Percutaneous coronary intervention has rapidly advanced from its inception to become a very sophisticated and widely practiced procedure. The introduction of drug-eluting stents (DES) resulted in a remarkable reduction in the inci-dence of restenosis, although concerns remain regarding their long-term safety, mainly due to the occurrence of stent thrombosis (ST). ST is a rare complication with a reported incidence of 0.5–2% per year, but this can have a disas-trous clinical impact, resulting in myocardial infarction (MI) and death with a fatality rate up to 45% [1,2]. A variety of factors including pre-mature discontinuation of antiplatelet therapy, patient factors such as diabetes, renal dysfunc-tion and left ventricular dysfunction, and lesion characteristics are recognized as predisposing factors [3]. In addition to these, stent properties themselves, especially the polymer coating that retains and elutes the drug, are thought to con-tribute to ST by aggravating inflammation and delaying vascular healing [4,5].
To improve the safety and efficacy of DES, developers are attempting to improve the three fundamental parts of the stent: the stent plat-form, the polymer and the antiproliferative drug. Here, the authors concentrate on recent advances in stent technology.
Stent platformRecent innovations in stent platforms include changes of the metallic alloy (i.e., use of titanium and shifting from cobalt–chromium or stainless
steel to platinum–chromium platforms) and the development of dedicated stent platforms for the treatment of specific lesion subsets (i.e., bifurca-tions and small-vessel lesions). The Element™ platform (Boston Scientific, MA, USA), for example, offers wider peaks to minimize recoil and shorter segments to improve conformability. The helical two-connector design is engineered for maximum flexibility and conformance to the vessel. Its strut thickness of 81 µm represents an important reduction from the 140 µm of the Cypher® sirolimus-eluting stent (SES; Cordis, NJ, USA).
DES dedicated to bifurcation lesions that are currently available include the biolimus-eluting Axxess™ (Biosensors, CA, USA), the paclitaxel-eluting Nile Pax® (Minvasys S.A.S., Gennevilliers, France), TAXUS Petal (Boston Scientific) and STENTYS (Stentys S.A.S., Paris, France) stents (Figure 1). The Axxess and STENTYS DES have a nitinol platform and are self-expanding, whereas the Nile PAX and TAXUS Petal have a cobalt–chromium and platinum–chromium platform, respectively [6]. Some of these dedicated stents are summarized in Table 1.
Despite recent advances in stent platform, the permanent presence of a metallic stent in the vessel has quite a few drawbacks. Mismatch of the stent can result in a smaller lumen, impair-ing blood flow. Permanent implants remaining beyond their intended function can prevent the lumen expansion seen with positive remodeling
Charis Costopoulos1–3, Azeem Latib*1,2, Toru Naganuma1,2, Alessandro Sticchi1, Francesco Giannini1 and Antonio Colombo1,2
1Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy2Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, 48 Via M Buonarroti, 20145 Milan, Italy3Imperial College London, London, UK*Author for correspondence: Tel.: +39 024 812 920 Fax: +39 024 819 3433 [email protected]
The introduction of drug-eluting stents has revolutionized the treatment of coronary artery disease. First-generation stents, however, were associated with relatively high revascularization rates and the risk of stent thrombosis. This has led to a worldwide search for improvements in stent technology that will reduce adverse cardiac events following stent implantation while providing optimal treatment. Here, the authors discuss recent advances in stent technology from improvements in stent platform and stent polymer to newer mechanisms of drug delivery and the incorporation of proendothelizing agents. The authors also introduce some of the newly available stents and discuss the evidence associated with their use in clinical practice.
and impair vessel geometry. Fully biodegradable stents can elim-inate these problems and facilitate later revascularization with percutaneous or surgical techniques if the need arises. Once the bioresorption of the temporary scaffold is completed, dual anti-platelet therapy (DAPT) could be stopped to potentially reduce bleeding complications. An ideal biodegradable stent would
completely disappear from the implant site over a period of time after it has fulfilled the function of recoil prevention, permitting normal vascular reactivity and remodeling. A number of bioresorbable stents are cur-rently being developed with some already in clinical practice. These stents represent one of the most important advancements in stent platform technology and will be discussed in detail later.
Stent polymerPercutaneous coronary angioplasty can-not be performed without damaging blood vessels, which in turn can elicit restenosis. Drug elution at the target site in order to prevent unnecessary cell proliferation is a clear solution to this problem. As a result, most currently approved DES are sur-rounded by a polymer drug-containing matrix. However, the use of early-gener-ation durable polymer DES was associ-ated with an increased risk of very late (>1 year) ST compared with bare metal stents (BMS). This has been attributed to delayed arterial healing and ongoing chronic inflammation as demonstrated by animal experiments, human autopsy results and intravascular investigation of throm-bosed DES specimens [7–11]. The presence of a durable polymer has been suggested as a potential culprit for this. This has led to the generation of DES with biodegradable polymer and in some cases no polymer at
all as this would render the stent surface free of a chronic inflam-matory stimulus and potentially improve long-term clinical out-comes following coronary stenting. Biodegradable polymer-based DES have been established as a safe and effective alternative to durable polymer-based stent platforms, as evidenced in several randomized clinical trials [12–15]. Moreover, an optical coherence
Figure 1. Dedicated bifurcation stents. (A) Nile Pax®, (B) Axxess™ and (C) STENTYS.
