppression of vascular smooth muscle cell proliferation, local delivery of sirolimus from stents also effectively inhibited neointimal proliferation. In vascular models of smooth muscle cells, sirolimus at concentrations as low as 1 ng/mL inhibited DNA synthesis and cell growth. , Histopathological analyses suggested that in comparison to paclitaxel, sirolimus did not promote apoptosis, reduction in medial and intimal smooth muscle cells and collagen content, or internal elastic lamina disruption. The more suitable drug characteristics have also been demonstrated on a transcriptional level, as sirolimus did not seem to promote pro-apoptotic mRNA transcripts seen with paclitaxel. The pharmacodynamic and pharmacokinetic properties of sirolimus and its wider therapeutic index have been linked to its superior performance compared to paclitaxel-eluting devices., , Early randomized studies of the first sirolimus- vs. paclitaxel-eluting stents (SES vs. PES) reflected these pre-clinical findings, by demonstrating superior in-segment late luminal loss and in-segment restenosis in favor of sirolimus. Later individual patient-data meta-analyses also confirmed these findings with a significant reduction in the risk for re-intervention and stent-thrombosis in patients receiving SES vs. PES.
Everolimus
Everolimus (C53H83NO14, molecular weight 958 Da), a sirolimus derivative in which the hydroxyl group at position C40 of sirolimus has been alkylated with a 2-hydroxy-ethyl group. It is slightly more lipophilic than sirolimus, and therefore it is more rapidly absorbed into the arterial wall. Although binding of everolimus to the FKBP-12 domain is 3-fold and immunosuppressive activity in vitro 2 to 5-fold lower than with sirolimus, oral everolimus proved at least as potent as sirolimus in models of autoimmune disease and heart transplantation. In addition, the everolimus-eluting stent (EES) platform is potentially associated with less inflammation than sirolimus- or paclitaxel-eluting stents.
Zotarolimus
Zotarolimus (C52H79N5O12, molecular weight 966 Da) is another sirolimus analogue, in which the C40 position is modified by a tetrazole ring resulting in its shorter circulating half-life. It is an equipotent analogue of sirolimus in vitro and in vivo. Although the binding affinity to the FKBP 12 domain for zotarolimus and sirolimus is similar, and the antiproliferative activities comparable, the immunosuppressive activity in vivo is 3 to 4-fold lower. The current Resolute Onxy ZES family (Medtronic, Minneapolis, MN , U.S.) uses the BioLinx™ polymer system for release of zotarolimus, which facilitates a more delayed release of the same concentration of zotarolimus as on the original Endeavor ZES (1.6 μg/mm2 stent surface area), with approximately 50% of drug released during the first 7 days, and 85% 60 days after stent implantation.
Biolimus A9
Biolimus-A9 is a highly lipophilic, semi-synthetic sirolimus analogue with an alkoxy-alkyl group replacing hydrogen at position 42-O. The drug is immersed at a concentration of 15.6 μg/cm2 into a biodegradable, PLA polymer, which is applied solely to the abluminal surface. Based on in vivo studies, PLA is fully converted to lactic acid at 6 months, with the polymer resorbed within 9 months. Biolimus-A9 is currently used in the BioMatrix and in the polymer-free BioFreedom platforms (Biosensors International PTE LTD, Singapore).
Novolimus
Novolimus is a macrocyclic lactone, which has been developed by removal of a methyl-group from carbon C16. Notably this differs from the other macrocyclic lactones that are used in DES, which have mainly been developed through modifications on the carbon C40 of the macrocyclic ring. Nevertheless, in a similar fashion to these other agents, novolimus inhibits mTOR. In vitro studies demonstrate it to have a potency to inhibit human smooth muscle cells (IC50 of 0.5nM) which is comparable to that of sirolimus. Novolimus was used on the DESyne™ (Elixir Medical, Sunnyvale, CA, USA) with a durable PBMA polymer, the DESyne™ BD with a PLA biodegradable polymer and the DESolve 100BVS. The DynamX novolimus-eluting Bioadaptor stent (Elixir Medical Corporation, Milpitas, CA) recently completed a first randomized comparison to the Onyx DES. ,
Myolimus
Myolimus is macrocyclic lactone, which is produced by replacement of the oxygen on C32 of the macrocyclic ring, which has a comparable potency, in terms of inhibition of smooth muscle cells, to sirolimus. Myolimus was used on the Elixir stent (Elixir Medical, Sunnyvale, CA, USA) which is no longer commercially available.
Ridaforolimus
Ridaforolimus (formerly deforolimus) is a C-40 phosphine oxide substituted parental nonprodrug formulation of rapamycin. The substance is currently used on the BioNIR / EluNIR stent platforms (Medinol, Tel Aviv, Israel) at a concentration of 1.1μg/mm2. The majority of the drug is eluted over a 180-day period, however, an initial peak (burst) concentration followed by diffusion does not occur and persistently low drug concentrations in the surrounding vascular tissue can be measured for 3 months.
Amphilimus
The amphilimus formulation is based on sirolimus mixed with long-chain free-fatty acids., Diabetic cells require up to 10-times higher limus concentrations to achieve similar inhibition as non-diabetic vascular smooth muscle cells. The fatty acid formulation modulates drug availability by encasing limus molecules during combined release and enhances cell-uptake through the fatty acid pathway. This drug delivery method was hypothesized to carry particular benefits in patients with diabetes and is used in the Cre8 CoCr stent platform (Alvimedica, Saluggia, Italy) in conjunction with an abluminal reservoir technique and passive carbon film coating.,
New generation Drug-Eluting Stent Overview
While there is consensus that the term early or first-generation DES applies to the Cypher sirolimus-eluting stent introduced in 2002 by Cordis/Johnson & Johnson, and the Taxus paclitaxel-eluting stent launched by Boston Scientific in 2004, the following generations of DES are arbitrarily defined. Second generation devices have been referred to as those with improved durable polymeric coatings, thinner struts and new drugs, third-generation as those distinguished by biodegradable polymers or polymer-free technologies, and forth generation as those with bioresorbable scaffolds (the latter not being recommended for clinical use outside of studies)., Due to the arbitrary and in some instances conflicting nature of these definitions across the multitude of available stent platform, this chapter refers to new generation DES and seeks to distinguish them by the eluted drug and polymer type. Bare-metal stents are no longer recommended for any patient subset in clinical guidelines, first-generation DES are no longer commercially available and some newer-generation devices have been discontinued or are no longer marketed. In-depth information on these platforms can be found in the appendix. Characteristics of the most frequently used platforms in a contemporary iteration are presented in Figure 16 and Tables 1-3. ndash; Clinical Experience in Head-to-Head Comparisons
Figure 16
Characteristics of most commonly studied and used new generation drug-eluting stent platforms with CE-mark and/or FDA approval. Metallic backbone in gray, polymer coloured: blue = durable, red = biodegradable, yellow = polymer-free, green = antibody coating.
Adapted from with permission or hand-drawn by the first author. *Strut cross-sections might vary depending on stent diameter, work-horse diameters presented. AES: amphilimus-eluting stent; BES: biolimus-eluting stent;EES: everolimus-eluting stent; PBMA: poly-n-butyl methacrylate, PCL: poly(ε-caprolactone), PDLLA: poly(D,L)-lactic acid, PLA: polylactic acid, PLLA: Poly-l-Lactic acid, PLCL: Poly(L-lactide-co-ε-caprolactone), PLGA: poly-DL-lactide-co-glycolide, PVDF-HFP: poly (vinylidene fluoride-co-hexafluoropropylene), PVP: polyvinyl pyrrolidone; RES: ridaforolimus-eluting stent; SES: sirolimus-eluting stent; ZES: zotarolimus-eluting stent
Drug-eluting stents with durable polymer coating – clinical experience in head-to-head comparisons
The physical properties of contemporary DES with durable polymer coating are summarised in Table 1. Commercially available platforms are presented in alphabetic order.
Table 1: Durable polymer drug-eluting stents with CE-mark and/or FDA approval
| Durable Polymer DES | ||||
|---|---|---|---|---|
| EluNIR | Onyx Frontier | PROMUS Premier | XIENCE Skypoint | |
| Manufacturer | Medinol | Medtronic | Boston Scientific | Abbott |
| Backbone | CoCr | Co shell, PtIr core | PtCr | CoCr |
| Strut cross-section* |  |
 |
 |
 |
| Strut thickness (µm) | 87 | 81 (2.0-4.0mm), 91 (4.5-5.0mm) | 81 (2.25-3.5mm), 86 (4mm) | 81 |
| Polymer | Elastomeric CarboSil & PBMA | BioLinx polyme blend C10 polymer, C19 polymer, and PVP | PBMA, PVDF-HFP | PBMA & PVDF-HFP |
| Polymer distribution | circumferential | circumferential | circumferential | circumferential |
| Polymer or coating thickness (µm) | - | 12 | 8 | 16 |
| Drug type | 1.1 μg/mm2 ridaforolimus | 1.6 µg/mm2 zotarolimus | 1.0 µg/mm2 everolimus | 1.0 µg/mm2 everolimus |
| Drug release | >95% in 6m | 100% in 6m | 80% in 30d, 100% in 3m | 100% in 4m |
| Approval | FDA, CE-mark | FDA, CE-mark | FDA, CE-mark | FDA, CE-mark |
| *Adapted from 22 or hand-drawn by the first author. Strut cross-sections might vary depending on stent diameter, work-horse diameters presented. CE: Conformité Européenne; CoCr: Cobalt Chromium; FDA: Food and Drug Administration; PBMA: poly-n-butyl methacrylate, PCL: poly(ε-caprolactone), PVDF-HFP: poly (vinylidene fluoride-co-hexafluoropropylene), PVP: polyvinyl pyrrolidone; PtCr: Platinum Chromium; PtIr: Platinum Iridium. | ||||
Everolimus-Eluting Stents
PROMUS (Boston Scientific, Natick, MA)
The PROMUS stent was commercially available until 2012 as the XIENCE V with a CoCr backbone. The PROMUS Element was based on a PtCr alloy and the PROMUS Element Plus incorporated a new delivery system consisting of a new dual-layer balloon, a strong outer layer, and a flexible inner layer, resulting in overall improved deliverability. The newest iterations PROMUS Premier and PROMUS Elite use a PtCr platform with 81µm strut thickness, and a durable PBMA / PVDF-HFP polymer coating loaded with 1.0 µg/mm2 everolimus (243µg on the largest 4.00 x 38mm stent) that is eluted mainly (80%) in the first month and entirely in 3 months. The updated design of the PROMUS Premier includes additional connectors at the proximal end (in total 4 for all stents <4.0mm, 5 for 4.0mm) to improve radial and longitudinal strength while the remainder of the stent has two connectors in order to maintain flexibility. This feature needs to be kept in mind when performing bifurcation PCI, as side branch access might be impeded in the very proximal end. , , , ,
- The multicenter PLATINUM Workhorse non-inferiority study randomised 1532 patients to treatment with the PROMUS Element or PROMUS Xience V EES stent. At 12-months follow-up the PROMUS Element stent met the primary non-inferiority endpoint of TLF compared to the PROMUS stent (3.4% vs. 2.9%, Pnon-inferiority = 0.001). In addition, rates of cardiac death (0.8% vs. 0.4%, p=0.51), target-vessel MI (0.8% vs. 1.6%, p=0.14), ischaemia-driven TLR (1.9% vs. 1.9%, p=0.96), TVR (2.7% vs. 2.9%, p=0.83) and ST (0.4% vs. 0.4%, p=0.99) were comparable between both stents. Comparable outcomes were maintained out to 5-year follow-up.,
- The single-arm PLATINUM Small vessel study enrolled 94 patients with lesions in vessels between 2.25 and 2.5 mm. The study met its primary endpoint of TLF at 12-months with a rate of 2.4% for the 2.25 mm stent, which was significantly lower than the pre-specified performance goal of 21.1% derived from historical outcomes of the 2.25 mm TAXUS Express PES. Clinical events out to 2-years were low.
- The single-arm PLATINUM Long lesion study enrolled 102 patients with lesions between 24 and 34 mm in length. The study met its pre-specified primary endpoint at 12-months with a rate of TLF of 3.2% for the 32mm and 38mm stents compared to the performance goal of 19.4% derived from historical outcomes of the 32 mm TAXUS Express PES. Clinical outcomes at 2-years were low.
- The multi-centre PLATINUM PLUS trial randomised 2,980 all-comers patients in a 2:1 ratio to PtCr EES (n=1,952) or the CoCr EES. The study met its primary endpoint at 12-months in the intention-to-treat analysis with TVF rates of 4.6% with PtCr EES and 3.2% with CoCr EES (Pnon-inferiority p=0.012; Psuperiority, p=0.08). In the per-protocol analysis the primary endpoint was significantly more common with the PtCr EES (HR 1.64, 95% CI: 1.05-2.55, p=0.03). The individual components of TVF and rates of definite/probable ST were similar between the stents.
XIENCE (Abbott Vascular, Santa Clara, CA)
The XIENCE DES family (XIENCE V, XIENCE PRIME, XIENCE Xpedition, XIENCE Alpine, XIENCE Sierra, XIENCE Skypoint) is the most studied DES to date, having been the benchmark stent for numerous competitor devices. The totality of evidence consists of >120 clinical trials, most of which were investigator initiated. Consistently the platform has used a L-605 CoCr alloy with 81µm strut thickness and a durable polymer of PVDF-HFP and PBMA, loaded with 1.0 µg/mm2 everolimus (nominal drug content for the 4.00 x 38mm device of 236µg) which is eluted over 120 days. The XIENCE V was also commercially available until 2012 as the Promus™ (Boston Scientific, Natick, MA) stent.
