MD FACC FESC
Professor and Chairman of
Drug-eluting stents have significantly reduced the rate of restenosis compared with bare-metal stents. The ideal drug for preventing restenosis must have an antiproliferative and antimigratory effect on smooth muscle cells and should effectively inhibit the anti-inflammatory response after a balloon-induced arterial injury. On the other hand, the drug should not completely prevent re-endothelialisation, a protection against late stent thrombosis. The polymer for controlled elution of the agent is important for clinical results as well as the choice of the drug. Hypersensitivity reactions have been reported, linked to the polymer resulting in late stent thrombosis. The stent design should also be flexible with a good radial strength and a large surface area for loading the drugs. The gaps between the struts have to be small enough to distribute the drug optimally and equally over the target lesion, but large enough to provide side-branch perfusion and access. This summary describes available drug-eluting stents as well as promising stent technologies.
The Cypher stent (eluting sirolimus, Johnson & Johnson) was released in 2002. It was the first drug-eluting stent to be approved by the Food and Drugs Administration (FDA) and receive a European Conformity (CE) marking. Several randomised trials have shown that sirolimus-eluting stents effectively lowered rates of coronary artery restenosis and target-lesion revascularisation compared with bare-metal stents up to at least three years.(1,2) A new phenomenon of very late (>12 months) stent thrombosis after implanting a Cypher stent has been observed. However, at present the overall rate of stent thrombosis has not increased compared with bare-metal stents.
The second drug-eluting stent approved by CE and the FDA was the Taxus stent (eluting paclitaxel, Boston Scientific). This stent has also been extensively investigated and has demonstrated effective prevention of restenosis and target lesion revascularisation.(3,4) Very late stent thrombosis has also been observed after Taxus stent implantation, but the overall risk of late stent thrombosis was again not higher than that of bare-metal stents during the available follow-up time. Several head-to-head trials directly compared the relative efficacy of Taxus and Cypher stents, revealing a somewhat better outcome in patients who were treated with Cypher stents.(5)
The Endeavor stent (eluting zotarolimus, Medtronic) is currently only available in Europe (with CE approval), but FDA approval is expected soon. The data of Endeavor I and II (controlled multicentre trial: zotarolimus-eluting stent compared with bare-metal stents) were presented at PCR 2006 and showed good long-term results (three years). There was a reduction of restenosis and target lesion revascularisation using the Endeavour stent as compared with bare-metal stents.(6) The Endeavor III trial showed an inferior angiographic outcome of the Endeavor stent when directly compared with the Cypher stent.
The Xience stent (eluting everolimus, Guidant) recently received CE approval in January 2006 and will be available in Europe at the end of this year. From a large trial programme (Spirit I to V), data from the first trial with 59 patients were presented at the American College of Cardiology’s (ACC) 2006 annual meeting and showed a significant reduction of restenosis in the everolimus-eluting group compared with the bare-metal stent group (4.3% compared with 34.6%).(7) Enrolment of the larger trials (Spirit II to V) is complete, and the first results will be presented at the end of this year.
The CoStar stent (eluting paclitaxel, Conor Medsystems) has been available on the European market since February 2006. The design incorporates hundreds of small pits, each acting as a reservoir where drug–polymer compositions can be loaded. It has the potential to deliver multiple drugs and a wider range of drugs, enhance control of the rate and direction of drug delivery, and potentially increase the range of clinical applications for drug-eluting stents. Small dose-finding studies (PISCES, COSTAR I, EuroStar) have showed promising results with a restenosis rate below 10%, depending on the dose.(8)
Janus Sorin stent
The Janus stent (eluting tacrolimus, Sorin Biomedica) received CE approval in February 2006. The drug, tacrolimus, is directly applied on the stent surface. The stent has multiple grooves (reservoirs) on its medial side where the drug is loaded inside sculptures on the stent’s external surface, which eliminates the need for a polymeric coating.