A B
C
Table 1. Bifurcation and small vessel-dedicated stents.
Stent (manufacturer) Drug Stent platform Strut thickness (µm)
Polymer Function
Nile Pax® (Minvasys) Paclitaxel Cobalt–chromium 73 Polymer free Bifurcation
tomography (OCT) study suggested improved healing of the stented coronary segment following treatment with biodegradable polymer DES compared with durable polymer SES at 9 months [16]. Biodegradable polymer DES are coated in most cases with poly-l-lactide, polylactic-co-glycolic acid, poly-d-lactide acid or a combination of the three. These are metabolized over a vari-able period to carbon dioxide and water, leaving behind a BMS. A number of biodegradable polymer DES are currently available and are summarized in Table 2. Here, the authors discuss some of the newer biodegradable polymer and polymer-free DES for which data from clinical trials have become available over the last year. Table 3 summarizes second-generation DES with durable polymer currently in use.
DES with biodegradable polymerThe Synergy™ Stent (Boston Scientific) consists of a platinum–chromium platform and a biodegradable everolimus-eluting poly-mer. Strut thickness is 74 µm, 7 µm less that the Promus Element (Boston Scientific). In the EVOLVE trial – which recruited 290 patients and randomized these to Promus Element Synergy everolimus half-dose and Synergy full-dose groups at a 1:1:1 ratio – target lesion revascularization (TLR) rates at 12 months were found to be lower in both Synergy groups compared with the Promus group (1.1% vs 5.1%, respectively). These findings, which will be evaluated further in the larger EVOLVE II trial, suggest that the absence of a durable polymer is associated with improvement in clinical outcomes [17].
Another DES with a biodegradable polymer currently under investigation is the BioMime™ Stent (Meril Life Sciences, Gujarat, India). This is a sirolimus cobalt–chromium stent with an open and closed hybrid cell design and ultrathin strut thick-ness (65 µm). In the meriT-I prospective single-center trial no major adverse cardiac events (MACE; defined as cardiac death, nonfatal MI, clinically or quantitative coronary angiography-driven TLR or ST) were detected at 2 years in a small cohort of 28 patients [18]. Results led to the nonrandomized, multicenter ‘real world’ meriT-II study, which recruited 250 patients. The results of this were reported at the Transcatheter Cardiovascular Therapeutics (TCT) Conference 2012. At 1-year follow-up, MACE was 6.0% (0.8% cardiac deaths; 1.2% nonfatal MIs; 4% clinically driven TLR) and ST was 1.2 % (0.4% subacute; 0.4% late; 0.4% very late). Quantitative coronary angiography at 8 months demonstrated in-stent late lumen loss (LLL) of 0.13 mm (0.05–0.34 mm). LLL at the proximal and distal edges was also low. Although the 2-year clinical outcomes of meriT-II are not expected until next year, the above results are promising with regards to the safety and efficacy of the BioMime Stent [19]. The results for another sirolimus-eluting cobalt–chromium stent with biodegradable polymer, the Inspiron™ SES (Scitech, São Paulo, Brazil), were also reported at this year’s TCT. In the INSPIRON I trial, Inspiron was found to be superior to the Cronus Plus BMS with regards to in-stent and in-segment loss at 6 months (in-stent loss: 0.22 vs 0.84 mm, p < 0.001; neointimal hyperplasia obstruction: 8.2 ± 7.4% vs 27.6 ± 11.1%, p < 0.001).
Table 2. Metallic stents with biodegradable polymer.
Stent (manufacturer) Drug Stent platform Strut thickness (µm)
It was also associated with less TLR and MACE at median fol-low-up of 878 days compared with the BMS control, although the patient number examined was small (n = 37) [20]. The cur-rent DESTINY trial comparing the Inspiron SES against the Biomatrix™ (Biosensors) biolimus-eluting stent in patients with up to two de novo lesions in 2.5–3.5 mm vessels will provide more information about the efficacy of this new SES in relation to a biodegradable polymer DES already in clinical use.
Updated results for another stent with a biodegradable poly-mer have also become available this year; the Firehawk® stent (MicroPort Medical, Shanghai, China) is an abluminal groove-filled bioabsorbable polymer-based targeting release SES. The TARGET I trial evaluated Firehawk against Xience V™ (Abbott Vascular, CA, USA) EES in a randomized trial of 460 patients. It included patients with a single de novo lesion <24 mm in length in 2.5–4.0 mm arteries. The primary end point was in-stent LLL at 9 months with clinical outcomes evaluated every year for 5 years. Results showed that Firehawk was noninferior to Xience V with regards to in-stent LLL (0.13 ± 0.24 mm vs 0.13 ± 0.18 mm; p < 0.0001) and with similar clinical outcomes at 1 year. No ST was seen in either stent groups [21]. The results of TARGET I sug-gest that this newer generation DES is safe and effective although larger trials are required to assess this fully.