The XIENCE Sierra differs from the Alpine platform in terms of the stent delivery system and has a very low crossing profile (0.99mm vs. 1.11mm). XIENCE Sierra offers a post-dilatation maximum expansion to 5.5 mm for 3.5- and 4.0-mm diameters with 0% shortening at maximum post-dilatation at 5.5 mm.74 The latest iteration, the XIENCE Skypoint offers a broader expansion range up to 3.75 mm for the 2.25-3.25 mm devices, and 5.75 mm for the 3.5-5.0 mm devices. XIENCE received CE and FDA approval for short DAPT (28 days) in high bleeding risk (HBR) patients in April and June 2021, respectively.
The SPIRIT first study was the earliest trial to clinically test everolimus eluted from a durable polymer on a CoCr platform, compared to an identical BMS. Among 60 patients with de-novo lesions, the EES demonstrated superior angiographic in-stent late lumen loss (LLL), diameter restenosis and neointimal hyperplasia as assessed by means of intravascular ultrasound. Six randomised trials have compared EES to PES in 8,819 patients with increasingly complex lesions ranging from those with up to two relatively simple de novo lesions in the SPIRIT II study, to the unrestricted all-comers population in the COMPARE study.[76-92] Irrespective of patient complexity or follow-up period, angiographic and clinical outcomes have consistently demonstrated superior outcomes in those treated with EES.
More recently, the XIENCE EES has demonstrated similar efficacy and safety compared to most other newer-generation DES, except for some individual trial data such as BIOFLOW V or BIOSTEMI.[93-98] A meta-analysis of 77 randomised trials including 99,039 patients with a median follow-up of 50 months compared several newer-generation DES. While Orsiro had the best cumulative ranking curve for TLF compared to several competitors (Xience, Nobori/Biomatrix, Resolute) at 1 year, this finding attenuated during long-term follow-up such that there were no significant differences in any combined or individual safety/efficacy endpoint between the best ranked Orsiro and Xience stent among 39 trials with 59,855 randomised patients. Large-scale “real-world” data confirm the similar performance of XIENCE compared to the Synergy BP-EES and other newer-generation DES platforms with absorbable polymers and thinner struts., Early trial evidence comparing EES to BMS and other DES platforms can be found in the appendix.
Ridafolimus-Eluting Stent
BioNIR and EluNIR (Medinol, Tel-Aviv, Israel)
The BioNIR stent elutes ridafolimus using an elastomeric durable polymer, which is resistant to bending, bonding, cracking, peeling and distortions unlike other contemporary DES. The stent platform is made from CoCr and is characterised by a variable strut size and width. The stent’s manufacturing process is distinctive as the stents are made from a thin sheet of cobalt alloy that is laser cut, spray coated with drug and rolled into a cylinder and laser welded. The device received FDA approval in 2017, as has it newest iteration EluNIR. The stent geometry is characterised by 87 μm thick struts and a dual-pattern strut-width design with adaptive narrow struts (72 μm) for radial strength and ultra-narrow struts (40 μm) for flexibility and conformability. To improve its visualisation during PCI the EluNIR features two radiopaque markers at each end of the stent, and a hybrid polymer-metal radiopaque catheter tip.
- The stent was first evaluated in the NIREUS FIM non-inferiority study, which randomised 302 patients in a 2:1 ratio to BioNIR (n=201) and R-ZES (n=101). The study met its primary endpoint of in-stent LLL at 6-months (BioNIR 0.04mm vs. R-ZES 0.03, Pnon-inferiority<0.001). Clinical event rates were low and comparable between the stents.
- Further assessment has taken place in the BIONICS multi-centre randomised trial which allocated 1,919 patients to the BioNIR (n=958) or the Resolute ZES (n=961). The primary endpoint was TLF at 12-months follow-up and rates were identical for both devices (5.3%), achieving the pre-specified criterion for non-inferiority (Pnon-inferiority=0.0012). No significant differences in the individual components of TLF and rates of ST were seen. In the pooled analysis of the BIONICS and NIREUS trials at 2-years, clinical outcomes were similar between BioNIR and the Resolute ZES.
- The EluNIR has been investigated in post-marketing single-arm registries. Among 315 HBR patients, TLF occurred in 4.9% after 12 months.,
Zotarolimus-Eluting Stents
The Resolute family (Medtronic, Minneapolis, MN)
The first, no longer commercially available iteration of the zotarolimus-eluting stent (ZES) was the Endeavour Sprint stent using the Driver CoCr platform and a phosphorylcholine polymer, which released 95% of the zotarolimus within the first 15-days. This rapid drug release led to higher angiographic LLL and poorer early clinical outcomes in RCTs compared to competitor devices, and the stent was replaced with the Endeavor Resolute device, which was identical, other than having a BioLinx polymer - a blend of 3 different polymers: the hydrophobic C10 polymer to control drug release; the biocompatible and hydrophilic C19 polymer; and polyvinyl pyrrolidone to allow an early burst of drug release. The polymer allows delayed drug release, such that at least 85% of the zotarolimus is released within 60 days, with the remainder being released within 180 days (Figure 17).
Figure 17
(A) The chemical structure of the three components of the BioLinx™ polymer system. The hydrophobic C10 polymer is based on hydrophobic butyl methacrylate to provide adequate hydrophobicity for zotarolimus. The hydrophilic C19 polymer is manufactured from a mixture of hydrophobic hexyl methacrylate, and hydrophilic vinyl pyrrolidinone and vinyl acetate monomers, to provide enhanced biocompatibility. The hydrophilic polyvinyl pyrrolidinone increases the initial drug burst and enhances biocompatibility. (B) The drug release pattern of zotarolimus: >85% is released within the first 60 days, with drug elution complete by 180 days. (C) A comparison of the relative arterial concentrations of zotarolimus in the porcine coronary artery model at various times post implantation of the Endeavor® and Endeavor® Resolute stents. The Endeavor® stent maintains effective drug levels through the initial loading of arterial tissue with zotarolimus during the first two weeks of elution. Conversely, the Endeavor® Resolute stent sustains an effective drug level in the tissue through continued, sustained elution. Reproduced with permission of the publisher
The second version of the Resolute ZES was called the Resolute Integrity, which differed from its predecessor by being manufactured using continuous sinusoid technology. This method of stent manufacturing molds one single strand of wire into a sinusoidal wave which is then wrapped into a helical pattern and laser-fused at certain points, making the stent comparable to a flexible spring - enhancing deliverability and conformability to the vessel wall.
The third iteration, Resolute Onyx, differs by incorporating a platinum-iridium core within the CoCr alloy to improve deliverability, conformability and increase radiopacity with no compromise to radial and longitudinal strength. The oval struts have a thickness of 81µm for all sizes up to 4.0mm and 91µm for the large 4.5mm and 5.0mm versions. Treatment of large vessels is supported by an expansion limit of up to 6mm for the 4.5-5.0mm devices. The Onyx Frontier uses an identical platform but with an updated delivery system and very low crossing profile of 0.038′′ (or 0.97mm) for the 3.0mm device., ,
- The initial evaluation of Resolute ZES took place in the 139 patient multi-centre, non-randomised, FIM RESOLUTE study which demonstrated an angiographic in-stent LLL of 0.22 mm at 9-months follow-up and respective rates of MACE, TLR and any definite/probable ST of 16.5%, 3.1% and 0.0% at 12-months follow-up, and 14.0%, 2.3% and 0.0% at 5-year follow-up., , ,
- The first randomised comparison against a second-generation DES (XIENCE V) was performed in the RESOLUTE all-comers trial which demonstrated non-inferiority of the Resolute ZES in terms of TLF at 12 months and 5 years., The ISAR TEST 5 trial compared the Resolute ZES with the Coroflex ISAR polymer-free sirolimus- and probucol-eluting stent. After 10 years of follow up, the incidence of TLF (43.8% vs. 43.0%), TLR (21.9% vs. 20.6%) and definite ST (0.8% for both) were nearly identical.
- In the randomised multi-center single-blind DUTCH PEERS TWENTE II trial including 1811 patients with broad inclusion criteria, the PROMUS Element and Resolute Integrity had similar safety and efficacy outcomes after 5 years of follow-up.,
- The Onyx ZES has been studied in patients with HBR with systematic use of 1 month DAPT in the international randomised single-blind ONYX ONE trial. Compared to the polymer free (PF) drug-coated Biofreedom stent, Onyx ZES was non-inferior with respect to the primary safety outcome (death from cardiac causes, myocardial infarction, or stent thrombosis) as well as TLF at 2 years. Rates of definite ST were low and comparable between groups (0.9% vs. 1.2%). The Resolute Onyx received both CE and FDA approval for short DAPT (1 month) in HBR patients in June and October 2020, respectively.
Drug-Eluting Stents With Biodegradable Polymer Coatings - Clinical Experience in Head-to-Head Comparisons
Durable polymer coatings have proven to be a successful method for drug loading and release, the key determinants of DES efficacy in clinical practice. However, an important limitation of durable coatings is their uncertain effects on long-term arterial healing and neoatheroslerosis. Several animal and human studies have identified durable polymer coatings of early generation DES as a possible stimulus for hypersensitivity reactions and nidus for chronic inflammation. These patho-mechanisms may play an important role in the predisposition for very late ST, neoatherosclerosis and delayed restenosis. Numerous newer generation DES platforms utilize biodegradable as opposed to durable polymers. In theory immediately after implantation these devices function like conventional DES, however after polymer breakdown, they speculatively may offer the long-term profile of BMS.
An overview of the most commonly used biodegradable polymer DES is presented in Figure 16, and more in-depth characteristics can be found in Table 2. The first iteration of biodegradable polymer devices (BioMatrix Biolimus-eluting stent [BES], Biosensors, Morges, Switzerland and Nobori BES, Terumo, Japan) have been in use for over a decade, and have been joined by a heterogeneous group of additional biodegradable polymer devices which use a platform of CoCr or PtCr instead of SS; elute other limus analogues such as sirolimus, everolimus, and novolimus; have struts which are between 61-80mm thick compared to 120-125mm and have polymers with a thickness of 2-15mm instead of 10-20mm.
Table 2: Biodegradable polymer drug-eluting stents with CE-mark and/or FDA approval
| Biodegradable Polymer DES | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Biomatrix Alpha | Biomime | COMBO | Evermine50 | Firehwak Liberty | HT Supreme | Inspiron | MiStent | Orsiro Mission | Supraflex Cruz | Synergy | Ultimaster Tansei | Yukon Choice PC | |
| Manufacturer | Biosensors | Meril Life Sciences | OrbusNeich | Meril Life Sciences | Microport | Sino Medical | Scitech | Stentys | Biotronik | SMT | Boston Scientific | Terumo | Translumina |
| Backbone | CoCr | CoCr | SS | CoCr | CoCr | CoCr | CoCr | CoCr | CoCr | CoCr | PtCr | CoCr | SS |
| Strut cross-section* |  |
 |
 |
 |
 |
 |
 |
 |
 |
|
 |
 |
 |
| Strut thickness (µm) | 84-88 | 65 | 100 | 50 | 86 (2.25-3.0mm), 97 (3.5-4.0mm) | 80 | 75 | 64 | 80 (3.5 & 4mm), 60 (<3.5mm) | 60 | 74 (2.25-2.75mm), 79 (3.0-3.5mm), 81 (4.0-5.0mm) | 80 | 87 |
| Polymer | PLA | BioPoly PLLA & PLGA | SynBiosysurethane-linked copolymer | PLLA & PLGA | PLA | PBMA (eG coating) & PLGA | PLA & PLGA | PLGA | Amorphous silicon carbide (proBIOTM) & bioabsorbable active (PLLA; BIOluteTM) | 3 layers PLLA/PLCL/PVP | PLGA | PDLLA‐PCL | PLA |
| Polymer distribution | abluminal | circumferential | abluminal | circumferential | abluminal in‐groove | electro-chemically synthesized circumferential | abluminal | circumferential | circumferential | circumferential | abluminal gradient (not on crown edges) | abluminal | abluminal |
| Polymer thickness (µm) | 8-11 | 2 | 5 | 2 | 10 | 3-10 | 5 | 2.7 (1-10) | 3.5 luminal, 7.5 abluminal | 4-6 | 4 | 15 | 5 |
| Polymer absorption time | 6-9m | up to 6m | 3m | 100% in 10w | 9m | 2m | 6-9m | 100% in 3m | >12 months | 98% in 12m | 4m | 4m | 6-9m |
| Drug type | 15.6 µg/mm Biolimus A9 | 1.25 µg/mm2 sirolimus | 5.0 μg/mm sirolimus and CD34 antibody coating | 1.25 µg/mm2 everolimus | 0.3 µg/mm2 sirolimus | 1.20 µg/mm2 sirolimus | sirolimus (total 56-130 µg) | sirolimus | 1.4 µg/mm2 sirolimus | 1.4 µg/mm2 sirolimus | 1.0 μg/mm2 everolimus | 0.7 μg/mm2 sirolimus | sirolimus |
| Drug release | 100% in 6-9m | ~94% in 1m | 100% in 1m | 100% in 7w | ~90% in 3m | >90% in 1m | 100% in 45d | 97% in 45d | ~3m | 100% in 3m | 100% in 3m | 100% in 4m | ~90% in 1m |
| Approval | CE-mark | CE-mark | CE-mark | CE-mark | CE-mark | CE-mark | CE-mark | CE-mark | FDA, CE-mark | CE-mark | FDA, CE-mark | CE-mark | CE-mark |
| *Adapted from 22 or hand-drawn by the first author. Strut cross-sections might vary depending on stent diameter, here work-horse diameters are presented. CE: Conformité Européenne; CoCr: Cobalt Chromium; FDA: Food and Drug Administration; PDLLA: poly(D,L)-lactic acid, PLA: polylactic acid, PLLA: Poly-l-Lactic acid, PLCL: Poly(L-lactide-co-ε-caprolactone), PLGA: poly-DL-lactide-co-glycolide; SS: stainless steel; PtCr: Platinum Chromium. | |||||||||||||
Biolimus A9-Eluting Stents
Two stent platforms utilize the combination of a biodegradable PLA polymer and the elution of biolimus A9:
Biomatrix™ (Biosensors International PTE LTD, Singapore)
The BioMatrix stent platform has undergone several modifications since it was first introduced in 2008. The first iteration, Biomatrix Flex was made of SS with a strut thickness of 120µm, whilst the latest iteration, Biomatrix Alpha, is based on CoCr with 84-88µm struts, with both applying biolimus A9 to the abluminal stent surface immersed at a concentration of 15.6 μg/mm into a biodegradable PLA polymer. The Nobori stent (Terumo, Japan) used the same PLA polymer, anti-proliferative agent, and SS-platform of the first-iteration Biomatrix stent. One difference between the Biomatrix Flex and the Nobori stent was an ultra-thin non-degradable parylene base-coating between the stent and the polymer on the Nobori stent to enhance polymer attachment to the stent struts., The Nobori stent is no longer marketed, and supporting information can be found in the appendix.
