tacrolimus and Coronary-Restenosis

Sirolimus and tacrolimus are potent immunosuppressants that are delivered by drug-eluting stents (DES) for the prevention of in-stent restenosis. Balloon angioplasty with stent implantation has emerged as a successful treatment for coronary stenoses; angioplasty dilates the vessel lumen and the stent prevents elastic recoil of the vessel walls. However, angioplasty and stent placement both produce vascular injuries that potently stimulate the proliferation of smooth muscle cells, resulting in a thickening of the vascular wall. The purpose of DES is to deliver pharmacological agents that counteract neointimal hyperplasia. The sirolimus-eluting-stent reduces the incidence of in-stent restenosis significantly, whereas the tacrolimus-eluting-stent demonstrates no improvement in clinical benefit compared with a bare stent. Although sirolimus and tacrolimus have similar molecular structures, these drugs regulate immune activation via different mechanisms of action. The effects of this class of drugs are mediated by binding to the FK-506-binding proteins (FKBPs), which are highly evolutionarily conserved across species. This review highlights the structure and function of sirolimus, tacrolimus and FKBPs, with particular focus on recent observations that the two drugs target signaling pathways involved in the control of vascular smooth muscle apoptosis and proliferation directly.

Topics: Animals; Cell Proliferation; Coronary Restenosis; Drug Delivery Systems; Drug-Eluting Stents; Humans; Immunosuppressive Agents; Models, Biological; Muscle, Smooth, Vascular; Protein Binding; Signal Transduction; Sirolimus; Tacrolimus; Tacrolimus Binding Proteins

Drug-eluting stents (DES) with antiproliferative drugs attached via polymers on the stent surface have reduced in-stent restenosis and repeat revascularization compared with bare metal stent (BMS) across nearly all lesion and patient subsets. However, the small number of patients with in-stent restenosis after DES treatment still exists. Furthermore, concerns about long-term safety of DES are raised, particularly regarding the higher-than-expected late-event thrombosis. There is no doubt that the DES will continue to play a pivotal role in the treatment of coronary artery disease, yet future designs need to incorporate features that reduce thrombosis and promote endothelialization along with maintaining the efficacy. This review focuses on novel generation of DES, discussing new programs, including new antiproliferative agents, novel polymeric and non polymeric stents.

Topics: Absorbable Implants; Coronary Artery Disease; Coronary Restenosis; Coronary Thrombosis; Drug-Eluting Stents; Equipment Design; Everolimus; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Polymers; Prosthesis Design; Sirolimus; Tacrolimus

Controversy exists about the clinical significance of in-stent late loss (ISLL) after drug-eluting stent (DES) implantation. We sought to clarify whether ISLL after DES implantation is related to a potential clinical impact.. We included in a meta-regression analysis 21 trials (8641 patients) that randomly compared DES with bare-metal stents (BMS). We evaluated the relationship between angiographic behaviour of DES and the clinical impact of using DES instead of BMS in each trial using meta-regression techniques, weighting by the number of patients included in each trial. Mean ISLL in patients allocated to DES and DeltaISLL (difference in ISLL in patients allocated to BMS and DES) were used as angiographic parameters of efficacy of DES. The number of patients needed to be treated (NNT) to prevent one target lesion revascularization (TLR) was used to quantify the clinical impact of using DES instead of BMS. There was a significant relationship between mean ISLL in patients allocated to DES and the clinical benefit of using DES instead of BMS, as measured with the NNT for TLR: NNT for TLR = 6.2 + 18.4 [ISLL-DES] (R = 0.62; P = 0.007). Therefore, a 0.1 mm increase in mean ISLL-DES was associated with a 1.8 increase in NNT for TLR. There was also a significant association between the degree of inhibition of neointimal hyperplasia of DES in comparison with BMS with the NNT for TLR: NNT for TLR = 17.1-11.8 [DeltaISLL] (R = 0.61; P = 0.008). Therefore, a 0.1 mm reduction in ISLL by using DES instead of BMS was associated with a 1.2 decrease in mean NNT for TLR.. There is a strong and significant association between the degree of inhibition of neointimal formation with the use of DES and the clinical impact of using DES instead of BMS.