The ABLUMINUS™ DES (Envision Scientific, Surat, India), like the Firehawk, has a cobalt–chromium platform, a biode-gradable polymer and abluminal sirolimus. Initial clinical work suggested that this is safe for further evaluation, which led to the enABL registry. This is a prospective ‘real world’ study aim-ing to recruit 3000 patients with clinical follow-up at 3, 9 and 12 months extending to 3 years and angiographic follow-up in 25% of the patients at 9 months. Primary outcomes will be MACE and clinically driven TLR at 12 months. Initial results at 6 months from some of the recruiting sites are encouraging, with further results expected in the near future [22].
The Orsiro DES (Biotronik SE, Berlin, Germany) is a novel stent with hybrid coating technology. It has a cobalt–chromium platform in a double-helix design with 60 µm strut thickness. Its coating consists of an active biodegradable poly-l-lactic acid (PLLA) polymer that elutes sirolimus and a passive silicon car-bide that encapsulates the stent surface. The silicon carbide coat-ing reduces the interaction between blood and the metallic stent surface, thereby limiting ion release by up to 95% according
to in vitro studies. This decrease is suspected to reduce chronic inflammation, which is associated with in-stent restenosis. In the first-in-man (FIM) study, BIOFLOW-I, which recruited 30 patients, was reported to have minimal in-stent LLL and only two cases (6.7%) of clinically driven TLR with no other MACE at 9 months. These promising results led to the prospective, non-inferiority, multicenter trial, BIOFLOW-II trial, which enrolled 440 patients and randomized them at a 2:1 ratio to Orsiro and Xience Prime (Abbott Vascular) groups. The primary end point was in-stent LLL at 9 months with clinical outcome results recorded each year for a 5-year period. The first results from this study are expected to be announced later this year [23].
The MiStent™ (Micell Technologies, NC, USA) is the last siroli-mus stent with bioabsorbable technology that will be discussed in this section. It has a cobalt–chromium platform and a polylactic-co-glycolic acid polymer. Complete drug elution and polymer absorp-tion is achieved within 90 days. The MiStent has been evaluated in the randomized, multicenter DISSOVE II study, where it was compared with the Endeavor Sprint Zotarolimus DES (Medtronic, CA, USA). The study recruited 155 patients who were randomized to MiStent and Endeavor Sprint groups at a 2:1 ratio. The primary efficacy end point was in-stent lumen loss at 9 months with MACE, also at 9 months, being the primary safety end point. Results showed less in-stent lumen loss with MiStent (0.27 ± 0.46 mm vs 0.58 ± 0.41 mm; p < 0.001) with comparable MACE rates between the two groups achieving the preset end points. More specifically, MACE and TLR rates with the MiStent were 4.3% and 0.9%, respectively, with no cases of probable or definite ST [24].
The Elixir DESyne™ BD (Elixir Medical, CA, USA) DES also have a biodegradable polymer, which elutes novolimus. It consists of a cobalt–chromium platform with 81-µm strut thickness and a polymer that degrades over 6–9 months, leaving a bare metal sur-face. Drug elution takes place over a course of 4 weeks. Its safety and efficacy were evaluated in the EXCELLA BD, single-blind, multicenter, randomized trial, which recruited 146 patients and compared the Elixir DESyne BD to Endeavor Sprint zotarolimus DES. Better results were seen with the DESyne BD stent with regards to in-stent lumen loss at 6 months (0.12 ± 0.17 mm vs 0.67 ± 0.47 mm; p < 0.001) and angiographic binary restenosis (0.0% vs 7.9%; p = 0.003). The composite end point of cardiac death, target vessel MI and clinically indicated TLR remained low at 1 year and similar between the two groups, demonstrating
Table 3. Stents with durable polymers.
Stent (manufacturer) Drug Stent platform Strut thickness (µm)
the clinical safety of the DESyne BD stent. Importantly, there was no ST over the same interval [25].
DES free from polymerAn obvious way of avoiding the chronic inflammation associated with the presence of a polymer is to avoid polymer use altogether. Although this approach has been utilized in the past prior to the commercialization of first-generation DES without any clear benefits, improvements in stent technology over recent years have allowed this approach to be revisited. Here, the authors once again discuss polymer-free DES (Table 4) with recently reported results.