- The angiographic efficacy of BES was first demonstrated in the randomised STEALTH-I study which reported significantly lower in-stent LLL (0.26mm vs. 0.74mm, p<0.001) and percent neointimal volume (3.2% vs. 32%, p<0.001) with BES compared to BMS at 6-months follow-up. In the angiographic follow-up group of the LEADERS study (described below), BES was non-inferior to SES for the principal angiographic endpoint of in-stent percent diameter stenosis (BES: 20.9% vs. SES: 23.3%, difference -2.2%, 95%-CI -6.0 to 1.6, Pnon-inferiority = 0.001, Psuperiority = 0.26) with no significant difference in any other angiographic endpoint. Comparisons with more contemporary devices took place in the EVERBIO II study, which randomised 238 patients 1:1:1 to BES, EES or Absorb BVS, and showed comparable rates of in-stent, and in-segment LLL at 9-months angiographic follow-up for all three devices.
- In the LEADERS study, the BioMatrix Flex BES was compared against SES in 1,707 all comer patients undergoing PCI. BES was found non-inferior to SES for the primary clinical endpoint, a composite of cardiac death, MI, or TVR (BES: 9.2% vs. SES: 10.5%, rate ratio 0.88, 95%-CI 0.64 to 1.19, Pnon-inferiority = 0.003, Psuperiority = 0.39)., BES was also non-inferior to SES for the principal angiographic endpoint of in-stent percent diameter stenosis. Five-year follow-up data showed similar rates of MACE (BES: 22.3% vs. SES: 26.1%, HR=0.83, 95% CI 0.69-1.02, Pnon-inferiority < 0.001, Psuperiority = 0.07). Beyond one year, an increasing difference in very late definite ST emerged with an annual incidence of definite ST amounting to 0.17% in BES and 0.63% in SES treated patients. This resulted in a significant relative risk reduction of 74% (HR 0.26, CI 0.10 – 0.68, p = 0.003) in favour of BES between year one and five. The reduction in very late ST translated into a lower incidence of clinical events associated with definite ST, whereas there was no reduction in clinical events not associated with ST.
- In the COMFORTABLE study, 1161 patients undergoing primary PCI for STEMI were randomised to receive either BES (n=575) or BMS (n=582). Data out to 1-year demonstrated comparable rates of cardiac death and ST, whilst use of BES lead to significantly lower rates of MACE (4.3% vs. 8.7%, p=0.004). The benefit of BES over BMS in terms of MACE continued to accrue out to 5 years (8.6 % vs. 14.9%, p=0.001) with clinical differences mainly driven by a significantly reduced risk for target vessel re-infarction (BES 2.2% vs. BMS 5.0%, p=0.02) and ischaemia-driven TLR (4.4% vs. 10.4%, p<0.001). Although approximately 10% of patients discontinued DAPT after 1 year and >80% at 2-years, comparable rates of very late ST were reported for BES and BMS.
- The all-comers SORT-OUT VI study randomised 2,999 patients to BES (n=1497) or R-ZES (n=1502). The study met its non-inferiority primary endpoint of MACE, a composite of cardiac death, target vessel MI, and ischaemia-driven TLR with rates of 5.3% and 5.0% for R-ZES and BES, respectively (Pnon-inferiority =0.004). There were no significant differences in rates of efficacy or safety, including ST. No between-stent differences emerged out to 3-year follow-up.
- Propensity score adjusted registry data of the BioMatrix Alpha (n=400) using the LEADERS trial cohort as the comparator suggested lower rates of MACE with the updated thin-strut CoCr device. Absolute rates of TVF (6%) and definite or probable ST (1.1%) at 2 years were reassuring.
Everolimus-eluting stents
SYNERGY stent (Boston Scientific, Marlborough, MA, USA)
The SYNERGY stent utilises the same PtCr alloy and stent design as the PROMUS Element stent platform, however strut thickness is somewhat lower (74-81µm) and the stent is coated in an abluminal ultrathin rollcoat bioerodable PLGA polymer that elutes everolimus (100 μg/cm2). The complete release of everolimus occurs by 90 days and biodegradation of the PLGA shortly thereafter. The SYNERGY platform is based on the PROMUS Premier platform, but with several differences, including the use of an ultrathin (4 µm) and lighter (200 μg load per 16 mm of stent) bioresorbable PLGA polymer with the coating limited to the abluminal strut surface and thinner stent struts. Additionally, the end rings of the SYNERGY EES are reinforced with 4 connectors instead of 2 throughout the body of the stent to prevent longitudinal compression, which was the main limitation of PtCr platforms. For large-vessel PCI, the SYNERGY MEGATRON with different connector design was developed allowing overexpansion from 3.5 mm to 6.0 mm to accommodate wide diameter mismatch.
- The safety and performance of the stent was assessed in the single-blind randomised, non-inferiority EVOLVE trial, which enrolled 291 patients in 29 sites in Europe, Australia, and New Zealand. The trial compared two doses of everolimus (PROMUS-like, 113 µg/20 mm stent; and half-dose, 56 µg/20 mm stent) on the SYNERGY stent to the Promus EES stent in patients with a single de novo native coronary artery lesion. At 6-month follow-up both SYNERGY stents were shown to be non-inferior to the Promus EES with respect to the primary angiographic endpoint of LLL (Standard dose 0.10 mm vs. Low dose 0.13 mm vs. EES 0.15, Pnon-inferiority < 0.001). In addition, rates of the primary clinical endpoint of TLF, a composite of cardiac death, MI, and TLR at 30 days were comparable between stents. After 5 years of follow-up, rates of TLF were similar between groups (Promus 7.2%, Synergy full dose 5.5%, Synergy half dose 5.2%, p=NS).
- In the EVOLVE II trial, 1684 patients scheduled for PCI due to stable CAD or Non-ST segment elevation MI were randomly assigned to receive either the SYNERGY stent or the PROMUS EES. Comparable rates of the primary composite endpoint, TLF at 12-month (6.7% vs. 6.5%, p=0.83 for difference) demonstrated the non-inferiority of the SYNERGY stent (Pnon-inferiority =0.0005). Rates of the individual components of TLF were similar for both study arms: cardiac death (0.5% vs. 0.9%, p= 0.34), MI (5.4% vs. 5.0%, p= 0.68), clinically indicated TLR (2.6% vs. 1.7%, p= 0.21). Comparable clinical safety was established in view of a similar rate of ST (0.4% vs. 0.6%, p= 0.50). At 2 years, rates of TLF were 9.4% in the SYNERGY groups vs 8.5% in the PROMUS EES (p=0.57). Three-year follow up data supported long term safety and efficacy of the SYNERGY stent with a 0.2% probable ST rate in the SYNERGY group versus 0.7% in the PROMUS EES (p=0.15). Based on the results from this study, the SYNERGY stent received FDA approval, and became the first biodegradable polymer DES available in the US.
- The single-blind, randomised SENIOR trial included 1200 patients aged 75 years or older presenting with acute or chronic coronary syndromes. Patients were randomly assigned to undergo treatment with the Synergy EES or a similar BMS with the intended duration of DAPT recorded (1 month for patients with stable presentation and 6 months for those with unstable presentation). The primary outcome (a composite of all-cause mortality, MI, stroke, or ID-TLR) occurred in 12% of patients treated with Synergy EES vs. 16% of patients treated with BMS (RR 0.71, 95% CI 0.52–0.94, p=0.02), ST occurred in 1% in both groups (p=0.13).
- As mentioned previously, the Orsiro SES, Synergy EES and Resolute ZES performed similarly in the randomised BIO-RESORT TWENTE III all-comers trial after final 5 years of follow-up (TVF 12.7% vs. 11.6% vs. 14.1%, treated with ZES, HR 0.89, 95% CI, 0.71-1.12, P(log-rank)=0.31; and HR 0.82, 95% CI 0.65-1.04, P(log-rank)=0.10).
Sirolimus-Eluting Stents
BioMime and Evermine50 (Meril Life Sciences, Gujarat, India)
The BioMime is an ultrathin (65 μm), cobalt-chromium, biodegradable polymer, sirolimus-eluting stent. The device presents a hybrid design with closed cells at both ends and open cells in the middle, potentially favouring a better stent expansion and lesser likelihood of edge dissection. The open cell design in the mid-part of the stent should also facilitate side branch access and treatment. The BioPoly biodegradable polymer has a low thickness (~2 μm), is composed by PLLA and PLGA, and degrades in approximately 60 days. The sirolimus concentration is 1.25 μg/mm2 and is released over 30–40 days after stent implantation.
The Biomime Morph is a further iteration of the Biomime SES technology featuring a tapered stent system with two different proximal and distal diameters (e.g., 2.75–2.25 mm; 3.00–2.50 mm, etc). The tapered stent system together with the long available lengths (30, 40, 50, 60 mm) allows the treatment of diffuse, long lesions.
The Evermine50 represents the same hybrid cell stent design, but the cobalt-chromium platform is thinner (50 μm). The stent releases everolimus, which is loaded at a concentration of 1.25 μg/mm2.
- The initial clinical assessment took place in the Merit-I study, which enrolled 28 patients, and reported an in-stent LLL of 0.15mm at 8-months angiographic follow-up. Following this was the Merit-2 study, which recruited 242 more complex patients, who had an in-stent LLL of 0.13 mm at 8-months. The rate of MACE was 6.2% at 1-year because of 2 cardiac deaths, 3 non-fatal MIs and 10 clinically-driven TLRs. In the Merit-3 observational post-marketing study including 1161 patients, rates of TLR and ST were 0.5% and 0.1% after 1 year of follow-up, respectively. MeriT-V randomised 256 patients with de-novo lesions to the BioMime SES vs. XIENCE EES. Rates of MACE and TV-MI were similar at 9 months, no ST occurred. At 2 years, the cumulative rate of MACE (defined as cardiac death, MI, or ischaemia-driven TVR) was comparable in both arms (7.74% vs. 9.52%, P = 0.62).
- The Evermine50 EES was investigated in 2 single-arm observational studies including 422 all-comer patients, of whom 165 had follow-up data up to 24 months. Rates of MACE were low (2.4%), and no ST was observed., The >40mm long device was studied in 711 patients (92% ACS, median stent length 54±14 mm). TLF occurred in 6.6% of patients after one year, definite ST was observed in 1.1%.
BuMA and HT Supreme Drug Coated Stent (Sino Medical, Tianjin, China)
The BuMA stent uses a SS backbone with a strut thickness of 100µm coated with PLGA (top-coat). Through an electro-chemical process, the proprietary eG Coating™ (base-coat of nonerodable brush of poly n-butyl methacrylate, PBMA) is synthesised onto the surface of the stent, creating a filament-like structure that acts as an adhesive for the polymer (Figure 18). Greater than 90% of sirolimus is released within 28 days, and the polymer degrades in a comparatively short time of approximately 2 months. The HT Supreme uses the same proprietary eG Coating™ technology on a laser cut CoCr platform, electropolished to a strut thickness of 80µm.
Figure 18
Electro-grafted coating on the BuMA and HT Supreme stents: The eG CoatingTM is electro-grafted (eG) onto the surface of the stent using a proprietary electo-chemical process. (A) The stent is submerged in a PBMA monomer solution. Electric current is applied, and the polymer is electro-grafted to the stent. (B) Electric current is cycled and a brush-like structure of eG Coating is synthesized onto the surface of the stent. (C) The filament-like structure of the eG Coating allows for interdigitation of the PLGA polymer matrix containing sirolimus drug. (D) The resulting biodegradable polymer-drug coating is robust and resistant to cracking, even in areas of elastic deformation. Reproduced with permission of the publisher
- The clinical performance was tested in the PANDA III trial, comparing the BuMA stent with the EXCEL SES (JWMS, Weihai, China), a SES with a biodegradable PLA polymer and a SS platform with 120-130μm thick struts. In total, 2,348 all-comer real-world patients were included, with the 1-year primary endpoint of TLF occurring in 6.4% of patients in each group, demonstrating non-inferiority. In the subgroup of patients with acute MI (n=732), rates of target vessel MI (2.2% vs. 5.8%, P=0.01) and definite/probable ST (0.3% vs. 2.2%, P=0.04) were lower in favour of the BuMA stent.
- The international, 2:1 randomized, single-blind PIONEER III trial compared the HT Supreme DCS to the Xience EES in 1629 patients with acute and chronic coronary syndromes. At 12 months, TLF occurred in 5.4% vs. 5.1% (absolute risk difference, 0.32%, 95% CI −1.87 - 2.5, p for non-inferiority 0.002). TLR was more frequently observed in patients receiving the HT Supreme stent (2.5% vs. 1.0%, HR 2.62, 95% CI 1.01-6.83, p=0.04).
