Comparative study of tacrolimus and paclitaxel stent coating in the porcine coronary model

SummaryBackground Tacrolimus is a potent antiproliferative and immunosuppressive agent allowing for improved endothelial regeneration. The aim of our study was the preclinical evaluation of tacrolimus in a drug eluting nonerodable polymer stent system and its comparison with paclitaxel.Methods and results A total of 40 domestic pigs and 10 mini-pigs underwent coronary stenting with a follow-up time between 6 hours and 3 months. Stents were implanted in coronary arteries with an overstretch ratio of 1.2. After 3 days, a 1.73 μg/mm² coating produced tacrolimus tissue levels of 20 μmol/l in the coronary artery wall. Effective tissue concentrations were sustained for 28 days. Based on histomorphometric analysis, tacrolimus stent treated vessels had a reduced extent of neointima formation compared with controls at 28 days (–51% compared to control) but not at 3 months. High dose paclitaxel stent coating (1.44 μg/mm²) was complicated by unexpected deaths of pigs and thrombotic stent occlusion at control angiography. Long-term porcine data showed no persistent inhibition of neointimal growth by paclitaxel and tacrolimus stent coating.Conclusions Similar to paclitaxel, tacrolimus stent coating reduces neointimal proliferation in the porcine coronary model. However, dosing and long-term efficacy remains a critical issue in stent-based local drug delivery.     

Sirolimus-eluting stents for the prevention of restenosis in a worst-case scenario of diffuse and recurrent in-stent restenosis.

For recurrent in-stent restenosis (ISR), surgical revascularization or brachytherapy is still the principal therapeutic options. The present investigation explores the efficacy of a sirolimus-eluting stent to prevent restenosis in these lesions with a high risk of recurrence. In 22 consecutive patients with a recurrent and diffuse ISR, a sirolimus-eluting stent was implanted to cover the restenotic lesion. All patients were followed clinically for at least 1 year and underwent a repeat angiography after 7 months. A quantitative coronary angiographic analysis was done. The target vessel failure was 14% in the sirolimus-eluting stent group, with an angiographic late loss of only 0.39 +/- 0.54. No subacute stent thrombosis was observed, and the 1-year event-free survival was 86%. The three cases with restenosis were all focal and could be successfully treated by additional drug-eluting stent implantation. This study showed the efficacy of a sirolimus-eluting stent for the prevention of restenosis in a worst-case scenario of recurrent and diffuse ISR. The observed restenosis rate is lower than that reported after brachytherapy and suggests that sirolimus-eluting stents are a promising treatment option for ISR.     

A novel paclitaxel-eluting porous carbon-carbon nanoparticle coated, nonpolymeric cobalt-chromium stent: evaluation in a porcine model.

OBJECTIVES: We aimed to evaluate the response of porcine coronary arteries to a novel paclitaxel-eluting porous carbon-carbon nanoparticle coated, nonpolymeric cobalt chromium stent. BACKGROUND: Polymer based drug-eluting stents significantly reduce restenosis. However, the indefinite presence of polymer is thought to initiate and sustain inflammation and contribute to the occurrence of late complications. METHODS: Sixteen carbon-carbon coated, nonpolymeric cobalt chromium stents with two different doses of paclitaxel (eight of each) were implanted in porcine coronary arteries. In addition, eight cobalt chromium stents coated with a biodegradable polymer were also studied. Animals were sacrificed 6 weeks after stent implantation and histomorphometric analysis was performed. Results were compared among the three groups of stents. RESULTS: The cobalt chromium stents coated with carbon-carbon with low and medium doses of paclitaxel both showed acceptable performance characteristics, with respect to endothelialization, neointimal hyperplasia, percentage diameter stenosis, inflammatory response, and tendency to fibrin deposition, when compared to historical data with the Cypher stent. On the other hand, the stents coated with poly(lactide) and poly(lactide-co-glycolide) biodegradable polymers and 0.7 microg/mm2 paclitaxel showed poor performance. There was a significant tendency to poor endothelialization, greater neointimal hyperplasia, percentage diameter stenosis, greater inflammatory response, and tendency to fibrin deposition (P < 0.01 for all parameters). CONCLUSIONS: This preclinical evaluation demonstrates the safety and efficacy of a novel cobalt chromium stent with a carbon-carbon coating and low and medium doses of paclitaxel.     

