Biodegradable coating for drug-eluting stents--more than a facelift?

Since its introduction 1977, percutaneous coronary angioplasty (PCI) has developed into the most common revascularization method of coronary artery disease (nearly 2 million procedures in Europe in 2003).1,2 Early complications of ‘plain old’ balloon angioplasty such as acute recoil and abrupt vessel closure were markedly reduced by bare metal stents (BMS; in 1987) providing mechanical scaffolding of the vessel.3 Metallic stents thereby not only reduced the need for emergency coronary artery bypass grafting to <0.5% but nearly halved high restenosis rates observed in up to 30–40% of patients within the first months after balloon angioplasty.4,5 Thereafter, 15 years were needed before the next major innovation of PCI, when the first-generation drug-eluting stents (DES) were introduced for clinical practice (2002).6 By reducing clinical restenosis significantly, DES became a breakthrough technology justifying percutaneous revascularization of more complex patient and lesion subsets, which in turn caused concern among cardiac surgery colleagues. Currently available DES consist of a metallic stent platform, a cytostatic or antimitotic pharmacological agent resulting in local suppression of neointimal hyperplasia, and a carrier vehicle, most frequently a polymer, serving for controlled drug delivery.7,8 After initial enthusiasm, however, there has been controversial debate on the long-term safety of DES, with a focus on the potential for an increased risk of late stent thrombosis (ST).9,10 Although the risk for very late ST (>1 year) appears to be relatively low (<0.5% annually), it is a severe condition. Therefore, its minimization will be a challenge for future DES. The mechanisms behind late ST appear to be multifactorial, varying from factors such as inappropriate stent deployment techniques to delayed or inadequate endothelialization of the stent surface. Since the presence of permanent polymer coatings may have pro-inflammatory and thrombogenic potential, present DES research has been focusing either on utilization of biodegradable polymer coating or on a completely polymer-free DES platform. However, in a recently published trial, a cobalt–chromium alloy DES platform without a polymer coating, designed to elute paclitaxel, failed to show non-inferiority compared with the first-generation DES with durable polymer coating for paclitaxel release (TaxusR).11 In the exciting study of Mehilli et al.,12 the authors investigate the relative efficacy of the type or presence of different polymer coatings on a metallic DES platform releasing the same drug, rapamycin.. Altogether 605 patients with de novo coronary artery lesions in native vessels were randomly assigned to three groups to receive either a stent with a biodegradable polymer coating, a stent with a permanent polymer (CypherR), or a polymer-free stent. The study showed that treatment of complex de novo coronary lesions in native vessels with both the biodegradable and the polymer-free DES is feasible without safety issues. However, based on primary end-point criteria (in-stent luminal late loss), biodegradable and permanent polymer rapamycin-eluting stents appeared to have equivalent efficacy, while the polymer-free stent provided inferior efficacy when compared with both polymer coatings. In terms of the secondary end-points of the study, clinical outcome, the use of a polymer-free stent appeared to be associated with a higher rate of target lesion re-interventions at 12 months when compared with the durable rapamycin-eluting stent. In fact, a slight though non-significant trend in favour of clinical restenosis was seen in patients with the biodegradable polymer stent coating (5.9% vs. 7.9% in the permanent polymer stent group vs. 12.9% in the polymer-free stent group). The study randomization appeared to be balanced in each group, and the investigators enrolled relatively complex patients with complex de novo coronary lesions. Therefore, their observations are most probably applicable to real-life practice. The facts that the study follow-up was not longer than 12 months, and that only a moderate number of patients were enrolled (605 patients), do not diminish the value of the trial. Complete clinical follow-up data were available on all patients, whereas coronary angiogram at 6–8 months was performed on 81% of the patients. Dual anti-platelet therapy was used in all patients for at least 6 months. The important findings of Mehilli et al. are likely to have future implications. Biodegradable coatings for controlled cytostatic drug release may well be the next step towards more sophisticated DES platforms, providing more optimal dosage and duration of the pharmacological drug effect. On the other hand, current polymer-free stent platforms as utilized in the present study for drug release may have a less bright future. Once the drug release has done its work (usually within 6–9 weeks), the benefits of polymer absorption from the stent surface appear tempting in reducing late complications. The target of cytostatic drug release is not to prevent endothelialization on the stent surface but to allow a moderate growth of neointima within the first weeks after stenting. Removal of any potential cause of either early or delayed inflammatory reaction, with a subsequent late catch-up phenomenon (delayed restenosis) as well as an increased risk for late ST is definitely worth further investigation. If all this came true, the potentially shorter dual antiplatelet therapy would be welcome, especially in developing countries where the cost of such therapy is one important limiting factor for DES usage. DES have definitely been a breakthrough in interventional cardiology with respect to both short- and mid-term outcome. Now the focus is on the long term. In fact, with current DES, interventional cardiology has reached a point where trials investigating any new emerging stent technology will require enormous efforts to prove superiority (or even non-inferority) when compared with the DES available. Much larger patient groups, more complex coronary lesions, and longer follow-ups than those we are used to in recent trials are most probably mandatory. This makes huge requirements not only of the industry but also of the regulatory bodies. The device industry must adopt and learn from those principles which have for decades been commonplace in research and development in the pharmaceutical industry. Nevertheless, the study of Mehilli et al.12 shows promising results, both short and mid term, with biodegradable rapamycin-eluting stent coating. How important this step will be in our challenge for an even better future for coronary patients undergoing PCI remains to be seen. Conflict of interest: none declared.