Combo Stent Platform (OrbusNeich, Fort Lauderdale, Fl, USA)
The Combo stent is a 100µm thick SS stent covered abluminally with a biodegradable polymer matrix allowing a controlled release of sirolimus. An additional circumferential layer of anti-CD34 antibodies is applied on the stent struts on top of the polymer aiming to accelerate endothelial coverage. CD-34 antibodies essentially capture endothelial progenitor cells which in theory might promote rapid in-stent re-endothelialisation (Figure 19) , Data from histology and OCT at 28 days follow-up in the porcine model indicates that this combination promotes endothelialisation, while also reducing neointimal formation and inflammation when compared to the standard SES and Genous EPC stent. The polymer is degraded within 90 days and sirolimus is applied at a dosage of 5µg/mm stent length.
Figure 19
The COMBO Dual Therapy Stent. Schematic representation of the endothelial progenitor cell (EPC) capture technology. A luminal pro-healing anti-CD34+ antibody layer attracts circulating endothelial progenitor cells. These endothelial progenitor cells can mature into normal endothelium, promoting endothelialization. Reproduced with permission of the publisher (https://doi.org/10.1016/j.jcin.2018.04.038)
- The Combo stent was tested in the REMEDEE trial, which randomised 183 patients 2:1 to the Combo stent or the Taxus Liberté PES, and met its angiographic non-inferiority primary endpoint of in-stent LLL at 6 month (Combo stent 0.39±0.45 mm versus Taxus PES 0.44 0.56 mm, p non-inferiority= 0.0012). These findings were corroborated in an IVUS sub study. Evaluation of the device in an all-comers population took place in the 1000 patient REMEDEE registry, which report low event rates out to 1-year follow-up. A propensity matched analysis between outcomes in patients receiving the Combo stent in the REMEDEE registry, and Promus EES or R-ZES from the Dutch Peers study, showed comparable clinical outcomes out to 2-years.
- The EGO-COMBO reported a 9-month LLL of 0.23 ± 0.36mm in 61 patients and neointimal regression at OCT follow-up from 9 to 24 months. The rate of MACE beyond 36 months was low (3.28%) and no definite ST occurred.
- The HARMONEE trial included 572 patients with stable CAD (4.5% NSTEMI) randomly assigned to the Combo vs. the XIENCE stent. An OCT sub-study in 133 lesions suggested improved tissue strut coverage with the Combo stent (91% vs. 75%). Rates of TVF (7.0% vs. 4.2%) were numerically higher in the COMBO arm. In the randomised, multicenter, single-blind, SORT OUT X trial (n=3146), the Combo stent did not demonstrate non-inferiority compared to Orsiro at 12 months due to higher rates of TLF with the Combo stent, mainly driven by higher rates of TLR (3.4% vs. 1.5%; incidence rate ratio 2.22, 95% CI 1.37–3.61).
FIREHAWK™ Stent (MicroPort, Shanghai, China)
The Firehawk thin strut (86-97µm) CoCr SES uses a biodegradable polymer that is localised in a series of abluminal grooves, with the aim of minimize drug concentrations and polymer burden, resulting in >80% of the stent surface being metallic.157 The drug density of sirolimus is 0.3 μg/mm2, which is the lowest amongst contemporary SES with approximately one fifth of the dose used in other platforms (such as Orsiro or Supraflex). The Firehawk Liberty uses an updated delivery system with improved crossability and trackability, according to the company.
- The safety and feasibility of the stent was confirmed in the TARGET FIM which enrolled 21 patients and showed in-stent LLL of 0.13 ± 0.18 mm and 0.16 ± 0.07 mm at 4- and 13-month respectively. Furthermore, a primary OCT endpoint showed that 96.2% of struts were fully covered at 4-months, whilst low clinical events rates were seen out to 12-months.
- Following this the TARGET I study randomised 458 patients to the FIREHAWK SES (n=227) or EES (n=231), and achieved its primary endpoint of non-inferiority for in-stent LLL at 9-month follow-up (0.13 vs. 0.13, Pnon-inferiority < 0.001). Clinical event rates remained low and comparable between both groups with no definite/probable ST events with the FIREHAWK out to 60-months.
- The 730 patient TARGET II registry also reported low event rates out to 60-months follow-up. In the randomised TARGET all-comers trial of 1653 patients, the Firehawk DES was non-inferior to Xience V in terms of TLF (6.1% vs. 5.9%) and LLL (0.17±0.48 vs. 0.11±0.52 mm) at 12 months. Final 5-year data confirmed the safety and efficacy of the device with similar rates of TLF (17% vs. 16%), and patient oriented composite outcomes (all-cause death, all MI, any revascularisation, 34% vs. 33%).
Inspiron stent (Scitech, Sao Paulo, Brazil)
The Inspiron has a CoCr platform coated with an abluminal PLA and PLGA polymer and elutes a low dose of sirolimus (56µg).
- Initial clinical evaluation took place in the INSPIRON I trial, which randomised 58 patients 2:1 to treatment with the Inspiron stent (n = 39) or its equivalent Cronus BMS (n=19). The study achieved its primary endpoint with a significantly lower in-segment LLL with the Inspiron stent compared to the control (0.19 vs. 0.58, p <0.001). In-stent LLL and percent neointimal obstruction were also both significantly lower with the Inspiron SES. MACE rates at 12-months were comparable, whilst no TLR was seen with the SES out to a median of 878 days.
- In the multi-center DESTINY trial including 170 patients, the Inspiron stent was non-inferior to the Biomatrix Flex BES for 9-month in stent LLL (0.20 vs. 0.15, Pnon-inferiority <0.001). IVUS and OCT findings showed slightly more neointimal hyperplasia and strut coverage compared with the Biomatrix stent, respectively.
- The prospective single-center INSPIRION all-comers registry included 790 consecutive patients between 2017-2019. At 12 months, the incidence of all-cause death was 11.5% (6.2% in-hospital and 5.3% during follow-up), definitive ST was 0.2%, and TLR 2.2%.
MiStent (Micell Technologies, Durham, NC, USA)
The MiStent is is an ultrathin (64 μm), CoCr stent with a PLGA bioabsorbable polymer which degrades over 45-60 days, and elutes sirolimus which is present in a crystalline formulation to facilitate modified release such that the stent’s anti-restenotic drug last three times longer than its polymer.
- The stent’s FIM study is the DESSOLVE I study which enrolled 30 patients and had a primary endpoint of in-stent LLL. Angiographic and IVUS follow-up demonstrated the stent’s efficacy with an in-stent LLL of 0.08 mm, and a neointimal percentage obstruction of 11.2% at 18-months. No binary restenosis or TLR was seen out to 18-months. Safety has been demonstrated on OCT with a mean strut coverage of >85%, and clinically at 5-years, with low MACE rates and no reported TLF or ST.
- Further evaluation took place in the DESSOLVE II study , which enrolled 184 patients who were randomised 2:1 between the MiStent (n=121) and the E- ZES (n=60). The primary endpoint of the study was met with a significantly lower in-stent LLL at 9-months with the MiStent compared with E-ZES (0.27 mm vs. 0.58 mm, p < 0.001). OCT performed in a selected group of patients showed a very low proportion of uncovered struts in both arms and mean neointimal thickness significantly lower in patients treated with the MiStent. Clinical event rates and ST were low and similar up to 5-year follow-up , .
- The most robust evaluation of the device took place in the multi-centre all-comers DESSOLVE III study which enrolled 1398 patients who were randomised 1:1 to the MiStent (n=703) or Xience EES (n=695). The study met its non-inferiority primary endpoint, a composite of cardiac death, target vessel MI and clinical indicated TLR at 12-months follow-up, with rates of 5.8% for MiStent and 6.5% for Xience (Pnon-inferiority<0.001). No significant differences were observed in rates of the individual clinical endpoints, including ST.
- The prospective, single-blind, multicenter, randomised DESSOLVE-C trial assigned patients with de novo coronary lesions to receive MiStent or TIVOLI stent in a 1:1 ratio. The primary endpoint was a non-inferiority comparison of in-stent LLL by quantitative coronary angiography at 9 months. The MiStent was superior to the Tivoli BP-SES for in-stent LLL at 9 months (0.23 ± 0.37mm vs. 0.34 ± 0.48mm, p superiority = 0.02), and showed numerically lower rates of TLF (3.70% vs. 6.60%; P = 0.17) .
Orsiro (Biotronik AG, Bülach, Switzerland)
The Orsiro SES is a CoCr stent with ultrathin struts (60μm) for the sizes <3.5mm (80μm for 3.5-4.0mm) and has a surface that is coated with a layer of an amorphous hydrogen-rich silicon carbide (proBIOTM), which acts as a diffusion barrier sealing the underlying bare metal surface and reducing ion release by up to 96%. The components of this silicon carbide include: silicon carbide, a ceramic material, carbon and a chemical compound of silicon. The superadjacent BIOluteTM PLLA polymer elutes sirolimus over a period of approximately 3 months and degrades thereafter over duration of 12-15 months . The polymer matrix has an asymmetric design that allows for the release of a greater drug dose on the abluminal than luminal side. The successor Orsiro Mission uses a re-engineered delivery system to improve deliverability, trackability and crossability.
The clinical trial program has been robust in comparing the device to newer-generation DP-DES , , and biodegradable polymer DESs , .
- The FIM study was the BIOFLOW-I which enrolled 30 patients, and reported a primary endpoint of in-stent LLL of 0.05 mm at 9-months . The 12-month MACE rate was 10% owing to one cardiac death, and two ischaemia driven TLRs.
- Further assessment took place in the multi-center BIOFLOW-II study, which randomised 452 stable patients to treatment with the Orsiro stent (n=298) and Xience EES (n=154). The study achieved its non-inferiority primary endpoint of in-stent LLL at 9-months (0.10±0.32mm vs. 0.11±0.29mm, Pnon-inferiority < 0.0001). Clinical event rates were low and comparable between both devices at one year: rates of the device-oriented endpoint, TLF, were 6.5% in the Orsiro arm vs. 8.0% in patients treated with XIENCE (p=0.58) . These findings were confirmed at 24 months in the overall population and also in diabetic and small vessel cohorts . Neointimal thickness assessed by OCT in a subgroup of patients was similar without differences in terms of uncovered or malapposed struts. After 5 years of follow-up, rates of TLF (10.4% vs. 12.7%) and definite or probable ST (0.7% vs. 2.8%) were comparable between Orsiro and XIENCE .
- In the randomised ORIENT study the Orsiro SES was shown to be non-inferior in terms of in-stent LLL at 9-months compared to the Resolute ZES (median 0.06 mm vs. 0.12 mm; Pnon-inferiority<0.001; Psuperiority=0.21) . Angiographic restenosis was lower with Orsiro (15% vs. 20%, p=0.002), whilst adverse clinical outcomes were low in both groups.
- In the BIOSCIENCE trial 2119 patients with minimal exclusion criteria, were randomly assigned to receive the Orsiro stent (n=1063) or the XIENCE EES (n=1056) . At 12 months, the comparable rate of the combined safety and efficacy primary endpoint supported the non-inferiority of the Orsiro stent compared with XIENCE. No significant differences were reported in rates of ST. Clinical outcomes continued to be similar between groups at 2-years and 5-years follow-up in the full cohort , and the pre-specified diabetic sub-group .
- The all-comers SORT OUT VII study was the first randomised study to compare the performance of two BP DES – the Orsiro SES (n=1261) and Nobori-BES (n=1264) . At 1-year the primary endpoint of TLF occurred in 3.8% and 4.6% of patients treated with Orsiro and Nobori, respectively, achieving the pre-specific criterion for non-inferiority (Pnon-inferiority<0.001). The overall clinical event rates were low with no between-stent differences in any clinical endpoints other than definite ST, which was significantly lower with Orsiro (0.4% vs. 1.2%, p=0.034) and driven by lower rates of sub-acute definite ST (0.1% vs. 0.6%, p=0.05). After 5 years, TLF did not differ among between Orsiro and Nobori (12.4% vs. 13.1%; RR 0.94, 95% CI 0.75-1.18) .
- The all-comers BIO-RESORT (TWENTE III) trial was a multicentre double-blinded trial, which randomised 3,514 patients to Orsiro (n=1,169), the Synergy EES (n=1,172) and the Resolute ZES (n=1,173) . The study’s two independent hypotheses were that Orsiro and Synergy would have non-inferior rates of TVF, a composite of cardiac death, target vessel MI and clinically indicated TVR at 12-months, when compared separately with the Resolute ZES. At 12-months the primary endpoint of TVF occurred in 4.7% and 5.4% of patients receiving Orsiro and Resolute ZES, respectively (HR 0.87, Pnon-inferiority<0.001). There were no significant differences in the components of TVF or ST. The final 5-year report indicated that Orsiro, Synergy, and Resolute were similar in terms of safety and efficacy, including mortality. A prespecified comparison in patients with diabetes revealed no significant differences between the devices .
- The BIOFLOW V randomised in a 2:1 ratio a total of 1334 patients to undergo PCI with the Orsiro SES or the Xience EES . The primary endpoint of TLF was significantly reduced among patients allocated to the Orsiro SES (6% vs. 10%, p=0.0399) due mainly to a lower occurrence of target-vessel MI in the experimental arm (5% vs. 8%, p=0.0155). After 5-years of follow-up TLF and the individual outcomes of cardiac death and TLR were similar with Orsiro and Xience. Both, target vessel MI (6.6% vs 10.3%, P = 0.015) and late/very late definite/probable ST (0.3% vs 1.6%, P = 0.021) were significantly lower with Orsiro .
- The BIOSTEMI trial was an investigator initiated, randomised, superiority, multi-center trial and enrolled 1300 patients with STEMI . Patients were randomised to receive treatment with either Orsiro or Xience. Historical data on STEMI patients from the Bioscience randomised trial were used as prior information in a Bayesian design. At 5 years, TLF occurred in 8% vs. 11% patients (difference of -3%; RR 0.70, 95% Bayesian credible interval 0.51-0.95; Bayesian posterior probability for superiority 0.988). The difference was mainly driven by reductions in TLR in favour of Orsiro (3.1% vs. 5.4%, Bayesian credible interval 0.32-0.96). Five-year rates of definite ST were 1.7% vs. 2.6% (Bayesian credible interval 0.28-1.20) .