Topics: Coronary Restenosis; Delayed-Action Preparations; Humans; Immunosuppressive Agents; Paclitaxel; Randomized Controlled Trials as Topic; Sirolimus; Stents; Tacrolimus; Tubulin Modulators

Topics: Animals; Antineoplastic Agents, Phytogenic; Coronary Artery Disease; Coronary Restenosis; Drug Delivery Systems; Humans; Immunosuppressive Agents; Paclitaxel; Stents; Tacrolimus

Drug eluting stents have been developed in order to reduce in-stent restenosis observed with a 20 to 40% rate in bare-stents. Neoinitimal smooth muscular cells proliferation have been characterized as the corner stone of in-stent restenosis. Consequently, many anti-mitotic and anti-inflammatory drugs have been evaluated in a new stent generation, so called coated stents or drug eluting stents. Three major components must be considered to evaluate the beneficial effects: the bare-stent, the drug, and the deliverance system, most usually a polymer. For the present, sirolimus eluting stent and paclitaxel eluting stent are available in the market with the european conformity label considering evidence based medicine established in randomized trials. Both stents have been shown to reduce in-stent restenosis incidence to less than 7%. Long-term follow-up still remain expected and would give answers to two safety queries: what is about the incidence of late stent thrombosis, what is about mal-apposition consequences in clinical feature. Utilization of drug eluting stent in clinical practice must considered materials with european conformity and must applied French society of cardiology guidelines restricting implantation to patients who meet high-risk restenosis criteria. Medicoeconomic approach must be considered beneficial at the present only in patients with high restenosis risk. Long-term antiplatelet regimen of aspirin and clopidogrel must be considered to avoid late stent thrombosis.

Topics: Clinical Trials as Topic; Coronary Restenosis; Drug Delivery Systems; Humans; Immunosuppressive Agents; ortho-Aminobenzoates; Paclitaxel; Platelet Aggregation Inhibitors; Sirolimus; Stents; Tacrolimus

The inhibitory action of the sirolimus-like agent everolimus on smooth muscle cell proliferation, evidenced in animal models, has triggered the interest in everolimus as stent coating for local inhibition of in-stent restenosis. For preclinical and clinical evaluation of safety and efficacy of an everolimus-eluting stent design, a new stent has recently been introduced by Biosensors International Inc, covered by a resorbable "composite" coating, that contains the immunosuppressive drug within a polyhydroxyacid biodegradable polymer matrix with roughly equal resorption rates. FUTURE I, the feasibility trial of this new stent concept, revealed a 30-day MACE (major adverse cardiac events) rate of 0% as well as a restenosis rate of 0% at 6-month follow-up in a total of 32 patients included. The more sensitive QCA (quantitative computerized analysis) and IVUS (intravascular ultrasound) parameters showed an 88% reduction of in-stent late loss and an 87% reduction of the neointimal volume. Adding a second feasibility trial including diabetics, the multicenter trial FUTURE II confirmed the initial beneficial findings of FUTURE I in a total of 64 patients in a 1 : 2 randomization to a bare metal control stent. Based on these results, the FUTURE program has now been expanded by Guidant with two large-scale multicenter studies, FUTURE III and IV, which evaluate this stent design in a larger patient population. Furthermore, FUTURE IV is addressed to demonstrate the non-inferiority of this stent concept in a head-to-head comparison to an approved drug-eluting stent (DES) concept. In contrast to everolimus, tacrolimus is a well-known potent antiproliferative agent, already used in various therapeutic areas. Preclinical studies on tacrolimus-eluting stents for treatment of native coronary artery lesions demonstrated safety and efficacy of this stent concept with significant reduction of neointimal proliferation within the implanted study stents. However, the clinical trial program of the first tacrolimus-eluting stent system in the treatment of native coronary lesions (PRESENT I, II) and saphenous vein graft lesions (EVIDENT) failed to prove the clinical benefit of the stent systems tested and demonstrated the impact of specific stent designs, especially the drug carrier characteristics, on the patient outcome. The progressive PRESET study, evaluating a directly coated tacrolimus-eluting stent, will provide important insights, that will clarify the potential of tacrolim