The first is the Cre8™ DES (CID, Saluggia, Italy) that utilizes abluminal reservoir technology, which controls and directs drug elution to the vessel wall. The stent platform is made of thin cobalt–chromium alloy with an 80 µm strut thickness. The outer surface of the stent is coated by amphilimus in reservoirs, which achieves complete drug elution within 90 days. The stent also fea-tures Carbofilm™, a coating that promotes fast cellular growth and therefore accelerated endothelization and strut coverage. In the NEXT trial a total of 323 patients were enrolled with 162 randomized to Cre8 stents and 161 to TAXUS Liberté (Boston Scientific). Multivariate analysis showed significantly less in-stent LLL at 6 months (primary end point) with Cre8 versus TAXUS. For this end point, Cre8 proved to be both noninferior and supe-rior to the TAXUS Liberté stent (p < 0.0001 for both). Six-month angiographic results also showed that Cre8 was associated with significantly less in-segment LLL (p = 0.0041), in-stent mini-mal lumen diameter (p = 0.0006), in-segment minimal lumen diameter (p = 0.0353), in-stent diameter stenosis (p < 0.0001) and in-segment diameter stenosis (p = 0.0022). Differences in binary restenosis between the two stents were not significant at 1 year. The 2-year results reported at TCT 2012 showed similar MACE and TLR rates between the two groups, although there was a trend towards improved MACE in the diabetic subgroup with the Cre8 stent (4.8% vs 12.1%; p = 0.394). To evaluate this further, the pARTicip8 multicenter trial will enroll 1000 patients across Europe with symptomatic de novo coronary disease and evaluate MACE at 6 months with the first 100 enrolled diabetic patients also receiving angiographic follow-up. A further trial, the RESERVOIR trial (currently recruiting) will randomize 112 dia-betic patients to Cre8 and Xience groups in order to examine neointimal hyperplasia volume obstruction and degree of strut coverage at 9 months as assessed by OCT [26,27].
The BioFreedom™ (Biosensors) stent is another polymer-free DES for which clini-cal results were reported at TCT 2012. It uses a stainless steel Bio-Flex II stent plat-form with a textured abluminal surface onto which BA9 in solvent is applied. Thus, there is little drug release on the luminal side of the stent where endotheli-alization and healing takes place. Complete drug elution is achieved within 50 h. The stent was assessed in the BioFreedom FIM study, which randomized 182 patients in
BioFreedom low dose, BioFreedom high dose and TAXUS groups at a 1:1:1 ratio. Clinical outcomes in terms of MACE, TLR and ST were similar in all three groups at 36 months although the BioFreedom high-dose group showed a significant lower in-stent LLL compared with TAXUS at 6 months (0.17 mm vs 0.35 mm; p = 0.001) [28]. The BioFreedom stent will be further assessed in the LEADERS FREE trial, which aims to enroll and rand-omize approximately 2500 patients into the BioFreedom DES and Gazelle BMS (Biosensors) groups. Both groups will receive 1 month of DAPT with single antiplatelet therapy thereafter. Primary end points will be noninferiority of BioFreedom with regards to MACE after 1 year and superiority with regards to TLR at 12 months over the Gazelle BMS (Figure 2).
The Yukon stent (Translumina, Hechingen, Germany) is also a polymer-free stent with a stainless steel platform and dual drug elution (sirolimus and probucol). This has been assessed in a number of studies. The latest trial with updated results, the ISAR-TEST 5 trial, recruited 3002 patients with de novo lesions and randomized these to Yukon and zotarolimus-eluting stent groups. The 2-year clinical outcomes, presented in TCT 2012, were found to be similar between the two groups (target lesion failure [TLF]: 15.9% vs 15.8%, respectively, p = 0.87; TLR: 12.2% vs 11.9%, respectively, p = 0.89) [29].
The VESTAsync™ Eluting Stent (MIV Therapeutics, GA, USA) is a thin cobalt–chromium platform (65 µm strut thick-ness) with a nanothin-microporous hydroxyapatite surface coating impregnated with a polymer-free low dose of sirolimus (55 µg) (Table 5). The drug completely elutes within 60 days. In the VESTASYNC II trial, 75 patients were enrolled and randomized to VESTAsync and its bare-metal platform version in a 2:1 ratio. At 2 years, MACE rates were 6% and 14% in the DES and BMS groups, respectively, and there were no cases of ST in either group. At 8 months, the DES group had a late loss of 0.39 ± 0.20 mm vs 0.78 ± 0.60 mm with the noneluted version (p = 0.03). By intravascular ultrasound (IVUS), percentage of stent obstruction (due to neointimal hyperplasia) was 9% with the DES vs 18% with the BMS (p < 0.001) [30].
The last stent to be discussed in this section is the Amazonia Pax® stent (Minvasys S.A.S.), which has a cobalt–chromium plat-form (73 µm strut thickness), is polymer-free and coated with paclitaxel. The PAX-A trial compared the Amazonia Pax with TAXUS Liberte in a small cohort of 31 patients to find similar angiographic and clinical outcomes between the two groups at
Table 4. Polymer-free metallic stents.
Stent (manufacturer) Drug Stent platform Strut thickness (µm)
4 months and 2 years, respectively. The PAX-B trial was a larger study, which included 103 lesions with length <20 mm and in vessels with 2.5–3.5 mm diameter treated with Amazonia Pax. At 9 months, binary restenosis was found to be high at 19.7%. There was also a high incidence of target vessel revascularization over the same time interval at 18.5%, which had increased to 25.2% by 24 months [31].
DrugsLocal drug delivery using DES provides a biological solution for the prevention of in-stent restenosis. The majority of these aim to limit cell proliferation at the abluminal side of the stent through their immunosuppressive, anti-inflammatory and/or antiprolif-erative properties. Other agents aim to accelerate endothelization
of the stent struts, thereby limiting chronic inflammation at the luminal side of the stent and ST.