The small JUPITER I study (safety study) showed an event-free survival of 100% at the one-month follow-up. The first efficacy trial (JUPITER II) was a randomised clinical study comparing the tacrolimus-eluting Janus Sorin stent with the bare Tecnic stent. The six-month angiographic follow up results were disappointing, with a similar degree of late loss and a measure of neointimal hyperplasia in the tacrolimus-coated stent group and the control group.(9)
Translumina has developed a unique therapeutic concept that received CE approval in September 2003. This Translumina stent-coating technology consists of the premounted stent system “Yukon Des” and a specially designed stent-coating machine. The cardiologist can directly choose different drugs and their doses. A recently published study showed a noninferior angiographic outcome of a sirolimus-coated Yukon stent when compared with the Taxus stent.(10)
The Axxion stent (eluting paclitaxel, Biosensors International Group) has been approved by CE since July 2005. Data from controlled studies are not available.
The Apollo stent (eluting paclitaxel, InTek) has been available on the European market since February 2006. Data from controlled studies are not available.
The Taxcor stent (eluting paclitaxel, Eurocor) received CE approval in July 2005. Data from controlled studies are not available.
Other stent platforms with promising data
Drug-eluting stents have been shown to reduce restenosis after stent implantation; however, the hypersensitivity of the polymer and the new phenomenon of very late stent thrombosis remain of concern.(11,12) Coatings based on biological substances such as fibrin, collagen, hyaluronic acid and biological oils can serve as alternative stent coatings. Bioactive stents (NO-coated titanium stents), gene-eluting stents, biodegradable polymer coatings and bioabsorbable magnesium stents have all been studied with promising results, although more long-term and in-vivo studies are needed.
The titanium-coated stent (Helistent, Titan2, Hexacath) is CE-certified. In a controlled multicentre study it showed a 50% reduced restenosis rate compared with the uncoated stent.(13) Registries of this stent reported a low rate of target vessel revascularisation.(14) A potential mechanism for the good clinical result is the high concentration of NO on the stent surface.
The hypothesis that naked plasmid DNA encoding human vascular endothelial growth factor (VEGF)-2 can be delivered locally by gene-eluting stents to reduce neointima formation has been tested. Plasmid-encoding, human VEGF-2 coated BiodivYsio (Abbott) phosphorylcholine polymer stents have been deployed and compared with uncoated stents in a randomised, blinded fashion in the iliac arteries of normocholesterolaemic and hypercholesterolaemic rabbits.(15) Re-endothelialisation was nearly complete in the VEGF stent group after 10 days and was significantly greater than in control stents.
At three months, intravascular ultrasound analysis showed that the lumen cross-sectional area was significantly greater and the percentage of cross-sectional narrowing was significantly lower with VEGF stents than with control stents. Acceleration of re-endothelialisation by VEGF-2 gene-eluting stents provides an alternative treatment strategy for the prevention of restenosis. VEGF-2 gene-eluting stents may be considered for standalone or combination treatment. More extensive studies with long-term follow-up are essential.
Biological biodissolvable stent coatings
Ziscoat and Lubbeek (personal communication) have studied the biocompatibility of biological oil-based stent coatings in a porcine coronary model. At five days, mural thrombus formation and inflammatory response were comparable in bare stents. At follow-up after four weeks, the stented arterial segments were completely healed and the inflammation score was even slightly lower in the coated-stent group than in the bare-stent group. Neointimal hyperplasia at that time was similar in the coated-stent group and the bare-stent group. Results suggest a very good short-term outcome of these totally biosoluble, biological, oil-based stent coatings – although long-term follow-up is needed. These coatings have potential for use in stent-mediated local drug delivery.
Bioabsorbable magnesium stents
Stenting technology has moved towards the development of temporary implants composed of biocompatible materials that mechanically support the vessel during the period of high recoil risk and completely biodegrade later. Biodegradable implants offer better physiological repair and reconstitution of local vascular compliance. This stent has a better radial straightening effect and a higher possibility of late positive remodelling. Experimental data have shown promising results with magnesium in ischaemia reperfusion injury, both in reducing infarct size and in reversing myocardial stunning. Three months after a bioabsorbable magnesium stent was implanted, preliminary data showed a clinical patency rate of nearly 90%.(16) Preclinical work has shown that absorbable metal stents based on magnesium are an option for improving both acute and long-term results of percutaneous coronary revascularisation. Yet there is an unacceptably high restenosis rate in small vessels.
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