- A large, updated network meta-analysis of 77 trials and 99 039 patients ranked Orsiro as the stent with the highest surface under the cumulative ranking curve for TLF in comparison to other new-generation DES at 1 year . Although this signal was attenuated at a median of 50 months follow-up, Orsiro had lower rates of ST compared to Nobori/BioMatrix and Resolute Onyx.
- Another meta-analysis restricted to DP-DES comparators in 9 randomised trials with 11 302 patients and 2.8 years follow-up, demonstrated a lower rate of TLF (1.3% absolute risk reduction, OR 0.82; 95% CI 0.69 to 0.98; p=0.03), driven by a reduction in TV-MI (OR 0.80; 95% CI 0.65 to 0.98; p=0.03) .
Supraflex (Sahajanand Medical Technologies, Surat, India)
The Supraflex Cruz SES with a CoCr backbone and circumferential biodegradable 3-component polymer (PLLA, PLCL and PVP) features an ultra-thin strut thickness of 60 μm for all diameters up to 4.5 mm with a very low crossing profile . 22 Supraflex Cruz differs from its predecessor Supraflex because of two long dual-Z connectors from “valley to valley” between the struts, to enhance deliverability and increase the flexibility of the stent, and a re-designed proximal shaft to allow a better pushability.28 The Supraflex Cruz Nevo provides an updated delivery system to enhance stent retention on the balloon and increase trackability. Sirolimus has a concentration of 1.4 μg/mm2, and the polymer gradually degrades over 9–12 months. Approximately 70% of the drug is released within 7 days, with the remainder eluted within 3 months.
- The randomised multi-center, single-blind non-inferiority TALENT trial enrolled 1435 “all-comer” patients (23% diabetes, 58% ACS, 16% bifurcation PCI) who were randomised to the Supraflex vs. Xience DES. At 3 years, rates of TLF (8.1% vs. 9.4%), clinically indicated TLR (5.0% vs. 5.9%) and definite ST (1.0% vs. 1.3%) were similar between groups , .
- The investigator-initiated, multi-centre, randomised COMPARE 60/80 trial compared the Supraflex Cruz 60μm ultra-thin strut to the Ultimaster Tansei 80μm thin-strut device in 732 HBR patients (mean age 75years, 73% men, approximately 30% ACS), who received an abbreviated 30-day course of DAPT. The primary endpoint of net adverse cardiovascular events, a composite of cardiovascular death, MI, TVR, stroke, and major bleeding occurred in 17.1% in the Ultimaster and 15.4% in the Supraflex arm (HR 0.89, 95% CI 0.62-1.28, p for non-inferiority 0.02) after 12 months, which met the noninferiority margin of 4.0%. There was no difference in any of the secondary endpoints, particularly ST .
- The multi-centre, randomised open-label FIRE trial assigned 1445 patients ≥75 years of age with STEMI or NSTEMI to either complete revascularisation guided by functional testing using (FFR, iFR, cFFR, QFR) or culprit-only revascularisation. All patients received the Supraflex Cruz as the study device. The primary outcome, a composite of death, MI, stroke, or any revascularisation at 1 year was reduced in favour of complete revascularisation (15.7% vs. 21%, HR 0.73, 95% CI 0.57 to 0.93; p=0.01). Rates of ST were reassuringly low in this high-risk cohort of elderly ACS patients (0.8%) .
Svelte (Svelte Medical Systems, New Providence, NJ, USA)
The Svelte is a sirolimus-eluting CoCr stent with 81μm strut thickness,191 which has a combined PLGA and amino acid-based coating which is highly biocompatible, non-thrombogenic, non-inflammatory and fully bioresorbable over 12-months.
The device uses 2 delivery platforms, the ultralow profile Integrated Delivery Stent System (IDS), and a conventional rapid exchange system. The IDS fixed-wire system eliminates the need for conventional guidewires and pre-dilatation balloons, has a low crossing profiles of 0.031”, and can be used with small caliber (≥4F) guide or diagnostic catheters. The stent balloon also has distinct features including two balloon control bands located on the proximal and distal balloon shoulders which are designed to facilitate smooth stent delivery; focus pressure under the stent for controlled stent deployment; and minimise longitudinal balloon growth and contact with the vessel wall. The balloons also have a lower compliance enabling higher-pressure inflations, which is important given the inability to pre-dilate the lesion.,
- The first clinical assessment of the stent took place in the DIRECT FIM study, which enrolled 30 patients and had a primary safety endpoint of angiographic TVF, and a primary efficacy endpoint of in-stent LLL. There was one device failure. Angiographic, IVUS and OCT follow-up reported an in-stent LLL of 0.22 mm; a neointimal percentage obstruction of 2.7%; and 97.9% strut coverage at 6-months, respectively. There was one binary restenosis, one angiographically driven TLR and no reported cardiac death, MI or ST at 60-months.
- The DIRECT II trial randomised 159 patients 2:1 to Svelte DES or the Resolute ZES, and showed non-inferiority of Svelte for 6-month LLL (0.09mm vs. 0.13mm, Pnon-inferiority<0.0001). Similar clinical outcomes were reported, with no ST.
- The randomised, single-blind non-inferiority OPTIMIZE trial enrolled 1639 patients scheduled to undergo PCI for NSTEMI (32% MI, 25% unstable angina) or stable CAD, who were treated with the Svelte DES or an EES (Xience or Promus). TLF occurred in 10.3% vs. 9.5% in the Svelte and control group, respectively (difference=0.8%; p for non-inferiority=0.034). Clinically indicated TLR and ST were observed in 1.5% vs. 1.9% (P=0.57) and 0.38% vs. 0.51% (P=0.72), respectively.
Tivoli (EssenTech, Beijing, China)
The Tivoli stent is an open cell, balloon expandable, CoCr stent (80 µm) coated with a biodegradable polymer (PLGA) containing sirolimus at a dose of 8 µg per mm of stent length. Most of the drug (75%) is released in 28 days.
It proved to be non-inferior for the occurrence of efficacy primary endpoint at 12 months compared with a DP SES sharing the same CoCr platform, the FIREBIRD 2 stent (MicroPort, Shanghai, China) in the randomised I-LOVE-IT-2 trial. 195 The prospective, single-blind, multicenter, randomised DESSOLVE-C trial assigned patients with de novo coronary lesions to receive MiStent or TIVOLI stent in a 1:1 ratio. The primary endpoint was a non-inferiority comparison of in-stent LLL by quantitative coronary angiography at 9 months, with the MiStent shown to have significantly lower LLL (0.23 ± 0.37mm vs. 0.34 ± 0.48mm, p for superiority = 0.02), and numerically lower rates of TLF (3.70% vs. 6.60%; p=0.17).170
Ultimaster (Terumo, Tokyo, Japan)
The Ultimaster stent is made of a CoCr platform with thin struts (80 µm), open cell design and an abluminal biodegradable polymer (poly-DL-lactic acid –PDLLA- and polycaprolactone co-polymer). The polymer elutes sirolimus (3.9 µg/mm stent length) and degrades during a period of 3-4 months. An aspect of this device is a gradient coating consisting of a lack of drug polymer on the stent areas experiencing the highest physical stress with the aim to reduce the risk of polymer cracking and delamination. The successor Ultimaster Tansei differs by an updated delivery system with a rounded shape tip to improve crossability, a stronger hypotube, and modified exit port aimed at improving coaxial alignment. The device has two stent models: one for small vessels (from 2.25 to 3.0 mm) and another for large vessels (3.5 and 4.0 mm). Although approved post-dilation limits are up to 4.5 mm for the smaller stent and up to 5.5 mm for the larger, an independent bench test confirmed overexpansion to 5.8 mm for larger stents.
- In the randomised CENTURY II trial, it showed a safety and efficacy profile similar to Xience. In a population of 1123 patients with broad inclusion criteria, freedom from TLF (a composite of cardiac death, target vessel MI and TLR) was 95.6% in the Ultimaster group and 95.1% in the Xience group (Pnon-inferiority<0.0001) at 9-month follow-up. A comparable short-term safety profile was also noted with non-significant differences in rates of cardiac death, MI and ST. Final five-year data from indicated similar safety and efficacy compared to XIENCE.
- The MASTER DAPT trial investigated an abbreviated (1 month) versus a standard (median 6 months) DAPT strategy in HBR patients undergoing PCI with the Ultimaster stent. Rates of net adverse clinical events and major adverse cardiac and cerebral events did not differ between groups in this all-comer PCI population, with or without an indication for oral anti-coagulation. Accordingly, the Ultimaster is CE approved for 1 months DAPT.
Yukon Choice PC (Translumina, Hechingen, Germany)
The Yukon stent was originally the first polymer-free DES and used a microstructured sirolimus-eluting SS platform. The microporous stent surface increases the drug reservoir capacity and allows gradual drug release without the obligatory application of a polymer. The Yukon Choice PC represents the PLA polymer coated iteration.
- The platform has been compared against two durable polymer DES platforms, the Cypher SES and the Xience V EES (n=1304) in the randomised, non-inferiority ISAR-TEST-4 trial. At 1-year the BP-SES was found to be non-inferior for the primary endpoint, a composite of cardiac death, MI, and TLR (13.8% vs. 14.4%, RR 0.96, 95% CI 0.78-1.17, Pnon-inferiority = 0.005, Psuperiority = 0.29). Likewise, there were no differences with respect to cardiac death or MI (6.3% vs 6.2%, p = 0.94), TLR (8.8% vs 9.4%, p = 0.58), and ARC definite or probable ST (1.0% vs 1.5%, p = 0.58). Similar trends were observed at 5-year follow-up with the primary endpoint occurring in 20.5% and 19.5% of patients treated with BP-DES and DP-DES, respectively (p=0.71). Rates of ST were similar between the BP SES and EES, and numerically higher with Cypher-SES vs. EES (2.4% vs. 1.4%, p=0.22).
Biodegradable vs. Durable-Polymer DES
Although BP-DES have been designed to further improve outcomes compared with DP-DES, current evidence has failed to show significant differences in clinical outcomes using newer-generation contemporary DES platforms. A meta-analysis of 20 studies including 20,005 patients compared early and newer generation DP-DES with BP-DES. While BP-DES reduced in-stent LLL compared to both early and newer generation DES, rates of ST were only lower compared to early-generation DES, and mortality and other clinical endpoints were similar. A more recent analysis of 32 randomised trials with 39,686 patients found no differences in terms of TVF between newer-generation DP-DES vs. BP-DES, even when accounting for differences in strut thickness among BP-DES. In the largest nationwide registry study to date (Swedish Coronary and Angioplasty Registry, SCAAR) including 16,504 and 79,106 patients in the BP-DES and DP-DES arms, respectively, rates of restenosis, definite ST, MI and all-cause mortality were similar between groups throughout 2 years of follow-up. Recently, the Orsiro sirolimus eluting BP-DES has gained attention due to lower rates of TLF compared to the Xience DP-DES in the BIOFLOW V trial at 3 years, and the BIOSTEMI trial at 5 years., , At the same time, the larger BIOSCIENCE trial with the same comparator and similar patient population as BIOFLOW V, and the even larger BIONYX trial (with the Onyx DP-DES as comparator and enrolling 71% ACS patients) showed similar rates of TLF at 5 and 2 years, respectively., The HOST-REDUCE-POLYTECH-ACS trial was an investigator-initiated randomised trial with a 2x2 factorial design, randomizing 3413 East Asian patients with acute coronary syndromes (ACS) to treatment with BP-DES vs. DP-DES and to de-escalation of prasugrel to 5mg daily after one month vs. continuation of prasugrel 10mg daily. In descending order of frequency, BP-DES comprised Orsiro, Biomatrix Flex, Nobori, Synergy and Biomatrix, while DP-DES comprised Promus Premier, Resolute Onxy, Xience and DESyne. With respect to the stent stratum, rates in the patient-oriented primary composite endpoint (all-cause death, nonfatal MI, repeat revascularisation) were similar between groups. The use of DP-DES was associated with a 46% relative risk reduction for TVR and TLR. In summary, currently available evidence suggests that most new generation DES have a similar efficacy and safety profile irrespective of durable versus biodegradable polymer based components. Notwithstanding, the comparisons are confounded by concomitant differences in strut thickness and conflicting data among ACS patients.
Polymer-Free Drug-Eluting Stents – Clinical Experience in Head-to-Head Comparisons
Non-polymeric DES offer the potential advantages of avoiding the long-term adverse effects of a polymer, improved healing, and an improvement to the integrity of the stent’s surface. The physical properties of these polymer-free stents are summarised in Table 3 , , , , , , , , , . Overall robust evidence that confirms the improvements in clinical safety hypothesised by their design are currently lacking.