Advanced c-myc antisense (AVI-4126)-eluting phosphorylcholine-coated stent implantation is associated with complete vascular healing and reduced neointimal formation in the porcine coronary restenosis model.

An advanced six-ring morpholino backbone c-myc antisense (AVI-4126) was shown to inhibit c-myc expression and intimal hyperplasia after local catheter delivery in a porcine balloon injury model. The purpose of this study was to investigate the effects of an AVI-4126-eluting phosphorylcholine-coated (PC) stent on c-myc expression restenosis and vascular healing after stent implantation in porcine coronary arteries. PC stents were loaded with AVI-4126 using soak trap. Nine pigs underwent AVI-4126 PC coronary stent implantation (two stents/animal). Two to six hours postprocedure, three pigs were sacrificed and stented segments were analyzed by Western blot for c-myc expression. In chronic experiments, six pigs (12 stent sites) were sacrificed at 28 days following intervention and vessels were perfusion-fixed. High-performance liquid chromatography analysis of plasma samples showed minimal presence of the antisense. Western blot analysis of the stented vessels demonstrated inhibition of c-myc expression at 2 and 6 hr after procedure. Quantitative histologic morphometry showed that the neointimal area was significantly reduced (by 40%) in the antisense-coated group compared with control (2.3 +/- 0.7 vs. 3.9 +/- 0.8 mm(2), respectively; P = 0.0077). Immunostaining and electron microscopy demonstrated complete endothelialization, without fibrin deposition, thrombosis, or necrosis in all implanted stents. In the porcine coronary model, an advanced c-myc-eluting PC stent blocked c-myc expression and significantly inhibited myointimal hyperplasia and allowed complete reendothelialization and healing response.     

Decreased risk of stent fracture‐related restenosis between paclitaxel‐eluting stents and sirolimus eluting stents: Results of long‐term follow‐up

Objective: To compare the outcomes between paclitaxel‐eluting stents (PES) and sirolimus‐eluting stents (SES) for the treatment of drug‐eluting stent (DES) fracture. Background: DES fracture is considered as an important predictor of in‐stent restenosis (ISR). However, little data are available evaluating the optimal treatment for this complication of coronary stenting. Methods: From January 1, 2004 to December 31, 2008, patients with DES ISR treated with a second DES were identified and evaluated for stent fracture. Stent fracture was defined by the presence of strut separation in multiple angiographic projections, assessed by two independent reviewers. Target lesion revascularization (TLR) at 6 and 12 months were the primary end points. Results: Of 131 lesions with DES ISR treated with a second DES, we found 24 patients (24 lesions, 18.2%) with angiographically confirmed stent fracture. Of these, 20 patients (20 lesions) treated with either PES (n = 11/55%) or SES (n = 9/45%) were included in the study. TLR at 6 months occurred in 9% of patients treated with PES and 22% of those treated with SES (P = 0.41). After 12 months, TLR was 9% and 55.5%, respectively (P = 0.024). Conclusions: This study demonstrates a high incidence of stent fracture in patients presenting with DES ISR in need of further treatment with another DES. The suggested association between treatment of stent fracture‐associated DES ISR with PES as compared with SES, and better long‐term outcomes, is in need of confirmation by larger prospective registries and randomized trials. © 2011 Wiley Periodicals, Inc.     

Synergistic effects of a novel nanoporous stent coating and tacrolimus on intima proliferation in rabbits.

