Local Drug Delivery for Treatment of Coronary and Peripheral Artery Disease

Local drug delivery (LDD), the direct application of a therapeutic agent to a focal location, has been used in cardiovascular interventions to prophylactically reduce neointimal hyperplasia and relieve clot burden. LDD allows targeted use of drugs whose toxicities inhibit their systemic use while stent delivery allows for consistent and prolonged delivery. Stents eluting limus family drugs or paclitaxel inhibit vascular smooth muscle cell hyperplasia and migration and clinical use of such stents have reduced restenosis rates after percutaneous coronary procedures. However, associated with the increased efficacy is an increased rate of late stent thrombosis associated with death and myocardial infarction. Recent innovations, including bioabsorbable polymers and completely bioabsorbable stents may expand the use of drug‐eluting stents. In this review, we discuss the development, the clinical use, and the effects of LDD from balloon and stent‐based platforms in the treatment of restenosis and thrombus.     

Drug-eluting stent: the emerging technique for the prevention of restenosis

Percutaneous coronary interventions (PCI) have surpassed coronary artery bypass grafting as the most common means for treating coronary artery disease, because of materials improvement, the use of stent and pharmacotherapy. However, despite the variety of mechanical techniques such as dilatation, debulking or conventional stent implantation, the incidence of restenosis on short and mid-term follow-up is still representing an important limitation to PCI. Restenosis is mainly due to elastic recoil, negative vessel remodelling and neointimal proliferation, as a response to vessel injury induced by angioplasty devices. The use of conventional stents has provided an efficient method to avoid elastic recoil and negative vessel remodelling, thus partially reducing restenosis as compared to conventional balloon dilatation. However, neointimal proliferation (biological vessel response to injury caused by stent implantation) is not affected by stenting technique. Thus, the extensive use of coronary stent, even in complex lesions, have produced again a "new" disease: the in-stent restenosis especially in some patients' subset (diabetics) or in some lesion subset (bifurcations, long lesions, small vessels, total occlusions, diffuse disease). Therefore, the main target of today's interventional cardiologists is to resolve this problem. The combination between mechanical control of elastic recoil and negative remodelling (stent) and the control of neointimal proliferation - biological response to vessel injury - (antiproliferative drugs) is the emerging approach against restenosis. This emerging approach consists in using the stent as drug carrier to the target site. Local delivery of antiproliferative or immunosuppressive agents using a drug-coated stent is supposed to inhibit in stent restenosis. The first antiproliferative agents being used successfully in clinical trials are sirolimus and paclitaxel and, so far, the data available of these trials demonstrated a marked reduction of restenosis using sirolimus- and paclitaxel-coated stents as compared to conventional stents. However, many questions are still to be answered and several other clinical trials with drug-eluting stents are ongoing, evaluating safety and efficacy of sirolimus and paclitaxel in a larger number of patients and in different subset of coronary lesions type and morphology. Based on the very impressive results available at the present time, we can expect, in the very near future, remarkable changes in our clinical practice and the beginning of a new "era" of interventional cardiology.     

Randomized evaluation of two drug‐eluting stents with identical metallic platform and biodegradable polymer but different agents (paclitaxel or sirolimus) compared against bare stents: 1‐Year results of the PAINT trial