Table 3: Polymer-free drug-eluting stents with CE-mark and/or FDA approval
| Polymer-free DES | ||||
|---|---|---|---|---|
| Biofreedom | Biofreedom Ultra | Coroflex ISAR neo | Cre8 Evo | |
| Manufacturer | Biosensors | Biosensors | B Braun | Alvimedica |
| Backbone | SS | CoCr | CoCr | CoCr |
| Strut cross-section* |  |
 |
 |
 |
| Strut thickness (µm) | 120 | 84-88 | 55 (2.0-3.0mm), 65 (3.5-4.0mm) | 70 (2.00-2.25mm), 80 (>2.25mm) |
| Coating | - | - | Probucol matrix | Passive pure carbon circumferential |
| Coating thickness (µm) | - | - | 4 | 0.3 |
| Coating absorption time | - | - | 3m | - |
| Drug type | 15.6 μg/mm abluminal Biolimus A9 | abluminal Biolimus A9 | 1.2 μg/mm2 sirolimus | 0.9µg/mm2 Amphilimus (sirolimus & fatty acid) |
| Drug release | ~98% in 1m | ~98% in 1m | 100% in 3m | 100% in 3m |
| Approval | FDA, CE-mark | CE-mark | CE-mark | CE-mark |
| *Adapted from 22 or hand-drawn by the first author. Strut cross-sections might vary depending on stent diameter, work-horse diameters presented. CE: Conformité Européenne; CoCr: Cobalt Chromium; FDA: Food and Drug Administration; SS: stainless steel. | ||||
BioFreedom Biolimus A9 Eluting Stent (Biosensors International PTE LTD, Singapore)
The first iteration of the PF-BES, BioFreedom (Biosensors International PTE LTD, Singapore) was made of SS with a strut thickness of 112 µm and a micro-structured, PF abluminal surface (Figure 20). The investigation of drug release kinetics revealed that >90% of the drug was released within 50 hours, however biolimus was still detectable in the neointima and myocardium surrounding the stent struts at 28 days. Pre-clinical studies of BioFreedom provide support for the concept of PF-DES. In a porcine model Tada et al. demonstrated comparable early, and more durable long-term, efficacy between PF-BES and a DP-SES. Furthermore, at 180-days compared with DP-SES, PF-BES use was associated with decreased fibrin, and less inflammation suggesting superior arterial healing. To address the shortcomings of the Biofreedom platform, namely its SS backbone and large strut thickness, its successor Biofreedom Ultra was subsequently developed, featuring a CoCr platform, thin 84-88µm struts, whilst still eluting the same concentration of Biolimus A9 from a micro-structured abluminal surface. In the BioFreedom QCA randomised trial, the mean in-stent LLL was very similar between the CoCr and SS platforms (0.34±0.49 mm vs. 0.29±0.37 mm, respectively). This observation also challenges the alleged concept of increased restenosis with the SS platforms, and highlights the complex interplay between all the DES components in modulating the antirestenotic performance of a specific device.
Figure 20
Scanning electron microscopy of the surface of three different polymer-free stents. The BioFreedom™ stent (A) is a polymer-free biolimus-eluting stent made of stainless steel and a micro-structured, polymer-free surface alteration at the abluminal stent side. The VESTAsync™ stent (B) has a nano-thin, microporous, hydroxyapatite surface coating impregnated with sirolimus. The Yukon stent (C) has a microporous surface, with pores which are 2 μm deep and impregnated with sirolimus.
- Clinical assessment of BioFreedom has taken place in the BioFreedom FIM study which randomised patients to treatment with either BioFreedom with standard dose biolimus (15.6 µg/mm stent length), BioFreedom with low dose biolimus (7.8 µg/mm stent length) or the Taxus Liberté PES.214 In total 182 patients were enrolled, 75 into the first cohort which had a primary endpoint of in-stent LLL at 4-months; with the remaining 107 patients entering into the second cohort which had a primary endpoint of in-stent LLL at 12-months. The first cohort achieved its primary endpoint with significantly lower LLL with the standard dose PF-BES (LLL 0.08 mm) and low dose PF-BES (LLL 0.12 mm) at 4 months compared with Taxus Liberté (0.37 mm, both p<0.001). The IVUS results confirmed the angiographic findings with a lower neointimal volume obstruction in the standard dose PF-BES (1.3%) compared to the low dose PF-BES (5.5%, p=0.003) and PES (6.6%, p=0.0003).
- Similarly, the second cohort also achieved its primary endpoint of non-inferiority for in-stent LLL with respective median LLL values for the standard dose PF-BES, low dose PF-BES, and TAXUS PES of 0.17mm, 0.22mm, and 0.35mm (standard dose vs. TAXUS P[non-inferiority]<0.001 and P[superiority]=0.11, low dose vs. TAXUS P[non-inferiority]<0.21). At 5 years, clinical event rates were similar, with no ST observed in any group.
- Further evaluation of PF-BES took place in the LEADERS FREE study, a randomised double blind study, which aimed to assess whether the rapid elution of biolimus in the absence of a polymer would offer a safety and efficacy advantage over BMS in patients unable to take prolonged DAPT. The LEADERS FREE study enrolled 2466 patients, who due to co-morbidity, or HBR (including age >75 in 64% patients), were unable to take DAPT beyond one-month, and randomised them to receive either the BioFreedom PF-BES or a BMS. The study had two 1-year primary endpoints: a non-inferior safety composite of cardiac death, MI and ST; and a superiority efficacy endpoint of clinically driven TLR. The primary safety endpoint occurred in 112 patients (9.4%) receiving the PF-BES and in 154 patients (12.9%) receiving a BMS (P[non-inferiority]<0.001 and P[superiority]=0.005) at 390 days. Clinically driven TVR occurred in 59 (5.1%) and in 113 (9.8%) patients in the PF-BES and BMS groups, respectively (p<0.001). Results at 2-years showed that BES-PF continued to remain both significantly safer and more effective than BMS in patients treated with 1-month DAPT.
- The randomised controlled Onyx ONE trial included 1003 patients with HBR who were randomly allocated to the BioFreedom PF-BES vs. the Onyx DP-DES. The primary outcome, a safety composite of death from cardiac causes, MI, or ST at 1 year was similar between groups (17.1% vs. 16.9%, risk difference, 0.2 percentage points, p=0.01 for noninferiority). There were no between-group differences with respect to the primary endpoint after final 2 years of follow-up. However, all revascularisation events (10.4% vs. 7.8%, p=0.048), as well as clinically-driven TLR (7.1% vs. 4.8%, p=0.04), were significantly increased in patients randomised to BioFreedom PF-BES.
- In the SORT OUT IX trial BioFreedom PF-BES failed to demonstrate non-inferiority compared to the ultra-thin strut Orsiro BP-SES in an all-comer population at 1 year of follow-up for the primary composite endpoint of cardiac death, target lesion MI, or TLR (absolute risk difference 1.29%, upper limit of one-sided 95% CI 2.50%, p for noninferiority=0.14). This difference was mainly attributable to a higher risk of TLR within the first year (3.5% vs 1.3%; RR 2.77, 95% CI: 1.66-4.62), which persisted at 2 years (5.1% vs 2.6%; RR 1.98, 95% CI: 1.26-2.89).,
- The LEADERS FREE III study compared 401 newly enrolled HBR patients receiving the Biofreedom Ultra vs. 1221 patients from the LEADERS FREE trial receiving its predecessor Biofreedom. In the propensity-score matched analysis, the primary safety endpoint was similar between groups, while Biofreedom Ultra appeared more efficacious in terms of TLR compared to BMS (4.2% vs. 9.3%, p<0.01).
Coroflex ISAR neo (B. Braun Melsungen, Berlin, Germany) / ISAR VIVO (Translumina Therapeutics, Dehradoon, India)
This stent platform is based on the CX-Blue Ultra stent for 2.0 to 3.0 mm diameters (55 μm) and on the CX-Blue Neo stent for 3.5 to 4.0 mm diameters (65 μm). The polymer-free matrix is contained on the abluminal aspect of the microporous stent surface and consists of sirolimus at a concentration of 1.2 μg/mm2 and probucol to control the drug release. Probucol serves as matrix-builder and is a highly lipophilic, lipid-lowering agent with antioxidant effects. Approximately 80% of sirolimus is released within 30 days, while the process is completed at 90 days. The Coroflex ISAR neo has an updated connector design with larger expansion capabilities while maintaining radial strength, and the lowest crossing profile (0.79-0.97mm) across the smaller size ranges compared to competitors 22, 227, 228
- The randomised non-inferiority ISAR-TEST-5 trial including 3002 patients with minimal exclusion criteria demonstrated similar composite outcomes vs. the Resolute ZES. 229 After 10 years of follow up, the incidence of TLF was very similar between groups (43.8% vs. 43.0%).114 Despite high absolute event rates (36% all-cause death), reflective of a high-risk population, rates of ST were extremely low in both groups at 10 years (0.8%). Although routine angiographic follow-up planned for all patients at 6-8 months might have inflated rates of revascularisation, TLR occurred in 21% at 10 years without between-group differences.114
- The open-label randomised multi-centre HOST-IDEA trial conducted in South Korea compared 3- to 6-month DAPT to 12-month DAPT after implantation of DES with ultrathin struts and advanced polymer technology (Orsiro and Coroflex ISAR), applying a non-inferiority design. There were no significant differences in TLF (HR 0.98, 95% CI 0.56–1.71, p=0.94) or major bleeding (HR 0.82, 95% CI, 0.41–1.61, p=0.56) between groups. A post-hoc propensity score adjusted analysis suggested lower rates of TLF in favour of Orsiro (1.1% vs. 3.4%, HR 3.21, 95% CI 1.28 – 8.05, p=0.01) at 12 months, mainly driven by the significant differences in clinically-driven TLR (0.5% vs. 2.6%).
Cre8 Sirolimus Eluting Stent (Alvimedica, Instanbul, Turkey)
The Cre8 stent is a thin-strut (70-80μm) PF stent which releases sirolimus using an abluminal reservoir technology such that drug elution is completed in 90 days. The stent uses an Amphilimus formulation – sirolimus formulated with a mixture of long chain fatty acids which enhances drug stability, facilitates sustained drug elution, and modulates drug bioavailability., Uniquely the BMS struts are coated in a second generation pure carbon coating which has a crystalline structure close to diamonds and provides excellent bio- and haemo-compatibiltity. The Cre8 DES has had CE-approval for 1-month DAPT since July 2019.
Pre-clinical data indicate the absence of a chronic inflammatory response with the Cre8 stent as evidenced by reduced inflammatory scores and neointimal thickness in porcine models when compared to controls comprising of the same stent platform without the carbon coating and the Cypher SES. Consistent with this are the results from the Demonstr8 OCT study which reported that strut coverage was non-inferior between the Cre8 stent at 3-months and a BMS at 1-month.
- The first clinical study was the multicentre prospective NEXT trial which randomised 323 patients to Cre8 stent (n=162) and the TAXUS PES (n=161). The study achieved its primary endpoint by demonstrating non-inferiority of the Cre8 stent with regards to in-stent LLL at 6-months (Cre8 0.14±0.36mm vs. PES 0.34±0.40mm, P[non-inferiority] <0.0001, P[superiority] <0.0001). The occurrence of MACE (cardiac death, any MI, any TLR) was similar in both groups (8.3% vs. 10.1%, p=0.59)
- The multi-centre, all-comers pARTicip8 registry enrolled 1186 patients treated with Cre8 stent and reported low rates of ST, device-oriented MACE and TLR at 1-year follow-up in the entire population, and a pre-specified diabetic sub-group. This latter group also underwent 6-month angiographic follow-up, with a reported LLL of 0.16mm.
- Specific assessment of the Cre8 stent in diabetic patients was performed in the RESERVOIR study, which randomised 112 patients to the Cre8 stent (n=56) or EES (n=56), and met its primary endpoint of % neointimal volume obstruction as assessed by OCT at 9-month follow-up (Cre8 11.97+/- 5.94% vs. EES 16.11 +/- 18.18%, P[non-inferiority]=0.0003, P[superority]=0.22).
- The ASTUTE registry supported the use of the Cre8 stent in patients requiring a short duration of DAPT (<3 months). The study reported comparable rates of 1-year TVF between the 106 patients receiving <3 months DAPT (5.7%) and the 1102 patients receiving >6 months (5.1%). Major bleeding based on the ARC criteria was significantly higher in the short DAPT group (3.4% vs. 0.2%, p=0.007), however this difference was not observed following a landmark analysis at 90-days (0% vs. 0.3%).
- The multicenter, non-inferiority ReCre8 trial included 1502 “all-comer” patients (40% ACS, 24% STEMI, 44% multivessel disease, 20% diabetes) who were randomised to the Cre8 vs. Resolute Integrity stent. The Cre8 demonstrated non-inferiority for the primary endpoint of TLF (5.6% vs. 6.2%, p for non-inferiority <0.01), with low rates of definite or probable ST (1%) at 1 year. The presence of diabetes did not seem to affect the relative efficacy or safety of the device (p for interaction = 0.64 for the primary endpoint).
- The investigator-initiated, randomised, controlled, assessor-blinded SUGAR trial was dedicated to patients with diabetes. The Creo8 EVO stent was non-inferior and superior in terms of TLF compared to the Onyx DES at 1 year (7.2% vs. 10.9%, HR 0.65, 95% CI 0.44-0.96), with numerically lower TLR events. At 2 years, TLF was no longer different (HR 0.84, 95% CI 0.60-1.19, presented at TCT 2022).
- The PARTHENOPE trial is an RCT with a 2x2 factorial design, comparing the Cre8 to the Synergy DES using a non-inferiority hypothesis, and a personalised DAPT strategy compared to standard DAPT with a superiority hypothesis in all-comer patients. The Cre8 stent was non-inferior to Synergy in terms of TLF at 12 months (8.2% vs. 7.2%, absolute risk difference 1%, upper limit of one-sided 95% CI 2.9%, p for non-inferiority 0.041), but there was a higher rate of definite or probable ST in the Cre8 arm (1% vs. 0.3%, HR 3.72, 95% CI 1.04-13.33, p=0.044, p=0.29 after adjustment for multiple comparisons, presented at TCT 2023).
Focus NP DES System (Envision Scientific, Surat, India)
The FOCUS np DES system is a DES which uses nanotechnology. Similar to biodegradable or polymer-free solutions, the technology aims to reduce the requirement for longer-term DAPT. These stents have a standard stent platform, with a nanomatrix coating, made up of nano-particles of an anti-proliferative drug combined with one or more stabilising excipients; this matrix functions as a substitute for the polymer. There are advantages of using nanoparticles for drug-delivery: (i) they enable controlled and reproducible drug release kinetics; (ii) they increase drug stability in vivo because of the encapsulation process; (iii) they are able to penetrate deeper into the vessel wall thereby improving efficacy; (iv) they facilitate rapid release of drug into the tissue, with a drug depot or reservoir effect, which enables the stent to become drug-free in a short period of time, leading to more rapid healing; (v) they allow increased intra-cellular uptake of drug, with a prolonged residence time at site; (vi) they permit a lower overall drug dosage; and (viii) they increase bio-availability at the target site.
