Evolution of stents: past, present and future

The introduction of metallic stents to treat coronary artery disease has been one of the most revolutionary breakthroughs in the history of cardiology. In the early stages of their development, these devices were mainly considered to represent the mechanical solution to abrupt vessel closure and elastic recoil following balloon angioplasty. For this reason, research and debate initially focused on issues surrounding stent design, including the assessment of different materials and surface treatments. More recently, following the introduction of drug-eluting stents (DESs), the debate has shifted to the research of the best vector for local drug delivery and modification of coronary plaque pathophysiology. The rationale for the introduction of DESs was to reduce the formation of neointimal hyperplasia, a proliferative maladaptive healing response to bare-metal stent implantation, potentially leading to restenosis and repeat revascularization.

To date, six limus family-related drugs are currently being studied in DES, namely sirolimus, everolimus, biolimus A9, zotarolimus, tacrolimus and pimecrolimus. Another non-limus-family-related drug that is studied widely for its efficacy in coronary stents is paclitaxel. While the effect of limus family-related drugs depends on blockage of the cell cycle, mainly of the smooth muscle cell, from the G₁ to S phase (i.e., sirolimus, everolimus, biolimus A9 and zotarolimus) or the inhibition of T-cell activation (i.e., tacrolimus and pimerolimus), the activity of paclitaxel has been explained by its ability to stabilize microtubules and, thereby, inhibit cell division in the G₀/G₁ and G₂/M phases.

The sirolimus-eluting stent (Cypher^®, Cordis Corp, NJ, USA) was the first DES to receive both the Conformité Européenne (CE)-mark and US FDA approval in 2002 and 2003, respectively. Several studies (Randomized Study with the Stimulus Coated Bx Velocity Balloon [RAVEL], Sirolimus-Eluting Stent in de novo Native Coronary Lesions [SIRIUS], European-SIRIUS, Canadian-SIRIUS [1–3] and registry data from Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital [RESEARCH] and e-CYPHER [4,5]) have demonstrated its efficacy in populations ranging from extensively selected patients with single lesions to unselected all comers.

The paclitaxel-eluting stent (Taxus^®, Boston Scientific, MS, USA) was the second DES to receive FDA approval, in 2004. The TAXUS family of trials has widely demonstrated their superiority compared with bare-metal stents in different subsets of patients and lesions [6–8]. Another new paclitaxel-coated device is the Asian Infinnium (Sahajanand Medical Technologies, Gujarat, India), which was the first DES from Asia to receive CE-mark approval.

The second-generation DESs include the zotarolimus-eluting stent (Endeavor^®; Medtronic, MN, USA) and the everolimus-eluting stent (Xience V™; Abbott Laboratories, IL, USA). The zotarolimus-eluting stent was tested in the ENDEAVOR I and II trials [9,10], with favorable results compared with bare-metal stents. While the recent ENDEAVOR III trial has failed to prove noninferiority of the Endeavor in comparison with the Cypher in terms of angiographic end points [11], data from the ENDEAVOR IV trial comparing Endeavor versus Taxus have shown similar rates of target vessel failure, thus enabling FDA approval [101]. Another zotarolimus-eluting device is the Zomaxx TriMaxx™ stent (Abbott Pharmaceuticals, IL, USA), whose trial program was discontinued by the manufacturer after the disappointing results of the Zomaxx I trial [12].

The everolimus-eluting stent was clinically evaluated in the Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions (SPIRIT) trial [13], which proved its superiority compared with a bare-metal stent. In the SPIRIT-II trial, the Xience V stent proved to be superior to Taxus for reduction of both late loss and binary restenosis [14]. Subsequently, the SPIRIT-III trial confirmed the positive expectations of previous trials, suggesting the superiority of the Xience V stent in comparison with Taxus in terms of clinical efficacy [15]. The upcoming SPIRIT-IV, SPIRIT-V and SPIRIT-WOMAN studies will provide further clinical data. Boston Scientific markets the everolimus-eluting stent as Promus™. Together, the Xience and the Promus represent the fourth DES to pass the approval process in the USA.

As a new concept, two biolimus-eluting stents with absorbable polymeric coatings are currently being evaluated in clinical trials. The Stent Eluting A9 Biolimus Trial in Humans (STEALTH) was the first-in-man trial to assess the safety and efficacy of the BioMATRIX^® stent (Biosensors International, Singapore) [16]. The recently presented 9-month results of the Nobori™ I clinical trial have shown significantly reduced late lumen loss when compared with Taxus [17].

The first-in-man study to evaluate the safety and efficacy of a pimecrolimus-eluting stent is currently ongoing.

