Inhibition of Neointima Formation by a Novel Drug-Eluting Stent System That Allows for Dose-Adjustable, Multiple, and On-Site Stent Coating

Abstract

Objective-The risk of in-stent restenosis can be considerably reduced by stents eluting cytostatic compounds. We created a novel drug-eluting stent system that includes several new features in the rapidly evolving field of stent-based drug delivery. Methods and Results-The aim of the present study was the preclinical evaluation of a stent-coating system permitting individual, on-site coating of stents with a unique microporous surface allowing for individualizable, dose-adjustable, and multiple coatings with identical or various compounds, designated ISAR (individualizable drug-eluting stent system to abrogate restenosis). Stents were coated with 0.75% rapamycin solution, and high-performance liquid chromatography (HPLC)-based determination of drug release profile indicated drug release for Ͼ21 days. Rapamycin-eluting microporous (REMP) stents implanted in porcine coronary arteries were safe. To determine the efficacy of REMP stents, this novel drug-eluting stent platform was compared with the standard sirolimus-eluting stent. At 30 days, in-stent neointima formation in porcine coronary arteries was similar in both groups, yielding a significant decrease of neointimal area and injury-dependent neointimal thickness compared with bare-metal stents. Conclusion-The ISAR drug-eluting stent platform as a novel concept for stent coating allows for a safe, effective, on-site stent coating process, thus justifying further clinical evaluation to decrease in-stent restenosis in humans. Key Words: drug-eluting stent Ⅲ rapamycin Ⅲ sirolimus Ⅲ stent platform I n-stent restenosis, the major adverse outcome after percutaneous coronary stent placement, 1 can be successfully reduced by drug-eluting stents (DES) releasing cytostatic compounds. Numerous large clinical trials consistently revealed an impressive reduction of in-stent restenosis in de novo lesions by DES. 2-4 However, in specific patient subsets, such as insulin-dependent diabetic subjects, 5 or in challenging interventional scenarios, like bifurcation stenting, 6 the rate of restenosis remains to be substantial at this point. Moreover, the outcome of treatment of in-stent restenosis within DES is currently not satisfactorily solved. 7 Dose adjustments at the discretion of the interventional cardiologist to individualize the dosage of the compound on the drug-eluting stent may be desirable to enable an individual dose adjustment for specific lesion or patient subsets, eg, higher rapamycin doses for diabetic patients. Further, in future scenarios, stent-coating with multiple compounds, for instance to inhibit smooth muscle cell proliferation and promote re-endothelialization, may be desirable. In addition, the presently approved drugeluting stent platforms use a polymer-based coating for retardation of drug release. There is evidence that application of polymers may lead to hypersensitivity reactions and, in few cases, late cardiac death. 8 Furthermore, the issue of late-stent thrombosis in DES, particularly after discontinuation of antiplatelet therapy, is currently s...

Polymer-Free Sirolimus- and Probucol-Eluting Versus New Generation Zotarolimus-Eluting Stents in Coronary Artery Disease

“…24 The availability of on-site coating technology has enabled the investigation of a variety of drug and polymer coatings in preclinical studies 11,12,25 and clinical trials. 9,10,13,26,27 The current device iteration is coated with a mixture of sirolimus and probucol.…”

“…A detailed description for creating the micropores and its rationale, the specifics of the coating process, and the sirolimus-and probucolrelease profile of the platform have been reported previously. 9,11,12 Description of stent platforms and elution characteristics of the zotarolimus-eluting stent are reported elsewhere. 5 The polymer-free sirolimus-and probucol-eluting stent was available in diameters of 2.0, 2.5, 3.0, and 3.5 mm and lengths of 8, 12, 18, 23, and 25 mm for each diameter.…”

Randomized Trial of a Nonpolymer-Based Rapamycin-Eluting Stent Versus a Polymer-Based Paclitaxel-Eluting Stent for the Reduction of Late Lumen Loss

“…Using a porcine coronary model of restenosis, we found that coating with rapamycin of a polymer-free microporous stent is feasible and effectively reduces neointimal proliferation. 11 More recently, in a clinical study in which the efficacy of several doses of rapamycin was assessed, we showed that a nonpolymer coating with rapamycin is safe and leads to a dose-dependent reduction in restenosis. 12 Although the advantage derived from the lack of a polymer coating in on-site-coated, rapamycin-eluting stents is readily understandable, their relative efficacy compared with commercially available polymer-based, DESs has yet to be evaluated.…”

Coronary Arterial Drug-Eluting Stent: From Structure to Clinical

“…For example, a titanium-nitric oxide alloy has been applied to stainless steel stents with encouraging results, including decreased platelet adhesion and neointimal hyperplasia compared with BMS 34 . A microporous stainless steel stent (Yukon, Translumina, Germany) allows for dose-adjustable, multiple drugs, and on-site coating 105 [63]. The system is therapeutically effective with rapamycin 106 .…”