Review
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Newly available and recent advances in drug-eluting stents Expert Rev. Cardiovasc. Ther. 11(5), 555–566 (2013)
Charis Costopoulos1–3, Azeem Latib*1,2, Toru Naganuma1,2, Alessandro Sticchi1, Francesco Giannini1 and Antonio Colombo1,2 Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy 2 Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, 48 Via M Buonarroti, 20145 Milan, Italy 3 Imperial College London, London, UK *Author for correspondence: Tel.: +39 024 812 920 Fax: +39 024 819 3433
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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.
1
Keywords: bioresorbable stent • coronary artery disease • drug-eluting stent • dual antiplatelet therapy • late lumen loss • percutaneous coronary intervention • polymer • stent thrombosis • target lesion revascularization
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 incidence 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 disastrous clinical impact, resulting in myocardial infarction (MI) and death with a fatality rate up to 45% [1,2] . A variety of factors including premature discontinuation of antiplatelet therapy, patient factors such as diabetes, renal dysfunction 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 contribute 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 platform, the polymer and the antiproliferative drug. Here, the authors concentrate on recent advances in stent technology. Stent platform
Recent innovations in stent platforms include changes of the metallic alloy (i.e., use of titanium and shifting from cobalt–chromium or stainless www.expert-reviews.com
10.1586/ERC.13.43
steel to platinum–chromium platforms) and the development of dedicated stent platforms for the treatment of specific lesion subsets (i.e., bifurcations 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 biolimuseluting 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, impairing blood flow. Permanent implants remaining beyond their intended function can prevent the lumen expansion seen with positive remodeling
© 2013 Expert Reviews Ltd
ISSN 1477-9072
555
Review
Costopoulos, Latib, Naganuma, Sticchi, Giannini & Colombo
A
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 currently 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.
B
Stent polymer
Percutaneous coronary angioplasty cannot 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, C most currently approved DES are surrounded by a polymer drug-containing matrix. However, the use of early-generation durable polymer DES was associated 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 thrombosed 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 Figure 1. Dedicated bifurcation stents. (A) Nile Pax , (B) Axxess™ and (C) STENTYS. polymer and in some cases no polymer at and impair vessel geometry. Fully biodegradable stents can elim- all as this would render the stent surface free of a chronic inflaminate these problems and facilitate later revascularization with matory stimulus and potentially improve long-term clinical outpercutaneous or surgical techniques if the need arises. Once the comes following coronary stenting. Biodegradable polymer-based bioresorption of the temporary scaffold is completed, dual anti- DES have been established as a safe and effective alternative to platelet therapy (DAPT) could be stopped to potentially reduce durable polymer-based stent platforms, as evidenced in several bleeding complications. An ideal biodegradable stent would randomized clinical trials [12–15] . Moreover, an optical coherence Table 1. Bifurcation and small vessel-dedicated stents. Stent (manufacturer)
Drug
Stent platform
Strut thickness Polymer (µm)
Function
Nile Pax® (Minvasys)
Paclitaxel
Cobalt–chromium
73
Polymer free
Bifurcation
TAXUS Petal (Boston Scientific)
Paclitaxel
Platinum–chromium 97
Translute: poly (styrene-bisobutylene-b-stylene)
Bifurcation
Axxess™ (Biosensors)
Biolimus A9
Nitinol
160
Poly-l-lactide
Bifurcation
STENTYS (Stentys S.A.S.)
Paclitaxel
Nitinol
77
Polysulfone
Bifurcation
Xience SBA (Abbott Vascular)
Everolimus
Cobalt–chromium
81
Fluorinated copolymer
Bifurcation
BiOSS® LIM/Expert (BALTON)
Sirolimus/ paclitaxel
Stainless steel
120
Poly-l-lactide
Bifurcation
CardioMind Sparrow™ (Biosensors)
Sirolimus
Nitinol
67
Poly-l-lactide
Small vessels
556
Expert Rev. Cardiovasc. Ther. 11(5), (2013)
Advances in drug-eluting stents
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 variable 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 polymer
The Synergy™ Stent (Boston Scientific) consists of a platinum– chromium platform and a biodegradable everolimus-eluting polymer. 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] .
Review
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 thickness (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 angiographydriven 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