Objectives: We tested two novel drug‐eluting stents (DES), covered with a biodegradable‐polymer carrier and releasing paclitaxel or sirolimus, which were compared against a bare metal stent (primary objective). The DES differed by the drug, but were identical otherwise, allowing to compare the anti‐restenosis effects of sirolimus versus paclitaxel (secondary objective). Background: The efficacy of novel DES with biodegradable polymers should be tested in the context of randomized trials, even when using drugs known to be effective, such as sirolimus and paclitaxel. Methods: Overall, 274 patients with de novo coronary lesions in native vessels scheduled for stent implantation were randomly assigned (2:2:1 ratio) for the paclitaxel (n = 111), sirolimus (n = 106), or bare metal stent (n = 57) groups. Angiographic follow‐up was obtained at 9 months and major cardiac adverse events up to 12 months. Results: Both paclitaxel and sirolimus stents reduced the 9‐month in‐stent late loss (0.54–0.44 mm, 0.32–0.43 mm, vs. 0.90–0.45 mm respectively), and 1‐year risk of target vessel revascularization and combined major adverse cardiac events (P < 0.05 for both, in all comparisons), compared with controls. Sirolimus stents had lower late loss than paclitaxel stents (P < 0.01), but similar 1‐year clinical outcomes. There were no differences in the risk of death, infarction, or stent thrombosis among the study groups. Conclusion: Both novel DES were effective in reducing neointimal hyperplasia and 1‐year re‐intervention, compared to bare metal stents. Our findings also suggest that sirolimus is more effective than paclitaxel in reducing angiographic neointima, although this effect was not associated with better clinical outcomes.© 2009 Wiley‐Liss, Inc.     

Estrogen‐eluting stent implantation inhibits neointimal formation and extracellular signal‐regulated kinase activation

Objectives : The goal of this study was to evaluate the efficacy and the mechanism of 17β‐estradiol‐eluting stents on inhibiting neointimal formation of abdominal aortas in rabbits fed with high fat diet. Background : Animal experiments have shown that local delivery of estrogen reduced neointimal formation after coronary angioplasty. Preliminary trial of estrogen‐eluting stent implantation in patients with coronary disease also suggests a reduction in restenosis. Methods : We implanted 17β‐estradiol‐eluting stents, or control phosphorylcholine‐ coated stents, or bare metal stents of abdominal aortas in rabbits fed with high fat diet. Histology, immunohistochemistry, and Western blot analysis were used to assess the efficacy and mechanism of inhibiting neointimal formation of 17β‐estradiol‐eluting stents. Results : Western blot analysis revealed marked increase in ERK phosphorylation in 30 min after deployment of phosphorylcholine‐coated or bare metal stents, indicating activation of MAP kinase pathway. Immunohistochemistry showed intense staining of phospho‐ERK in the medial smooth muscle cells in stent‐implanted region. Extensive neointimal hyperplasia developed 12 weeks after stenting. In contrast, we observed significant inhibition of ERK phosphorylation and neointimal thickening in estrogen‐eluting stent‐implanted animals. Immunohistochemistry of factor VIII‐related antigen demonstrated an accelerated reendothelialization as compared with the bare metal stent or phosphorylcholine‐coated stent‐implanted controls. Conclusions : Current study suggests that estrogen‐eluting stents reduce neointimal formation and hence prevent restenosis after angioplasty possibly by inhibiting ERK activation in smooth muscle cells and promoting reendothelialization. © 2007 Wiley‐Liss, Inc.     

Experiment Study Of The Preventive Effects Of Valsartan Eluting Stent On In- stent Restenosis

Objectives Background -Neointima hyperplasia and arterial remodeling are the main mechanisms of restenosis after percutaneous transluminal coronary angioplasty. The successful use of coronary stents neutralizes the acute elastic recoil and improves the remodeling mode with reducing restenosis rate by 10 % . But the in - stent neointima hyperplasia becomes more severe. This study aims to set up model of in - stent restenosis in vivo, and to e-valuate the preventive role of implantation of valsartan eluting stent for restenosis. Methods and Results Twenty - two male New Zealand white rabbits were divided into control group and valsartan group. In-travascular ultrasonic (IVUS) results showed the in-trastent neointimal areas of the control group were larger than those of the valsartan group (P < 0. 01) . The minimal lumen area of control group was smaller than that of the valsartan group ( P < 0. 01). Angiog-raphy results showed the normal lumen diameters were similar between two groups ( P> 0.05) . The lum     

Restenosis after PCI: Battered but not beaten

• In patients with bare‐metal stent (BMS) restenosis, drug‐eluting stents (DES) are superior to vascular brachytherapy (VBT), leading to a lower risk of clinical restenosis and target vessel revascularization, but not to less stent thrombosis, myocardial infarction, or death; these benefits persist for 2–5 years.
• The optimal management of DES restenosis is unknown, but recent studies suggest that drug‐eluting balloons (DEB) and DES have similar efficacy and safety.
• Since DEB are not commercially available in the United States, VBT may be a reasonable alternative to repeated DES.