To overcome the problem of in-stent restenosis, the concept of local delivery of antiproliferative or immunosuppressive drugs has been introduced into interventional cardiology. Local drug delivery can be achieved by drug-eluting stents coated with polymer surfaces used for controlled drug release. However, several polymer coatings have shown an induction of inflammatory response and increased neointima formation. In the present study, the effect of a new inorganic ceramic nanoporous aluminum oxide (Al(2)O(3)) coating on neointima proliferation and its suitability as a carrier for the immunosuppressive drug tacrolimus have been investigated. 316 L stainless steel coronary stents were coated with a 500 nm thin nanoporous aluminum oxide layer. This ceramic nanolayer was used as a carrier for tacrolimus. Bare stents (n = 6), ceramic coated stents (n = 6), and ceramic coated stents loaded with 60 (n = 7) and 120 mug (n = 6) tacrolimus were implanted in the common carotid artery of New Zealand rabbits. The ceramic coating caused no significant reduction of neointimal thickness after 28 days. Loading the ceramic stents with tacrolimus led to a significant reduction of neointima thickness by 52% for 60 mug (P = 0.047) and 56% for 120 mug (P = 0.036) as compared to the bare stents. The ceramic coating alone as well as in combination with tacrolimus led to a reduced infiltration of lymphocytes and macrophages in the intima in response to stent implantation. Ceramic coating of coronary stents with a nanoporous layer of aluminum oxide in combination with tacrolimus resulted in a significant reduction in neointima formation and inflammatory response. The synergistic effects of the ceramic coating and tacrolimus suggest that this new approach may have a high potential to translate into clinical benefit.     

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.     

Unprotected left main bifurcation restenosis treated with a 2‐stent technique

The present case report refers to the percutaneous treatment of severe left main stem stenosis as a consequence of proliferative in‐stent restenosis of left circumflex coronary with retrograde involvement. A reverse mini‐crush technique with 2 stents was described. © 2012 Wiley Periodicals, Inc.     

Late restenosis following placement of a sirolimus eluting stent for in-stent restenosis

Drug eluting stents (DES) are rapidly replacing intravascular brachytherapy for the treatment of bare metal in-stent restenosis (ISR). To date, there are no long-term follow up data supporting this practise. We report symptomatic repeat in-stent restenosis occurring 27 months after sirolimus eluting stent deployment for de novo in-stent restenosis. This case suggests that in a subgroup of patients with ISR, as with brachytherapy, the drug eluting stent may be simply delaying rather than inhibiting the restenotic process.     

Treatment of drug‐eluting stent restenosis: An emerging challenge

Drug eluting stent (DES) restenosis has emerged as a significant clinical entity owing to the increasing use of DES in complex lesions and patients. However, to date, there is a paucity of studies that have addressed the management of DES restenosis and the resulting outcome, leaving the interventional cardiologist with a therapeutic dilemma. The purpose of this paper is therefore to provide a consise review of available data's dealing with the treatment of DES restenosis, including the outcome of patients treated for DES restenosis, the prognostic importance of the angiographic pattern and the available therapeutic modalities. © 2009 Wiley‐Liss, Inc.     

Clinical outcomes for sirolimus-eluting stent implantation and vascular brachytherapy for the treatment of in-stent restenosis.

The purpose of this study was to compare the mid-term clinical outcome of sirolimus-eluting stent (SES) implantation and vascular brachytherapy (VBT) for in-stent restenosis (ISR). We assessed the 9-month occurrence of major adverse cardiac events (MACE) in 44 consecutive patients with ISR treated with SES implantation and 43 consecutive patients treated with VBT in the period immediately prior. Baseline clinical and angiographic characteristics of the two groups were similar. During follow-up, three patients (7%) died in the VBT group and none in the SES group. The incidence of myocardial infarction was 2.3% in both groups. Target lesion revascularization was performed in 11.6% of the VBT patients and 16.3% of the SES patients (P = NS). The 9-month MACE-free survival was similar in both groups (79.1% VBT vs. 81.5% SES; P = 0.8 by log rank). The result of this nonrandomized study suggests that sirolimus-eluting stent implantation is at least as effective as vascular brachytherapy in the treatment of in-stent restenosis.     