To date, two clinical trials evaluating the safety and efficacy of tacrolimus-eluting stents (Janus^®; Sorin, Saluggia, Italy) have been completed: European Direct Stenting of de novo Coronary Artery Stenosis With Tacrolimus-Eluting Versus Carbon-Coated Carbostents (JUPITER) I, a first-in-man study, and JUPITER II [18], a randomized, controlled study that compared the Janus stent with its bare-metal stent counterpart. Safety concerns regarding clinical usage of tacrolimus-eluting stents have recently been reported in two registries [19,20].

Although DESs have markedly reduced restenosis, several limitations of their use have emerged, including association with an increased rate of possible adverse clinical events, such as late stent thrombosis; therefore, there is need for long-term dual antiplatelet therapy with increased cost and risk of severe bleeding. Therefore, novel approaches regarding modifying stents are continuously developed to address the limitations of both bare metal stents and DESs. Recent advances in platform, carrier and pharmacological technology will, therefore, be examined briefly to understand the direction in which these developments may go in the future.

The rationale for developing new coatings is that many polymer coatings are not entirely inert, and hypersensitivity reactions against the polymer have frequently been reported. Given these concerns, research is focusing on polymers that are biodegradable (i.e., derived from lactic and glycolic acid [21]) or biomimetic (i.e., hydroxyapatite or heparin) and on the possibility of a polymer-free approach.

Initial attempts to use dissolvable metallic alloys (magnesium) resulted in high rates of repeat revascularization [22]. In a search for more biocompatible coatings, promising first-in-man results of a novel stent covered with a nanothin poly(bis[trifluoroethoxy])phosphazene surface modification (CATANIA™, Celonova Biosciences Inc., GA, USA) have recently been reported [23]. The Randomized Trial of a Nonpolymer-Based Rapamycin-Eluting Stent Versus a Polymer-Based Paclitaxel-Eluting Stent for the Prevention of Restenosis (ISAR-TEST) study recently showed noninferiority in terms of reduction of restenosis of a polymer-free, microporous, sirolimus-coated stent (Yukon^®; Translumina, The Drug-Eluting System Company, Hechinger, Germany) compared with Taxus [24].

Another appealing, although preliminary, new concept is the ‘dual DES’, a trilayer stent that elutes two drugs (i.e., zotarolimus/dexamethasone, pimecrolimus/paclitaxel or sirolimus/genistein) and aims to suppress the production and effects of an inflammatory response. Also, novel stents are engineered for targeted drug elution (Conor MedStent^®, Conor Medsystems, CA, USA) with controllable-release kinetics due to a porous design [25]. Coating stents with an agent that would facilitate endothelialization by attracting endothelial cells represent yet another approach to improve the safety of DESs. Safety and efficacy of an endothelial progenitor cell-captured stent (Genous Bioengineered R Stent™, OrbusNeich, FL, USA) were favorably evaluated in the Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth (HEALING) and HEALING II studies [26,27]. Further clinical studies using this technology are ongoing.

Further advancements are currently devoted to enhancing deliverability and developing newer stents that are dedicated to specific lesions so as to minimize the complexity of the procedure and improve the overall outcome. In particular, the challenges in treating coronary bifurcations have inspired the development of the dedicated bifurcating stent. The multicenter Axxess Plus Biolimus Stent in LMCA Bifurcations registry was established to evaluate the safety and efficacy of a bifurcation stent (DEVAX–AXXESS™, Devax Inc., CA, USA) for use in the left main coronary artery, with encouraging early results [28].

Another new concept is that of a modular system for long lesions, multiple lesions and multivessel disease, consisting of multiple segments that allow for in situ customization of stent length. Following the positive results of the CUSTOM-I registry, the device is currently under investigation in the CUSTOM-II trial.

To summarize, design criteria for a novel stent include deliverability, safety and efficacy [29]. First, most new DES systems have lowered crossing profiles, and to further lower the crossing profiles, guidewire-based stents are currently under development. Stents that are designed to be fully biodegradable are also being developed, with their deliverability and performance not yet fully elucidated. Second, efforts to improve efficacy of DES are shifting toward a lesion-specific approach, including the design of stents dedicated to bifurcation lesions. Refinements in dedicated stents are warranted in order to improve the potential clinical outcomes of a complex subset of lesions. Other future directions are a disease-specific approach or an approach using DES as local drug-delivery devices. Finally, safety issues related to the first-generation DESs have encouraged the development of biologically based platforms, which include fully biodegradable stents as well as stents that use biomimetic and biodegradable polymers.

Hopefully, the integration of mechanical, pharmacologic and manufacturing endeavors will generate the ideal device able to mark a new step forward in the struggle against coronary artery disease.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.