     

Particle debris from a nanoporous stent coating obscures potential antiproliferative effects of tacrolimus-eluting stents in a porcine model of restenosis.

Polymer stent coatings may not be suitable for drug elution because of inherent proinflammatory effects. A previous study suggested a beneficial effect of a stent eluting tacrolimus from a nanoporous ceramic aluminum oxide coating in a rabbit restenosis model. We investigated whether this stent is effective in preventing in-stent restenosis in a porcine restenosis model. Thirty-four juvenile swine underwent balloon overstretch injury and were subjected to implantation of either stainless steel (bare) stents, bare stents coated with nanoporous aluminum oxide alone, and coated stents eluting 50 and 180 mug of tacrolimus (FK506). In-stent restenosis was quantified at 1 and 3 months after stent placement by histomorphometry. A significant increase of neointimal hyperplasia was noted with the stents coated with aluminum oxide alone compared with bare stents (2.92 +/- 1.02 and 1.38 +/- 0.51 mm(2), respectively; P < 0.02). In all arteries containing coated stents, particle debris was found in the media and neointima, resulting in augmented vascular inflammation. In the group of stents coated with aluminum oxide, FK506 elution at a dose 180 mug reduced neointimal hyperplasia vs. no drug elution (1.66 +/- 0.49 vs. 2.92 +/- 1.02 mm(2); 180 mug vs. ceramic alone; P < 0.03). At a dose of 50 mug stent-based delivery of FK506, no reduction of neointimal hyperplasia was found (2.88 +/- 1.31 and 2.92 +/- 1.02 mm(2), respectively; P = NS; FK506 vs. ceramic alone). In summary, particle debris shed from a drug-eluting aluminum oxide coating of a stainless steel stent counteracts potential antiproliferative effects of stent-based tacrolimus delivery in a porcine model of restenosis. We propose that stent coatings eluting drugs need to be routinely tested for being tightly anchored into the stent surface. Alternatively, omission of any coating used as a drug reservoir may eliminate inflammatory particle debris after placement of drug-eluting stents.     

In‐Stent Restenosis

The introduction of coronary stents marked a major turning point in the practice of interventional cardiology. Whereas the efficacy of balloon angioplasty was challenged both by immediate mechanical complications and by a high incidence of restenosis, coronary stents offered cardiologists a means by which to not only augment immediate procedural success, but also to reduce the incidence of restenosis following coronary intervention. However, despite technological advances and an improved understanding of the restenotic process, the overall rate of in‐stent restenosis following bare metal stent implantation remains high. Although the introduction of drug‐eluting stents has further reduced the incidence of restenosis, the “real‐world” application of drug‐eluting stents in increasingly complex lesion and patient subsets has given way to the even greater clinical challenge of managing drug‐eluting stent restenosis. Although the standard treatment of bare metal stent restenosis typically involves placement of a drug‐eluting stent, the optimal therapeutic approach to drug‐eluting stent restenosis remains less defined. The issue of in‐stent restenosis (especially following implantation of a drug‐eluting stent) remains a clinical challenge, and investigation into therapeutic options remains ongoing. As technology evolves, such investigation will likely incorporate novel approaches including drug‐coated balloons novel stent designs.     