Drug‐eluting stents in bifurcation lesions: To stent one branch or both?

OBJECTIVES: The objective of this study was to compare two techniques to treat bifurcation lesions: a single drug-eluting stent (DES) implanted in the main branch combined with balloon dilatation for the side branch vs. stenting of both branches (double stent). BACKGROUND: Percutaneous coronary intervention in coronary bifurcation lesions remains challenging. Although DES reduce restenosis in lesions, the double stent procedure has not shown clear advantages over a single stent with balloon dilation. METHODS: Fifty-three symptomatic patients with true bifurcation lesions were treated using either the double stent technique (n = 25) or one stent in the parent vessel plus balloon angioplasty of the side branch (n = 28). Procedural results and major adverse cardiac event rates (MACE: cardiac death, myocardial infarction, target vessel revascularization (TVR)) were compared. RESULTS: Angiographic procedural success (residual stenosis <30% in both branches) was 75% in the single stent group and 100% in the double stent group (P = 0.01). All differences were due to residual stenosis of the side branch. Clinical follow-up (6-18 months) was available for all patients; 90.5% of patients had a coronary angiography or nuclear stress test. Three patients (11%) in the single stent group and two (8%) in the double stent group had ischemia-driven TVR (P = NS). Asymptomatic angiographic restenosis (>50% diameter stenosis) in the ostium of the side branch was seen in two patients in the double-stent group. At 6 months, MACE-free was comparable between groups (89.3% vs. 88%, P = 0.7). CONCLUSIONS: When treating bifurcation lesions with sirolimus-eluting stents, restenosis following a single stent procedure is comparable to stenting both parent and side branch vessels. Thus, stenting the main-branch lesion, coupled with balloon angioplasty in the side branch, produces a high success rate and good clinical outcomes at 6 months.     

Estrogen-eluting, phosphorylcholine-coated stent implantation is associated with reduced neointimal formation but no delay in vascular repair in a porcine coronary model.

Estrogen can inhibit intimal proliferation and accelerate endothelial regeneration after angioplasty. This suggests that estrogen may prevent in-stent restenosis. Unlike other therapies to prevent restenosis, estrogen may also not delay endothelial regrowth, thereby avoiding the risk of late stent thrombosis. The purpose of this work was to determine the effect of a 17beta-estradiol-eluting stent on neointimal formation in a porcine model. Each artery of six pigs was randomized to either a control, low-dose, or high-dose 17beta-estradiol-eluting stent. All animals were sacrificed at 30 days for histopathological analysis. There was a 40% reduction in intimal area in the high-dose stents compared with control stents (2.54 +/- 1.0 vs. 4.13 +/- 1.1 mm(2), for high dose vs. control, respectively; P < 0.05). There was complete endothelial regeneration at 30 days and similar inflammatory response to stenting on histopathology in all the stent groups. This is the first study to show that 17beta-estradiol-eluting stents are associated with reduced neointimal formation without affecting endothelial regeneration in the pig model of in-stent restenosis. Estrogen-coated stents may have a potential benefit in the prevention and treatment of in-stent restenosis.     

Aneurysm formation after drug‐eluting balloon treatment of drug‐eluting in‐stent restenosis: First case report

A 55‐year‐old male underwent paclitaxel‐eluting stent implantation in a bifurcation lesion of his left anterior descending artery (LAD) during an episode of unstable angina in 2008. A late in‐stent restenosis developed 15 months after implantation of the drug‐eluting stent (DES) and was treated with paclitaxel eluting balloon. Two months later, during angiography for functional assessment of the significance of lesions in the circumflex artery, an aneurysm at the place of drug‐eluting balloon (DEB) inflation was observed. The patient was left on double antiplatelet therapy and scheduled for clinical observation after 3 months and control coronary angiography after 6 months for aneurysm progression follow‐up. © 2012 Wiley Periodicals, Inc.