First-generation DES used sirolimus and paclitaxel, with zotarolimus and everolimus being the most commonly used drugs in second-generation stents. Newer drugs used in more recent DES are mostly of the -limus family and include biolimus A9, novolimus and myolimus. Limus family drugs are derived from macrocyclic lactones and function by inhibiting the mTOR, interrupting the cell cycle. Previous clinical studies have dem-onstrated overall superiority, both in reducing LLL and repeat revascularization, of mTOR-inhibiting DES compared to those eluting paclitaxel.
Biolimus A9 is a highly lipophilic, semisynthetic analogue of sirolimus with enhanced anti-inflammatory and antiproliferative
activity as well as an improved pharmaco-kinetic profile compared with sirolimus. It is currently being utilized in the Nobori® (Terumo, Tokyo, Japan) and Biomatrix stents, both of which have a biodegradable polymer. Both stents have confirmed non-inferiority over first-generation DES in the NOBORI and LEADERS trials [14,32,33]. In the NOBORI 2 ‘real world’ study, the Nobori stent demonstrated good clinical outcomes at 2 years with low MACE and ST rates. Encouraging results were also seen in the more ‘complex’ subgroups such as the diabetic and chronic total occlusion cohorts with TLF rates (defined as TLR, target vessel MI and death) at 7.2 and 5.2%, respectively [34]. The 5-year results from the LEADERS trial, which compared the biolimus-eluting stent with SES and were presented at TCT 2012, demonstrated a trend towards lower MACE at 5 years with a statistically sig-nificant improvement in patient-orientated composite end points (defined as any-cause death, all revascularization and all MI) compared with SES [35].
Other -limus drugs currently utilized include novolimus, incorporated in the Elixir DESyne BD and Elixir stents; myoli-mus, used in the Elixir DESolve bioresorb-able stent; and amphilimus in the Cre8 polymer-free stent. The Symbio™ (Cordis Corp., FL, USA) stent uses both pimecroli-mus and paclitaxel loaded in adjacent res-ervoirs, although this failed to show non-inferiority over a paclitaxel-only stent in the GENESIS trial. The merilimus-eluting Mitsu stent (Meril Life Sciences) is dis-cussed elsewhere. Tacrolimus is an another limus drug of promise although not uti-lized in currently available DES. Although this has less vascular smooth-muscle cell
Figure 2. Novel mechanisms of drug release. (A) Hollow core and hole release system, (B) abluminal reservoir system and (C) Micropore release system.
antiproliferative activity than other limus drugs, its additional potent anti-inflam-matory effect makes this a promising compound for the future. Another drug with potent anti-inflammatory effects is dexamethasone, which has been shown to suppress neointimal proliferation both in vitro and in vivo.
Newer agents with antiproliferative properties currently under investigation include cilostazol, which is incorporated in the pacli-taxel-eluting Cilotax Stent (CardioTech, Seoul, South Korea). Cilostazol is a potent inhibitor of phosphodiesterase and has both antiplatelet and antiproliferative effects. In animal studies, incor-poration of cilostazol showed reduction of neointimal proliferation compared with BMS alone. In the CILOTAX trial, which rand-omized 111 patients to Cilotax and TAXUS Liberte, the cilostazol and paclitaxel dual DES were found to be associated with less in-stent restenosis at 9 months compared with the paclitaxel-only DES (0.22 ± 0.31 mm vs 0.50 ± 0.55 mm; p = 0.002). MACE rate and in-segment loss did not differ significantly between the two groups. Whether Cilotax is associated with lower in-stent LLL compared with newer generation stents, at least in diabetic patients, will be evaluated in the ESSENCE-DM III trial, where it will be compared against the Xience EES [36].
New developments in drug technology aim not only to limit excessive cell proliferation but also to enhance endothelization fol-lowing DES implantation. The PROTEX Coronary Stent System (Nexeon MedSystems, WV, USA) combines Nexeon’s RIVIERA coronary stent implant with SurModics’ Finale™ Prohealing Coating. The Finale coating, which incorporates extracellular matrix proteins, is designed to improve and accelerate tissue heal-ing. Extracellular matrix proteins stimulate the specific migration and proliferation of endothelial cells to promote healing. In a FIM, prospective, multicenter, single-arm trial of PROTEX, serial (baseline and 6 months) IVUS was performed in 38 patients. The trial demonstrated favorable vessel responses with almost complete tissue coverage of struts within 6 months [37]. Further clinical trials using this innovative system are awaited. Another exciting possi-bility is the use of monoclonal antibodies to either enhance healing or reduce thrombogenicity in the stented area. The Combo™ Dual Therapy Stent (OrbusNeich, Hong Kong, China) combines Genous technology with a stainless steel biodegradable polymer SES. The Genous prohealing technology has an antibody surface coating that captures circulating CD34+ endothelial progenitor cells (EPCs) to the device, forming a functional endothelial layer over the stent to protect against thrombus and minimize reste-nosis. The safety and efficacy of the Combo stent is currently evaluated in the REMEDEE trial. This trial recruited 183 patients with single de novo lesions <20 mm length in 2.5–3.5 mm diam-eter vessels. Patients were randomized at a 2:1 ratio to Combo and TAXUS Liberte groups. Noninferiority of the Combo stent was demonstrated by less LLL at 9 months (0.39 ± 0.45 mm vs 0.44 ± 0.56 mm; p = 0.0120). Regarding clinical outcomes, the incidence of clinically driven TLR was less with Combo but not statistically significant (4.9% vs 8.5%; p = not significant). Virtual
histology-IVUS showed that Combo stents had significantly less necrotic core than TAXUS stents at 9 months. OCT, however, revealed homogeneous neointimal responses with Combo stents compared with variable, heterogeneous responses with TAXUS stents at 9 months. Larger trials are required to fully evaluate the benefit of endothelial capture [38,39].