Estrogen-Eluting Stents

Coronary stenting is routinely utilized to treat symptomatic obstructive coronary artery disease. However, the efficacy of bare metal coronary stents has been historically limited by restenosis, which is primarily due to excessive neointima formation. Drug-eluting stents (DES) are composed of a stainless steel backbone encompassed by a polymer in which a variety of drugs that inhibit smooth muscle cell proliferation and excessive neointima formation are incorporated. DES have significantly reduced the incidence of restenosis but are also associated with a small (~0.5% per year) but significant risk of late stent thrombosis. In that regard, estrogen-eluting stents have also undergone clinical evaluation in reducing restenosis with the additional potential benefit of enhancing reendothelialization of the stent surface to reduce stent thrombosis. Estrogen directly promotes vasodilatation, enhances endothelial healing, and prevents smooth muscle cell migration and proliferation. Due to these mechanisms, estrogen has been postulated to reduce neointimal hyperplasia without delaying endothelial healing. In animal studies, estrogen treatment was effective in decreasing neointimal hyperplasia after both balloon angioplasty and stenting regardless of the method of drug delivery. The first uncontrolled human study using estrogen-coated stents demonstrated acceptable efficacy in reducing late lumen loss. However, subsequent randomized clinical trials did not show superiority of estrogen-eluting stents over bare metal stents or DES. Further studies are required to determine optimal dose and method of estrogen delivery with coronary stenting and whether this approach will be a viable alternative to the current DES armamentarium.     

Differences in drug-eluting stents used in coronary artery disease

The introduction of drug-eluting stents (DES) has improved the efficacy of percutaneous coronary intervention by addressing the issue of neointimal proliferation, a pathology contributing to restenosis. First-generation stents eluting sirolimus or paclitaxel were joined by second-generation stents, such as the everolimus- and the zotarolimus-eluting stents, promising increased safety and efficacy. As a result, there is a plethora of drug-eluting stents available, with differences in the stent platform, the polymer coating and the eluted drug, which translate into differences in biological markers of efficacy, such as late loss. However, it remains controversial whether these discrepancies have an impact on clinical markers of safety and efficacy, or if the improved efficacy of DES is a class effect. This article reviews the differences between DES by looking into the biological differences and into trials and registries of DES.     

New developments in coronary stent technology

Coronary stent technology has rapidly evolved from a mechanical solution to abrupt vessel closure and elastic recoil following plain balloon angioplasty, to become a vector for local drug delivery and modification of coronary plaque pathophysiology. The advent of drug-eluting stents (DES) has significantly reduced restenosis, although there is increasing concern over the risk of late stent thrombosis, particularly following cessation of antiplatelet therapy. Here we consider the limitations of the current generation of DES, and review recent advances in platform, carrier, and pharmacological technology, and their place in future clinical practice.     

An intravascular ultrasound study of Cypher, Taxus, and endeavor stents on relation between neointimal proliferation and residual plaque burden

Background: Studies on balloon angioplasty, atherectomy, and bare metal stent have shown a direct relation between residual plaque burden and restenosis. We investigated the relation between residual plaque burden and neointimal proliferation after drug‐eluting stent (DES) implantation. Methods: Over a period of 12 months, 65 patients (Cypher, n = 25; Taxus, n = 28; Endeavor, n = 12) from two centers underwent intravascular ultrasound (IVUS) examination at 8.2 (interquartile range 6.8–9.5) months after coronary stent implantation in native de novo coronary arteries. IVUS images were acquired with motorized pullback at 0.5 mm/s, and cross‐sectional measurements were performed within the stents at 1‐mm intervals. The following measurements were obtained: (1) lumen area (LA), (2) stent area (SA), (3) external elastic membrane area (EEMA), (4) percent neointimal hyperplasia area (SA‐LA/SA) × 100, and (5) percent residual plaque area (EEMA‐SA)/EEMA × 100. Results: The analysis of 1,173 cross sections (Cypher, n = 436; Taxus, n = 532, Endeavor, n = 205) using mixed model to account for intrasubject correlation showed an absence of relation between percent residual plaque area and percent neointimal hyperplasia area (P = 0.189). Mean residual plaque burden outside the stent for Cypher, Taxus, and Endeavor groups was similar (45.7%, 44.8%, and 42.4%, respectively). Mean percent neointimal hyperplasia area for the Cypher, Taxus, and Endeavor groups was 12.0%, 15.0%, and 16.2%, respectively (P = 0.163). Conclusion: In patients after first‐generation DES implantation and without significant in‐stent restenosis, late in‐stent neointimal proliferation is not related to the amount of residual plaque burden after stent implantation. This suggests against routine plaque removal before DES implantation to reduce neointimal proliferation.     