The FOCUS np polymer-free stent has a CoCr stent platform and is coated with nano-particles containing sirolimus within two excipients, which were selected to create a two-phase programmed drug release. The first phase is a burst release from the top layer of nano-particles occurring within 60 seconds of stent deployment; whilst the second phase is a programmed release from the bottom layer. Drug delivery is completed in 28-days. The stent balloon shoulders are also coated in the nanomatrix to allow delivery of drug at edges of the stent to avoid edge restenosis. Following successful pre-clinical studies, the Nano ActiveFIM- IN study has completed enrolment of 83 patients divided in cohort A (n= 55, simple lesions) and B (n=28, real world scenario). Data from 6-month and 1-year follow-up are expected.
YUKON – Sirolimus eluting stent (Translumina, Hechingen, Germany)
The SS YUKON SES was the first polymer-free DES. The stent had a micro-porous surface, with pores that are 2 μm deep and effectively function as a drug reservoir removing the obligatory need for a polymer. The dose of sirolimus was customised in the cath lab, just prior to stent implantation, in a coating process taking approximately eight minutes (Figure 21); studies established that the optimal concentration of sirolimus to prevent restenosis was 2%.
Figure 21
Scanning electron microscopy of the surface of three different polymer-free stents. The BioFreedom™ stent (A) is a polymer-free biolimus-eluting stent made of stainless steel and a micro-structured, polymer-free surface alteration at the abluminal stent side. The VESTAsync™ stent (B) has a nano-thin, microporous, hydroxyapatite surface coating impregnated with sirolimus. The Yukon stent (C) has a microporous surface, with pores which are 2 μm deep and impregnated with sirolimus.
- After complete drug release the remaining micro-porous surface appears to favour the adhesion of endothelial cells, a hypothesis initially suggested by angiographic follow-up data, and subsequently confirmed by OCT, which has demonstrated significantly greater neointimal thickening, and stent strut coverage with the YUKON stent compared to SES at 3-months follow-up.
- In the randomised ISAR-TEST study comparable rates of TLR (16.5% vs. 16.4%, p = 0.89), death/MI (16.6% vs. 20.0%, p = 0.52), MACE (27.3% vs. 31.7%, p = 0.40) and ST were seen (0.5% vs. 1.6%, p = 0.32) with YUKON compared to a PES out to 5-year follow-up.
- Observational data extending out to 2-year follow-up indicated that the YUKON stent was less susceptible to delayed restenosis when compared to conventional DES. Byrne et al. reported a significantly lower change in LLL between 6-8 months and 2 years for the YUKON stent, when compared with DP-SES and DP-PES (YUKON 0.01±0.42 mm, SES 0.17 ± 0.50 mm, and PES 0.13 ± 0.50mm, p < 0.001). This finding has also been observed during similar 2-year follow-up of the ISAR-TEST 2 and ISAR-TEST 3 studies, both of which randomised patients to treatment with PF-SESs, or DP-DES or BP-DES., , ,
Randomised clinical trials comparing newer generation DES with at least 5 years of follow-up and including more than 1000 patients are summarised in Table 4.
Table 4: Randomized trials of newer generation drug-eluting stents including at least 1000 patients and providing follow-up data of at least 5 years.
| Trial acronym | Patient population | Patients randomised | Study device | Comparator device | Primary Endpoint | Incidence primary EP at 1 year | Longest follow-up (years) | Incidence primary EP at longest follow-up |
|---|---|---|---|---|---|---|---|---|
| BIOFLOW V , | All-comers | 1334 | Orisor SES | Xience EES | TLF (cardiac dath, TV-MI, clinically indicated TLR) | 6% vs. 10%, HR 0.64, 95% CI 0.42–0·96, p=0·0322 | 5 | 12.3% vs. 15.3%, ARD -2.9, 95% CI -7.0 - 1.1), p=0.11 |
| BIOSTEMI , | STEMI | 1300 | Orsiro SES | Xience EES | TLF (cardiac dath, TV-MI, clinically indicated TLR) | 4% vs. 6% RR 0.59, 95% Bayesian credibility interval 0.37-0.94; posterior probability of superiority 0.986 | 5 | 8% vs. 11%, RR 0.70, 95% Bayesian credible interval 0.51-0.95; Bayesian posterior probability for superiority 0.988 |
| BIO-RESORT TWENTE III , | All-comers | 3514 | Orsiro SES, Synergy EES | Resolute Integrity ZES | TVF (cardiac mortality, TV-MI, TVR) | 5% vs. 5% vs. 5% Both -0.7% ARD, 95% CI -2.4-1.1, p non-inferiority <0.01 | 5 | 12.7% vs. 11.6% vs. 14.1%, HR 0.89; 95% CI, 0.71-1.12, Plog-rank=0.31; and HR, 0.82, 95% CI 0.65-1.04, Plog-rank=0.10 |
| DUTCH PEERS TWENTE II , | All-comers | 1811 | Resolute Integrity ZES | Promus EES | TVF (cardiac death, TV-MI, TVR) | 6% vs. 5%, ARD 0.88%, 95% CI -1.24%- 3.01%, p for non-inferiority <0.01 | 5 | 13.2% vs. 14.2%, HR 0.94, 95% CI 0.73-1.21, p= 0.62 |
| ISAR TEST 4 , | All-comers | 3255 | Yukon Choice PC SES | Xience EES, Cypher EES | MACE (death, TV-MI, TLR) | 13.8% vs. 13.6% vs. 15.2%, RR 1.01, 95% CI 0.78–1.31, p=0.94 and RR 0.90, 95% CI 0.71–1.16, p=0.43 | 10 | 47.7% vs. 46.0% vs. 54.9%, HR 0.82, 95% CI 0.69–0.96 and HR 0.79, 95% CI 0.65–0.96 |
| ISAR TEST 5 , | All-comers | 3002 | Coroflex ISAR polymer-free sirolimus- and probucol-eluting stent | Resolute ZES | TLF (cardiac death, TV-MI, TLR) | 13.1% vs. 13.5%, HR 0.97, 95% CI 0.78-1.19; p for superiority=0.74, p for non-inferiority <0.01 | 10 | 43.8% vs. 43.0%, HR 1.01, 95% CI 0.89-1.14; p = 0.90 |
| NEXT , | All-comers | 3241 | Nobori BES | Xience EES | TLR | 4.2% vs. 4.2%, HR 1.01, 95% CI 0.72–1.43, p=0.93 | 10 | 15.9% of vs. 14.1%, HR 1.12, 95% CI 0.90-1.40, p=0.32 |
| RESOLUTE all-comer , | All-comers | 2292 | Resolute ZES | Xience EES | TLF (cardiac death, TV-MI, TLR) | 8.2% vs. 8.3%, ARD -0.1%, 95% CI -2.4-2.2, p=0.94 | 5 | 35.3% vs. 32.0%, ARD 3.2%, 95% CI -0.7-7.1%, p=0.11 |
| SORT OUT VII , | All-comers | 1261 | Orsiro SES | Nobori BES | TLF (cardiac death, TV-MI, TLR) | 3.8% vs. 4.6%, RR 0.83, 95% CI 0.56-1.22, p=0.34, p for non-inferiority <0.01 | 5 | 12.4% vs. 13.1%, RR 0.94, 95% CI 0.75-1.18, p=ns |
| TIDES ACS , | ACS | 1491 | OPTIMAX TiNO-coated stent | Synergy EES | TLF (cardiac death, TV-MI, TLR) | 6.3% vs. 7.0%, HR 0.93; 95% CI 0.71-1.22; p for superiority = 0.66; p for noninferiority < 0.001 | 5 | 11.2% vs. 12.0%, HR 0.94, 95% CI 0.69-1.28, P=0.69 |
| TWENTE , | All-comers | 1391 | Endeavor Resolute ZES | Xience EES | TVF (cardiac death, TV-MI, TVR) | 8.2% vs. 8.1%, ARD 0.1%, 95% CI -2.8% - 3.0%, p for noninferiority = 0.001 | 5 | 16.1% vs. 18.1%, HR 0.89, 95% CI 0.69-1.15, p=0.36 |
| Legend: ACS: acute coronary syndromes; ARD: absolute risk difference; BES: biolimus-eluting stent; CI: confidence interval; EES: everolimus-eluting stent; HR: hazard ratio; MI; myocardial infarction; SES: sirolimus-eluting stent; TLF: target lesion failure; TVF: target vessel failure; TVR: target vessel revascularisation; ZES: zotarolimus-eluting stent | ||||||||
Novel Stent Coatings
Polyzene F Coated stents (CeloNova BioSciences, Tx, USA)
Polyzene F is a biocompatible, biostatic, proprietary formulation of poly[bis(trifluoro-ethoxy)phosphazene], which has anti-inflammatory, bacteria-resistant and pro-healing qualities. Its application onto a stent was therefore proposed as a method of creating very low surface thrombogenecity, thereby potentially reducing the risk of ST. Pre-clinical studies demonstrated reduced inflammation, neointimal hyperplasia, and thrombogenicity with stents coated with Polyzene F compared to uncoated stents. Subsequently two commercial stents have been developed by applying a 40nm thick layer of Polyzene F onto the surface of CoCr struts creating the Catania stent (CeloNova BioSciences, Tx, US), and its newer iteration the Cobra stent (CeloNova BioSciences, Tx, US).
- The FIM ATLANTA study reported a 6-month LLL of 0.60±0.48mm, whilst at 12-months follow-up there were no reported deaths or MI, and a clinically driven TLR rate of 3.6% in the 55 patients treated with the Catania stent. No ST was observed, despite DAPT being given for only 30-days. In addition OCT, which was performed in 15 patients, showed that 99.5% of struts were fully covered at 6-months. Registry data have also demonstrated the absence of ST at 6-months follow-up amongst 94 patients with ACS who were treated with the Catania stent, and received only 30-days of DAPT. A broader, more real world cohort were enrolled in the follow-up ATLANTA-II registry, which enrolled 300 patients, 14% of whom presented with STEMI. At 1-year follow-up, the cumulative rate of MACE was 8.8%, with individual rates of cardiac death, MI and TLR of 2.5%, 0.7% and 6.5%, respectively. DAPT was again given for only 30-days, and the rate of ST was 0.7% due to two cases of sub-acute ST.
- The Cobra stent was evaluated in the non-randomised 296 patient PzF SHIELD study, which achieved its primary endpoint with a rate of TVF, a composite of cardiac death, MI and clinically driven TLR at 9-months follow-up, of 11.5% which met the pre-specified performance goal of 19.62%, that had been derived from historical meta-analyses of BMS. The study also met its powered secondary endpoint with a LLL of 0.84mm, compared with the performance goal of 1.1mm. There were no ST events. On the background of these results the device gained FDA approval in 2017.
- Further evaluation took place in the COBRA-REDUCE trial, which randomised 996 patients at high-risk of bleeding due to the need for oral anti-coagulation, to the Cobra stent and 14-days of DAPT or a conventional DP-DES with 3-6 months of DAPT. The rates for the co-primary bleeding endpoint of BARC class≥2 bleeding, and the thrombotic endpoint, a composite of all-cause death, MI, definite/probable ST and ischaemic stroke at 6-months were similar between both stents. Furthermore, whilst bleeding endpoints were also comparable, the Cobra stent had a significantly high rate of the composite secondary endpoint of cardiac death, MI, ischaemia-driven TLR, ST and ischaemic stroke at 12-months (13.1% vs. 8.7%, p=0.03), which was driven by TLR.,
Titanium-nitride oxide coated stents (Hexacath, Rueil-Malmaison, France)
Titanium-nitride oxide has been shown to inhibit platelet aggregation, minimise fibrin deposition, reduce inflammation, and promote healing, and consequently has been utilised as a coating on the three iterations of the TiTAN coronary stent (Hexacath, France). The first two versions (TiTAN and TiTAN-2) had a platform of SS, whilst the newest iteration, the TiTAN Optimax, uses CoCr, which offers greater radio-opacity and enables the struts to be 20% thinner.
- The TiNOX study randomised 92 patients to treatment with either a BMS, or a BMS coated with titanium-nitride oxide and reported a significant reduction in LLL (0.55 ± 0.63 mm vs. 0.90 ± 0.76 mm, p = 0.03) at 6-months follow-up. Clinical evaluation demonstrated significantly reduced MACE, which was driven primarily by a reduction in TLR, with the titanium-coated stent at 6-months follow-up, with this benefit maintained out to 5-years.
- Additional studies include the TiTAX-AMI trial, which randomised 425 patients with ST-elevation MI to treatment with either the TiTAN stent or the TAXUS PES. At 12-months there were no significant differences in the primary endpoint (p=0.5), however the TiTAN stent had significantly lower rates of ST (0.9% vs. 4.3%, p=0.03). At 5-years, use of the TiTAN stent lead to a significantly lower incidence of MACE, cardiac death, re-infarction, and ST. Furthermore, despite the absence of an anti-proliferative drug, the rate of TLR was comparable. In contrast, the TiTAN stent failed to demonstrate non-inferiority when compared to the E-ZES in the randomised 300 patient TIDE study. At 6-months angiographic follow-up, in-stent LLL was 0.64 ± 0.61 mm and 0.47 ± 0.48 mm for the TiTAN-2 stent and E-ZES, respectively (Pnon-inferiority = 0.54). Of note, differences in LLL were more pronounced in patients with diabetes, small vessel disease and patients over 65. Clinical outcomes assessed up to five years of follow-up were comparable. The majority of events occurred within the first year after PCI and were mostly related to clinically-indicated TVR.