The use of antibody technology is not limited to EPC recruit-ment. Aggarwal et al. evaluated the use of an antiplatelet GP IIb/IIIa antibody-eluting cellulose polymer-coated stent in a rab-bit model. The study showed that these antibody-eluting stents effectively inhibit platelet aggregation in the stent microenviron-ment, thus reducing thrombus formation, improving blood flow and arterial potency, and inhibiting cyclic blood flow variation [40]. Other technologies currently under investigation in animal models include the human recombinant tropoelastin-coated stent and the arsenic trioxide-eluting stent. Elastin is an important vas-cular matrix protein that interacts favorably with endothelial cells and inhibits smooth muscle cell proliferation. It is also believed to reduce metal thrombogenicity. Its incorporation in metallic stents can therefore in theory be beneficial as it may allow earlier endothelization and reduced smooth muscle proliferation, leading to a lower incidence of in-stent restenosis and ST [41]. Arsenic triox-ide-eluting stents may also have similar benefits through the dose-dependent inhibition of smooth muscle cell proliferation and type III collagen expression according to animal studies [42]. However, in a pig coronary artery stent model imatinib-NP (Gleevec) DES markedly reduced in-stent neointimal formation as assessed by angiographic, IVUS and histopathological studies without affect-ing re-endothelization, suggesting that incorporation of imatinib nanoparticles in DES may have a role in the future [43].
Mechanism of drug deliveryIn the majority of commercially available stents, a polymer holds and elutes the drug of choice to the arterial wall. In many cases, release is abluminal, aiming thus to inhibit neointimal growth due to smooth muscle cell proliferation and restenosis without compromising stent endothelization. Polymer-free DES use a number of different mecha-nisms to achieve this. Cre8, for example, uses an abluminal reservoir system on the stent’s outer surface. BioFreedom, VESTAsync and Yukon DES achieve this through micropores on the stent surface. Here, the authors discuss some of the newer technologies devel-oped for drug release. The Medtronic drug-filled stent technology involves a hollow-core DES into which the drug is incorporated and subsequently released through holes drilled by a laser on the stent surface. In vitro and porcine coronary studies have shown that drug-filled stents achieve significant inhibition of neointimal formation compared with BMS, with 100% endothelization at 28 days [44].
Table 5. Metallic stents with specialized coating.
Another novel system for drug delivery is the nanoparticle technol-ogy in which the drug is encapsulated by nanoparticles. This is supposed to protect the drug during stent delivery while achieving adequate and controlled drug release to the vessel without the need for a polymer. This technology is utilized by the FOCUS np stent (Envision Scientific), which has been tested in animal models. In these studies, FOCUS np SES is associated with less neointimal hyperplasia compared with BMS, BMS followed by drug-eluting balloon or a biolimus-eluting stent with biodegradable polymer (Biomatrix). This led to the NANOACTIVE FIM study results which were presented at TCT 2012. The study enrolled 100 patients in two cohorts. Cohort A consisted of patients with a maximum of two de novo lesions (n = 55) and cohort B contained all comers with coronary artery disease (n = 45). In cohort A, procedural success was 100% with two cases of TLR at 6 months (3.6%). Detailed results from both cohorts will be available later in the year [45].
Another stent that utilizes nanotechnology is the Mitsu DES. This is an ultrathin cobalt–chromium stent with 45 µm strut thickness and a hybrid cell design. It has good radial strength, low foreshortening, low recoil, low profile and eludes merilimus, which has a better toxicology profile than sirolimus as well as a wider therapeutic window as it is more lipophilic. Clinical results regarding the efficacy and safety of this stent are awaited. Other advancements include the development of nanoparticle magnetic stents, which are currently being assessed in animal studies [46].
DES with integrated delivery systemThe Svelte DES (Svelte Medical Systems, NJ, USA) have an inte-grated delivery system consisting of a standard luer hub, a torquer, a 0.012” platinum–iridium atraumatic wire with a flexible tip and a cobalt–chromium SES loaded on a nylon balloon. The poly-mer is amino acid based, degrading by erosion over 12 months, and strut thickness is 81 µm. In the FIM, DIRECT trial, using an integrated delivery system, 30 patients with de novo lesions <20 mm in length in 2.5–3.5 mm vessels were treated with the Svelte DES. Device delivery was successful in 29 out of 30 patients and one MACE occurred in the first 6 months. At 6 months and in a 15-patient cohort, in-stent LLL was 0.15 ± 0.23 mm and OCT results from nine patients showed 97 ± 4% strut coverage. The CE Mark study for this device was due to start in the last quarter of 2012 [47]. Potential advantages of an integrated delivery system include shorter procedural times and lower costs.