Arsenic trioxide eluting stent reduces neointima formation in a rabbit iliac artery injury model

OBJECTIVE: In-stent restenosis is caused by the neointimal hyperplasia, which involves abnormal growth of vascular smooth muscle cells (VSMC). Arsenic trioxide (As2O3) is known to be a potent inhibitor of cell proliferation. We therefore studied the role of an As2O3 eluting stent in the prevention of restenosis in a rabbit iliac artery model. METHODS AND RESULTS: Bare stents, or stents coated with poly-L-lactic acid (PLLA) and either 40 microg of As2O3, 180 microg of paclitaxel or vehicle were implanted into the left proximal iliac arteries of New Zealand rabbits. The delivery of drugs from stents in vitro and in vivo was evaluated by atomic fluorescence spectrophotometry and high-performance liquid chromatography, respectively. Histomorphometric measurements at 7 or 28 days showed that, comparing to rabbits receiving the PLLA stent, in animals treated with As2O3 eluting or paclitaxel eluting stent neointima thickness was reduced by 50% and 46%, the absolute neointimal area was reduced by 53% and 44%, while the absolute luminal area was increased by 46% and 43%, respectively. There were no significant differences in injury or inflammation scores among PLLA, As2O3 eluting and paclitaxel eluting stents. As2O3 eluting stent induced more TUNEL-positiv VSMC than the other stents. As2O3 levels measured in the arterial tissue were much higher than those in serum, which were nearly undetectable at 7 days after stent implantation. In in vitro studies, cultured rabbit arterial VSMC were stimulated with As2O3 or paclitaxel and analyzed for their cell cycle progression and apoptosis by flow cytometry and electron microscopy. As2O3 treatment resulted in a reduction of VSMC number in G1 phase with a concomitant increase in apoptosis of VSMC, whereas paclitaxel treatment led to blocking of VSMC in the G2/M phase. CONCLUSION: In a rabbit iliac artery model PLLA coated As2O3 eluting stent significantly suppressed in-stent restenosis by reducing proliferation and inducing apoptosis of VSMC.     

Current Status of Drug‐Eluting Stents

First‐generation drug‐eluting stents (DES) with controlled release of sirolimus or paclitaxel from durable polymers compared with bare‐metal stents have been consistently shown to reduce the risk of repeat revascularization procedures due to restenosis. The superior efficacy was found across a wide range of patients and lesion subsets and persisted up to 5 years whereas similar outcomes have been observed in terms of death and myocardial infarction. Newer generation DES have been developed with the goal to further improve upon the safety profile of first‐generation DES while maintaining efficacy. These platforms include DES with improved and more biocompatible durable polymers, DES using bioabsorbable polymers for drug release, DES with polymer‐free drug release, and fully bioabsorbable DES. Newer generation DES with durable polymers such as zotarolimus‐eluting or everolimus‐eluting XIENCE V stents have been directly compared with first‐generation DES. Most recent results of large scale clinical trials are encouraging in terms of similar or increased efficacy while improving safety by reducing the rates of myocardial infarctions and stent thrombosis. DES using biodegradable polymers for drug release represent the next technological modification and preliminary results are favorable and demonstrate similar angiographic and clinical efficacy as first‐generation DES, but only longer term follow‐up and investigation in larger patient cohorts will determine whether their use is associated with improved long‐term safety. Fully bioabsorbable stents represent another innovative approach. Whether this innovative concept will enter into clinical routine remains yet to be determined.     

Paclitaxel‐Eluting Stents: Are They All Equal?