- Further assessment took place in the BASE-ACS trial, which enrolled 827 patients with ACS who were randomised to the TiTAN-2 stent (n=417) or EES (n=410). At 1-year the study met its primary non-inferior endpoint of MACE, a composite of cardiac death, non-fatal MI or ischaemia-driven TLR (9.6% vs. EES 9.0%, Pnon-inferiority <0.001). A 5-years follow-up the TiTAN-2 stent remained non-inferior in terms of MACE; whilst its use was associated with lower rates of non-fatal MI (5.9% vs. 9.7%, p=0.03), and comparable rates of cardiac death and TLR.
- A more contemporary study in ACS patients is the TIDES ACS trial, which randomised 1491 ACS patients in a 2:1 ratio to the TiTAN Optimax or Synergy EES. The primary end point was MACE, a composite of cardiac death, MI, or target lesion revascularisation at 12-month follow-up. The TiNO-coated stent was non-inferior compared to Synergy in terms of MACE (HR 0.93; 95% CI 0.71 to 1.22; p = 0.66 for superiority; p < 0.001 for noninferiority), and superior for the co-primary endpoint of cardiac death and MI (HR 0.64; 95% CI 0.51 to 0.80; p = 0.001). whilst rates of TLR were similar (5.8% vs. 4.4%; p = 0.27). At 5 years, MACE occurred in 11.2% in the TiNO group vs 12% in the EES group (HR, 0.94; 95% CI, 0.69-1.28; P = 0.69). Rates of cardiac death (0.9% vs. 3.0%, HR 0.30; 95% CI, 0.13-0.69; P = 0.005), MI (4.6% vs. 7.0%, HR 0.64; 95% CI, 0.41-0.99; P = 0.049) and ST (1.2% vs. 2.8%, HR 0.43; 95% CI, 0.20-0.93; P = 0.034) were lower in favour of the TiNO-coated stent.
DESyne BDS Plus (Elixir Medical, Milpitas, CA)
The DESyne BDS Plus is the first triple drug-eluting coronary stent with site-specific delivery of antithrombotic drugs. Little technical specifications are currently available, apart from the composition of the delivered drugs, namely two anticoagulants (rivaroxaban and argatroban) and sirolimus. The DESyne BDS Plus RCT is a prospective, multicenter, randomised, single-blind study of 202 patients with de-novo native coronary artery lesions. Patient were randomised to receive either the DESyne BDS Plus DES or the CE Mark approved DESyne X2 NES, a DP-DES.
Six-month LLL (0.14±0.05mm in DESyne BDS Plus versus 0.09±0.05mm in the DP-DES) and percent diameter stenosis (11.3±6.2% in DESyne BDS Plus versus 12.3±6.3% in the DP-DES) were similar between devices. At six months, TLF rates were 1.0% for the DESyne BDS Plus and 8.2% for the DP-DES (95%CI -14.8% to -1.3%, p=0.035), with no definite or probable ST, TV-MI or cardiovascular death observed with the DESyne BDS Plus study device (presented at TCT 2023).
Special Types of Coronary Stents
Stent with Uncaging Elements to Improve Vasomotion
The DynamX novolimus-eluting Bioadaptor stent (Elixir Medical Corporation, Milpitas, CA) initially behaves like a contemporary DES by using a conventional backbone (71 μm CoCr) and novolimus (5μg/mm) for drug elution but differs by including three uncaging elements per ring along the length of the device held together by a bioresorbable polymer coating (PLLA basecoat, ~6μm). Absorption of this thin layer over 6 months results in the unlocking of the helical strands, improving vasomotion and pulsatility of the stented segment. The device has been clinically tested in the BIOADAPTOR trial, a multicenter, single-blind, study that included 445 patients with de-novo lesions. At 1-year follow-up, clinical outcomes were similar between the DynamX bioadaptor vs. Resolute Onyx (TLF 1.8% vs. 2.8%, p for non-inferiority <0.001). In the subset of patients with angiographic and intravascular-imaging data, in-device LLL was superior with DynamX (0.09 mm vs. 0.25 mm, p=0.038), while other angiographic parameters such as in-segment LLL, minimum lumen diameter data and diameter stenosis were similar, as was neo-intimal coverage (OCT). Surrogates of vessel cyclic pulsatility (change in lumen area during cardiac cycle, calculated as the change between the maximal lumen area and minimal lumen area during the cardiac cycle), significant plaque reduction behind the sten and vessel compliance were improved with the DynamX device. Whether the functional improvements achieved after “uncaging” translate into a clinically detectable benefit remains yet to be established.
Stent with a longitudinal polymeric meshs tructure
IoNIR Ridaforolimus DES (Medinol,Tel Aviv, Israel)
The IoNIR stent is a hybrid DES that has a CoCr backbone with ultra-thin 60 µm struts, and embedded radiopaque markers. Uniquely its abluminal PLA polymer, which biodegrades within 90 days, is present in the form of a mesh which is spread over the entire surface of the stent providing longitudinal stability, and facilitates spatial and temporally uniform elution of ridaforolimus, which is present in a drastically reduced dose. The 3-5 µm fibres of the mesh incorporate into the vessel wall and biodegrade without inflammation. The on-going multi-centre, single-arm, open-label first in human IonMAN study enrolled 61 patients with co-primary endpoints of in-stent LLL at 13-months and TLF at 12-months. Preliminary results in the first 15 patients show a LLL at 30-days of 0.15mm, with 2 TLFs at a median of 180 days follow-up (TCT 2023).
Covered Stents (Table 5)
Table 5
Covered stents.
Reproduced with the permission of the publisher.
Aneugraft (ITGI Medical, Or Akiva, Israel)
The Aneugraft stent consists of a single, thin-strut, 316L SS, laser-cut, balloon-expandable stent which is covered with a single layer of equine pericardium. This approach enables higher deliverability and trackability, and aims to support endothelial regrowth and vessel healing. Rates of restenosis, TLR and ST in 27 patients followed in the SCAAR registry for one year were 7%, 9.3% and 0%, respectively.
BeGraft (Bentley Innomed, Hechingen, Germany)
In contrast to early-generation "sandwich-design", the BeGraft uses a single layer CoCr platform with a strut thickness of 80-90 μm covered with expanded polytetrafluoroethylene (ePTFE). The Micro-porous ePTFE tubing adds a thickness of 89± 25μm. The BeGraft is compatible with 5Fr guiding catheters, a property shared by devices <4mm of the PK Papyrus and devices <4mm of the Direct-Stent. In a retrospective multi-center study of 30 patients, the incidence of TLR and ST were 10% and 3.3% after one year.
Direct-Stent (InSitu Technologies, St Paul, MN, U.S.)
The Direct-Stent (also marketed as Celosia Covered Stent) uses a of 80 μm thick CoCr alloy covered with ePTFE in a sandwiched fashion (90-120 μm), using a proprietary microporous ePTFE technology. Implementation of a hybrid open-closed cell design allows the stent ends to be flairable.
Graftmaster (Abbott, Santa Clara, CA, U.S.)
The Graftmaster covered stent uses a SS platform with expandable ePTFE sandwiched between two identical stents. The double wall thickness of this design is 520μm. The crossing profile is 1.63mm, while crossing profiles of new generation DES would be somewhere in the range of 1mm. Long-term outcome data are scarce. The CRACK-II registry reported data from 106 consecutive patients who received either Graftmaster (n=51) or Papyrus (n=55) for coronary artery perforations. MACE defined as cardiac death, TLR or MI was similar between groups at 30-days and 1-year. Rates of TLR were lower in favour of Papyrus (30 days 17.6% vs. 3.6%, p=0.02; 1 year 21.6% vs. 9.1%, p=0.07). Acute ST occurred in 3 (5.9%) patients who received Graftmaster and 1 (1.8%) who received Papyrus. Registry data from 61 patients with coronary artery perforations suggested similar procedural success between Graftmaster and PK Papyrus, and similar rates of MACE (death, MI, TVR/TLR, need for surgical repair), with a trend towards lower rates of TVR at 1 year in favour of PK Papyrus (21% vs. 5%, p=0.08). Rates of restenosis, TLR and ST in 142 patients followed in the SCAAR registry for one year were 5%, 9% and 5.5%, respectively.
PK Papyrus (Biotronik, Bülach, Switzerland)
The PK Papyrus is based on the Orsiro/PRO-Kinetic Energy platform using CoCr with proBIO (Amorphous Silicon Carbide) coating and a non-woven, electrospun polyurethane as cover material with 90μm thickness. The platform itself has the same strut dimensions as Orsiro with 60-80μm thickness for the 2.5-4.0mm devices, and 120μm for the 4.5-5.0mm device; the crossing profile is lower compared to Graftmaster (crossing profile 1.25mm vs. 1.63mm).
In a retrospective analysis from the US PK Papyrus HDE post-market surveillance clinical dataset, delivery success was achieved in 97.7%, and acute/subacute ST occurred in 10 of 1094 patients (1.1%). Spanish registry data from 108 patients receiving the device either for aneurysms or perforation reported a similarly high technical success rate (96%). After a mean follow-up of 22 months, MACE occurred in 7.1% [cardiacdeath:2%,MI:5%,TLR:5%andST:3%]. Rates of MACE were similar for both indications, however, ST occurred more frequently in devices implanted into aneurysms (0% vs 7.1%; p = .04).
In a study including 299 reports on covered coronary stents, the most common failure mechanisms of covered stents were in descending order failure to deliver the stent, followed by stent dislodgment and failure to seal the perforation. Of interest, failure to deliver the stent was more common with the Graftmaster, whereas stent dislodgment was more common with PK Papyrus. In the CRACK-II registry, including 106 patients with coronary artery perforation, TVR and TLR rates were lower in patients treated with the PK Papyrus than Graftmaster stent.
Personal perspective
Stephan Windecker
Coronary artery stents constitute the most important advancement in the field of percutaneous coronary intervention since the introduction of balloon angioplasty. Stents are used in more than 90% of procedures today and have enabled the technique to become one of the most frequently performed therapeutic interventions in medicine. The most important benefit of coronary artery stents has been the effective treatment of abrupt or threatened vessel closure eliminating the need of emergency bypass surgery required in 5-8% of patients in the balloon angioplasty era.
Impressive technological advances in the past 3 decades were accompanied by a substantial improvement of efficacy through a transition to DES, and improved long-term safety with second- and third-generation devices. Since the first PCI in 1977, restenosis has become the exception rather than the rule, and the feared complications of ST has waned to a degree that studies with sufficient power became difficult to conduct. ,
In addition, the technique of coronary artery stenting has allowed reproducible results and resulted in a short procedure requiring only minutes in uncomplicated cases. Controlled release of anti-proliferative drugs from polymer coatings immobilised on the stent surface were realised in the form of drug-eluting stents. These devices effectively reduced restenosis and lowered the need of repeat revascularisation of the target lesion to below 5%. Of note, newer generation DES have overcome the limitation of first-generation DES – the problem of very late ST thus combining improved efficacy while maintaining an excellent safety profile.
The totality of current evidence suggests that the numerous iterations of newer-generation DES, many of which claimed to have unique strut designs, polymers, and antiproliferative drug properties, has resulted in a plateau in terms of benefit of one device over another. , , , The successful evolution of coronary artery stents and their associated clinical benefits have been further leveraged by progress in advanced implantation techniques improved medical management as well as intravascular imaging guidance (see chapters Intravascular ultrasound ; Optical coherence tomography ; Near-infrared spectroscopy).
Nevertheless, several unmet needs remain with metallic DES. Indeed, about 50% of adverse events following PCI are attributable to stent-related events rather than a progression of the underlying disease. Intravascular imaging-guided interventions appear key to maximise the benefits of modern stent technologies. Long-term results with the first broadly tested fully bioresorbable scaffold could not meet expectations, however, the concept of avoiding life-long persistence of stents in the vessel wall remains valid to promote vessel healing, vasomotor function and long-term clinical outcomes. While polymer or magnesium based BVS with thin struts, improved drug kinetics and more fracture resistant polymers are under investigation, drug-coated balloons have become a reasonable alternative to DES in many lesion subsets (e.g. small vessels, bifurcation disease, HBR, in-stent restenosis)., , , , Stringent secondary prevention strategies need to be emphasised, also for the reduction of stent-related long-term events.
Conflict of interest statement
Miklos Rohla reports advisory fees from Daiichi Sankyo, Sanofi Aventis, COR2ED, Novartis and Medtronic, and lecturing fees from Daiichi Sankyo, Biotronik and Takeda Pharma, all outside the submitted work
Scot Garg reports consultancy fees from Biosensors
Raffaele Piccolo reports consulting fees from Abiomed, Biotronik, and Medtronic, outside the submitted work
Sharmaine Thirunavukarasu reports no conflict of interest
Patrick W Serruys reports consultancy for Philips, Merillife, Xeltis, Novartis and SMT
Stephan Windecker reports research, travel or educational grants to the institution without personal remuneration from Abbott, Abiomed, Amgen, Astra Zeneca, Bayer, Braun, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardinal Health, CardioValve, Cordis Medical, Corflow Therapeutics, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Farapulse Inc. Fumedica, Guerbet, Idorsia, Inari Medical, InfraRedx, Janssen-Cilag, Johnson & Johnson, Medalliance, Medicure, Medtronic, Merck Sharp & Dohm, Miracor Medical, Novartis, Novo Nordisk, Organon, OrPha Suisse, Pharming Tech. Pfizer, Polares, Regeneron, Sanofi-Aventis, Servier, Sinomed, Terumo, Vifor, V-Wave. Stephan Windecker served as advisory board member and/or member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, Astra Zeneca, Bayer, Boston Scientific, Biotronik, Bristol Myers Squibb, Edwards Lifesciences, MedAlliance, Medtronic, Novartis, Polares, Recardio, Sinomed, Terumo, and V-Wave with payments to the institution but no personal payments. He is also member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. He is Vicepresident of the ESC, and Associate Editor of JACC CV Interventions.