Bioresorbable stentsThe Igaki-Tamai Stent (Kyoto Medical Planning, Kyoto, Japan) is a non-DES made of PLLA and was the first fully bioabsorbable stent successfully implanted in man. This pioneering stent was implanted using a balloon-expandable covered sheath system but also had a temperature-induced self-expanding property. The need to use a balloon with heated contrast made the stent cumbersome to use. Recently, Nishio et al. published the 10-year follow-up after implantation of the first-generation Igaki-Tamai stent in 50 patients (63 lesions). At 10 years, there were seven deaths, one of unknown cause and six secondary to noncardiac causes, and three MIs of which only one was lesion related. At 3-year follow-up, there was a
LLL of 0.59 ± 0.50 mm and in patients interrogated with IVUS, the scaffold was no longer detectable [48]. Although results were promis-ing, procedural difficulties such as the need for a larger guide and heated contrast heralded further studies with the first-generation stent. Since then, improvements in the device allow the use of a 6F catheter and nonheated contrast. The second-generation stent is currently undergoing preclinical evaluation in Germany.
The Abbott Vascular bioresorbable vascular scaffold (BVS; Abbott Vascular) is made from semicrystalline PLLA coated with amorphous poly-d-lactide acid polymer, which contains and con-trols the release of the antiproliferative drug everolimus. Complete degradation of the scaffold takes 2–3 years. Two versions of the BVS have been tested in clinical trials. The safety and feasibility of the first BVS (Revision 1.0) was tested in the open-label prospective FIM ABSORB trial, which recruited 30 patients [49]. Clinical fol-low-up and multimodality imaging including multislice computed tomography, angiography, IVUS, derived morphology parameters (virtual histology, palpography and echogenicity) and OCT were performed. At 6-month follow-up, the angiographic in-stent LLL was 0.44 ± 0.35 mm, similar to some DES and was mainly due to a mild reduction of the stent area (-11.8%) as measured by IVUS. At 2 years, the scaffold was almost completely bioabsorbed and there was no significant restenosis. Interestingly, vasomotion appeared to be restored with vasoconstriction induced by methylergonovine maleate and vasodilatation induced by nitroglycerin in the treated segment. This raises the possibility that the healed stented area will have a normal physiological response to vasoreactive stimuli. Longer follow-up of this cohort of patients demonstrated freedom from late ST and a sustained low MACE rate of 3.4% [50].
The second-generation BVS device (Revision 1.1) improved upon the previous scaffold in order to provide radial support for longer, even though the polymer used and the total absorption time remained the same. In-phase zigzag hoops with linking bridges help uniform strut distribution with better wall support and drug delivery. While the first version had to be stored at -20°C and had a limited shelf life of 8 weeks, Revision 1.1 can be stored at room temperature and has a shelf life of 6 months. The efficacy of the Revision 1.1 device was assessed in the multicenter, single-arm ABSORB Cohort B trial recruiting 101 patients with single or two-vessel de novo disease [51]. All patients received a 3 × 18 mm BVS. Patients were divided into two groups for follow-up purposes: group 1 was followed up at 6 months and 2 years and group 2 at 1 and 3 years with IVUS ± OCT assessment. Computed tomography coronary angiography was performed for all patients at 18 months. In the first group, at 6-month follow-up, there was only one TLR, and LLL was 0.19 ± 0.18 mm. At 2 years, LLL was 0.27 ± 0.20 mm. Scaffold area progressively increased during follow-up; however, at 6 months there was a significant reduction in mean lumen area on IVUS compared with baseline (6.37 ± 1.12 vs 6.60 ± 1.22 mm2; p < 0.005) [52]. Although 3-year follow-up is not available for group 2, at 1 year there were two non-ST elevation MIs, two TLR and LLL of 0.27 ± 0.32 mm [53]. More studies are currently underway evaluating BVS 1.1. The ABSORB Extend study is a worldwide registry recruiting 1000 patients with de novo single- or two-vessel disease and aiming to examine the safety and efficacy of the device.
It allows recruitment of patients with significant disease in smaller vessels (>2.0 mm) as well as those with long lesions, thus giving the opportunity to evaluate the scaffold’s role in these cohorts too. The ABSORB Physiology study will examine the acute and long-term effects of BVS 1.1 on coronary physiology compared with metallic DES. The efficacy of the scaffold compared with cur-rently used DES will be examined in the ABSORB II study. This is a prospective, randomized controlled trial comparing BVS 1.1 versus the Xience Prime stent. It will recruit 500 patients with stable angina and single- or two-vessel disease and randomize them on a 2:1 basis to BVS 1.1 and Xience Prime stent implantation therefore also allowing the evaluation of the safety of the BVS 1.1. The trial is expected to be completed in 2015. The multicenter, randomized ABSORB III trial will recruit over 2000 patients with up to two de novo lesions in different epicardial vessels (vessel diam-eter: 2.5–3.75 mm; length ≤24 mm) and randomize these to BVS 1.1 and Xience groups at a 2:1 ratio. The primary end point will be TLF at 1 year. The ABSORB IV will aim to add another 4000 patients to ABSORB III and will assess superiority of BVS 1.1 over Xience with regards to TLF between 1 and 5 years.