In Germany, four different drug eluting stents (DES) systems are currently commercially available. Whereas sirolimus has been clinically tested in only a single type of stent with a single type of coating in only a single dose, paclitaxel has been tested on various stent designs, in various dose densities, and in various relase formulations with or without a polymer carrier. Therefore, the question arises: are all paclitaxel stents equally safe and effective? Six clinical randomized trials investigated the safety and efficacy of paclitaxel‐eluting stents in patients with de‐novo lesions: TAXUS‐I (61 pats), TAXUS‐II (536 pats), ASPECT (177 pats), ELUTES (190 pats), DELIVER‐I (1041 pats) and TAXUS‐IV (1314 pats). In the TAXUS‐series, paclitaxel released from the stent was controlled by the Translute? polymer. In the other studies, however, no polymer carrier was used. In TAXUS‐I, II & IV, the dose density of 1 μg/mm² significantly reduced angiographic parameters of restenosis and improved clinical outcomes. In ASPECT and ELUTES there was a dose‐dependent effect on angiographic parameters of restenosis with the best results for a paclitaxel dose density of apprimately 3.0 μg/mm². Clinical outcomes at 6 and 12 months, however, were not improved in these studies without coating. The studies unanimously show that the paclitaxel‐eluting stents are safe, if clopidogrel is added to ASA for 3 to 6 months. The safety of paclitaxel‐eluting stents is independent of the stent design, the dose density and the presence or absence of a polymer carrier system. For paclitaxel‐eluting stents using a polymer carrier, the dose density of 1 μg/mm² is highly effective, whereas for paclitaxel‐eluting stents without a polymer carrier, the minimal effective dose density is much higher (3 μg/mm²). Despite their improvement of angiographic parameters, paclitaxel‐eluting stents without a polymer carrier did not demonstrate a positive effect on clinical outcome. In contrast, polymer‐based paclitaxel elution produced significant clinical benefit. (J Interven Cardiol 2003;16:485–490)     

Kissing drug eluting balloons for in‐stent restenosis complicating bifurcations treated with drug‐eluting stents

The management of in‐stent restenosis (ISR) complicating bifurcation lesions is technically challenging and implant of further stents may not be feasible. The use of drug‐eluting balloons provides an attractive option for treatment of such lesions allowing a technically simple procedure without the need for further complex stenting. The SeQuent Please paclitaxel‐eluting balloon (B. Braun, Berlin, Germany) has been shown to be superior to a paclitaxel eluting stent or balloon angioplasty for ISR complicating a bare‐metal stent. However, there is no data on the efficacy of the SeQuent Please in ISR complicating drug‐eluting stents or bifurcation lesions. We report two cases where the SeQuent Please was used in this setting with angiographic success and freedom from target vessel failure and angina at 24 months. In both cases the Sheathless Eau Cath guide (Asahi Intecc, Japan) was employed to perform a kissing‐balloon dilatation with the SeQuent Please, so allowing treatment via radial access. © 2012 Wiley Periodicals, Inc.     

Markedly different tissue types on optical coherence tomography imaging in a patient with multiple lesion drug‐eluting stent in‐stent restenosis

The treatment of in‐stent restenosis after drug‐eluting stent (DES) implantation remains a major clinical challenge. Optical coherence tomography (OCT) imaging at the time of presentation can provide important information on mechanical factors contributing to stent failure as well as on tissue characteristics of the in‐stent neointimal tissue. We report a case of markedly different tissue types—characterized by heterogeneous and homogeneous signal intensity—observed in a patient with multiple lesion DES in‐stent restenosis. Although both lesions were initially successfully treated with drug‐coated balloon angioplasty, the patient presented with recurrent in‐stent restenosis in the lesion with homogeneous tissue characteristics. Future studies should evaluate whether OCT tissue characterization can guide optimal treatment strategy in patients with DES restenosis. © 2016 Wiley Periodicals, Inc.     

Paclitaxel-coated Gianturco-Roubin II (GR II) stents reduce neointimal hyperplasia in a porcine coronary in-stent restenosis model.

BACKGROUND: Drug-coated stents may treat both mechanisms of restenosis, namely, geometric remodeling and neointimal hyperplasia. Paclitaxel, an antimicrotubule agent, has been shown to inhibit smooth muscle cell proliferation and migration, and may be an excellent candidate for local elution from a stent platform. METHODS: To study the antirestenosis effects of drug-coated stents, we impregnated paclitaxel (175-200 microg/stent with programmed elution over 6 months) on Gianturco-Roubin II (GR II) stents. These stents and control stents without drugs were implanted in porcine coronary arteries (stent/artery approx. 1.1) and evaluated 4 weeks later. RESULTS: The vessel size and the stent-to-artery ratio were similar between the groups. However, at 4 weeks, the paclitaxel group had significantly reduced in-stent restenosis compared with the controls (51 +/- 27 versus 27 +/- 27% diameter stenosis, P < 0.05 and 669 +/- 357 versus 403 +/- 197 microm neointimal thickness, P < 0.05). This study further confirmed the biocompatibility of the polymer, with no foreign body reaction in any of the groups. CONCLUSIONS: This study shows that the paclitaxel-coated stents significantly reduced in-stent restenosis without eliciting inflammation.     

Drug-eluting stents. The third revolution in percutaneous coronary intervention.

Local stent-based drug delivery (drug-eluting stent - DES) is a new technology aimed to prevent the development of neointimal hyperplasia and restenosis following percutaneous coronary interventions. A number of DESs have been developed using different carrier stents, different kind of coatings, and different drugs. However, to date only two polymer-coated DESs (the Cypher sirolimus-eluting stent from Cordis, Johnson & Johnson, Miami Lake, FL, USA; and the Taxus paclitaxel-eluting stent, Boston Scientific, Natick, MA, USA) have become commercially available after a number of randomized trials showed their ability to reduce late luminal loss, binary restenosis and the need for repeat revascularization when compared to bare metal stents. This review describes the general concept of DES and summarizes the results of the principal clinical trials on DESs, both approved for clinical use or under development. For the marketed stents, we also report the results of the first clinical evaluations in real life and a few insights into the most controversial issues.     

The effect of variable dose and release kinetics on neointimal hyperplasia using a novel paclitaxel-eluting stent platform: the Paclitaxel In-Stent Controlled Elution Study (PISCES)

OBJECTIVES: The aim of this study was to evaluate the effect of variable dose and release kinetics of paclitaxel on neointimal hyperplasia. BACKGROUND: Conventional paclitaxel-eluting stents use a durable polymer coating as a vehicle for drug delivery. The Conor stent (Conor Medsystems, Menlo Park, California) with intra-strut wells and erodable polymer is specifically designed for drug delivery with programmable pharmacokinetics. METHODS: Two hundred and forty-four patients with single vessel disease received either a bare metal Conor stent (n = 53) or one of six different release formulations that varied in dose (10 or 30 microg) and elution release kinetics (first order, zero order), direction (abluminal, luminal), and duration (5, 10, and 30 days). End points at six months (bare stent group) and at four months (eluting stent groups) were angiographic late loss and neointimal tissue volume by intravascular ultrasound and the rate of major adverse cardiac events (MACE). RESULTS: The lowest in-stent late loss (0.38 mm, p <0.01, and 0.30 mm, p <0.01) and volume obstruction (8%, p <0.01, and 5%, p <0.01) were observed with the 10-microg and 30-microg doses in the 30-day release groups respectively, whereas the highest in-stent late loss (0.88 mm), volume obstruction (26%), and restenosis rate (11.6%) were observed in the bare stent group. The overall MACE rate of the eluting stent group was 8.6%: death 0.5%, myocardial infarction 2.7%, and target lesion revascularization (TLR) 5.3%. Sub-acute thrombosis was 0.5%. The TLR rates in the two 30-day release groups were 0% and 3.4%. CONCLUSIONS: This novel eluting stent platform, using an erodable polymer with complete elution of low doses of paclitaxel, is safe. The inhibition of the in-stent neointimal hyperplasia was best in the long release groups.