Biotronik (Biotronik SE) has manufactured a balloon-expand-able absorbable metallic stent, AMS-1, composed of magnesium alloy, which has sufficient radial strength on deployment and is
degraded to inert products within 4 months. The PROGRESS AMS trial was a nonrandomized, prospective multicenter trial that enrolled 63 patients with single de novo lesion in a native coronary artery [54]. The immediate angiographic effect was simi-lar to results seen with other metallic stents. The resorption was relatively quick and IVUS at 4 months showed only remnants of strut embedded in the intima. The TLR rate was very high (45%) at 12-month follow-up. This was possibly due to the early rapid stent-degradation time resulting in loss of radial force and the absence of an antiproliferative drug. Second-generation devices, AMS-2 and AMS-3, have since been designed with different mag-nesium alloy and slower degradation time. AMS-3 DREAMS combines a bioresorbable matrix with an antiproliferative drug (paclitaxel) aiming to prevent the restenosis. The FIM clinical study to test the safety and feasibility of Biotronik DREAMS, BIOSOLVE-I trial enrolled 46 patients with a single de novo lesion and reference diameter of 3.0–3.5 mm. At 6 months, there were no cardiac events and the TLR rate was 4.6%. LLL was 0.64 ± 0.55 mm [55]. DREAMS was further modified to DREAMS 2, which has tantalum radiopaque markers at the end and elutes sirolimus. Its use in animal models was associated with better endothelization and reduced inflammation compared with DREAMS 1 [56]. It has yet to be evaluated in humans.
• Coronary artery disease is a major cause of morbidity and mortality worldwide.
• Percutaneous coronary intervention is an important therapeutic option for this. Since its advent, its use has increased exponentially.
• First-generation drug-eluting stents (DES) were limited by a relatively high target lesion revascularization rate as well as being associated with stent thrombosis.
• Improvements have been achieved since in stent platform, polymer and drug characteristics.
• Newer platforms with thinner struts have improved device delivery allowing the treatment of more complex disease. Dedicated stents also allow the treatment of more difficult lesions such as those at bifurcation sites.
• Polymers with greater biocompatibility not only allow drug delivery but are also associated with reduced inflammation following DES implantation. The introduction of DES with biodegradable polymers may reduce such inflammation further and therefore reduce adverse cardiac events. Duration of dual-antiplatelet therapy could be reduced and thus associated bleeding risks. Polymer-free DES may also have similar beneficial effects.
• Newer drugs, antirestenotic drugs as well as agents that promote endothelialization are expected to decrease revascularization rates following DES implantation.
• The introduction of bioresorbable DES enables the treatment of disease without metallic remnants, which can allow future treatment (if required) without the addition of metallic layers to the vessel wall and maintain access for coronary artery bypass grafting.
A number of other bioresorbable stents are currently under development, some of which are under evaluation in small clinical trials. Their main properties are summarized in Table 6.
Expert commentaryAdvances in stent technology have revolutionized the field of interventional cardiology and treatment of ischemic heart disease. Concerns, however, remain with regard to bleeding complications due to prolonged DAPT, ST and reduced effectiveness in certain patient cohorts. Recent trials, albeit with older generation DES, have suggested that coronary artery bypass grafting may be asso-ciated with better outcomes in patients with complex multivessel disease or diabetes. It has also been suggested that patients with nonprognostic, significant disease may have similar outcomes with medical therapy compared with percutaneous coronary intervention. Despite such uncertainties, DES will remain an important treatment option in patients with coronary artery dis-ease, especially in those with nonsurgical disease, acute coronary syndromes and in those with refractory angina despite adequate medical therapy. Further developments in stent technology will hopefully address the aforementioned issues.
Five-year viewThe ideal stent should prevent acute recoil, provide uniform sup-port, prevent restenosis, have excellent deliverability and not pre-dispose to thrombus formation [57]. It should also endo thelialize
quickly to allow early discontinuation of DAPT, thereby reducing patient bleeding risk. Recent advancements in stent technology have led to improvements in most of these fields. The future direction of stent development seems to be moving towards bio-degradable polymer or polymer-free platforms and completely bioresorbable stents. Incorporation of new agents that limit neointimal hyperplasia further while promoting endothelization may also be of benefit. Such improvements may allow reduction in the duration of DAPT therapy and therefore bleeding risk. They may also lead to further reductions in TLR and ST, allow-ing the percutaneous treatment of more complex disease and patients that currently experience higher rates of adverse events, such as those with diabetes and chronic renal failure. Finally, the introduction of bioresorbable stents in routine clinical practice will allow the percutaneous treatment of coronary artery disease while maintaining access for coronary artery bypass grafting, if this were to be required at a future date and it may also elimi-nate the risk of late thrombotic events in treated segments of the vessel.
Financial & competing interests disclosureA Latib serves on a Medtronic Advisory Board. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest
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