Topics: Angioplasty, Balloon, Coronary; Animals; Antibiotics, Antineoplastic; Coated Materials, Biocompatible; Coronary Restenosis; Coronary Stenosis; Coronary Vessels; Everolimus; Feasibility Studies; Humans; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Sirolimus; Stents; Structure-Activity Relationship; Tacrolimus; Treatment Outcome

Stents represent a major step forward in the treatment of coronary artery disease since the introduction of balloon angioplasty. They have demonstrated the reduction of angiographic indexes of restenosis and rates of repeat revascularization. However, in-stent neointimal proliferation represents the persisting limitation and challenge. Local delivery using a stent platform for deposition of therapeutic drug concentration in the arterial wall has emerged as an effective strategy to reduce in-stent neointimal hyperplasia and restenosis. The purpose of this article is to describe the design characteristics of a new drug-eluting stent. Its unique features consist of integral Carbofilm thromboresistant coating combined with the capability to load the drug into and to release it from deep sculptures made on the external surface of the stent. The advantages of this design are the possibility to load higher amounts of drug, to selectively deliver it to the vessel wall without loss in the blood stream, and to improve the biocompatibility and thromboresistance of the stent. Preclinical studies, using tacrolimus as the biological agent, showed excellent vessel tissue response and mild inflammation scores. A significant reduction of intimal proliferation was observed in comparison with a control stent. The enrollment in a safety first-in-man evaluation has been successfully completed. A randomized, double-blind, multicenter study is expected to start at the completion of the "safety" evaluation.

Topics: Adult; Aged; Aged, 80 and over; Animals; Coated Materials, Biocompatible; Coronary Artery Disease; Coronary Restenosis; Drug Carriers; Equipment Design; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Rabbits; Stents; Tacrolimus

Restenosis is the process of luminal narrowing in an atherosclerotic artery after an intra-arterial intervention such as balloon angioplasty and stenting. It is believed that this process is mainly characterized by migration and proliferation of smooth muscle cells and extracellular matrix accumulation. However, there is now increasing evidence for a role of inflammation in the development of restenosis. The underlying molecular mechanisms of restenosis are, in fact, most probably regulated by inflammatory mediators, such as cytokines. Understanding the molecular mechanisms in restenosis is crucial for the development of a suitable therapy for this disease. Recently, the use of immunosuppressives in drug-eluting stents has provided very promising results in the treatment of restenosis. In this review, we will describe the molecular mechanisms involved in restenosis with a focus on the role of inflammation and the use of immunosuppressive therapy.

Topics: Coronary Restenosis; Cyclosporine; Humans; Immunosuppressive Agents; Inflammation; Inflammation Mediators; Sirolimus; Tacrolimus

The main limitation to further expansion of PTCI (percutaneous transluminal coronary intervention) is restenosis that occurs in 30% of the patients within 6-months after the procedure. Coronary stenting decreases the percent of restenosis due to arterial remodeling after PTCI but proliferation of smooth muscle cells due to vascular injury still remains. A mechanical approach the only treatment up to now (further balloon expansion, plaque removal with rotablator or directional atherectomy) failed. Because the restenotic process is due to a complex series of biological events which start with platelet aggregation, grow-factors and cytochine release, the use of antiflammatory, antithrombotic and antiproliferative drugs were attempted. Cortisone and heparin showed low benefits in clinical trial. New drugs (rapamycin, taxol, actinomycin D, tacrolimus, estradiol, dexamethazone) with antiproliferative and antiflammatory activities are under evaluation. They act as inhibitors of the cell migration and of the cell cicle progression with different specific molecular mechanisms. The first pilot study performed in 45 patients with sirolimus-eluting stents has shown a sustained suppression (25% in the fast release group and 23% in the slow release group) of neointimal formation at 12 months after procedure with absence of restenosis. The Ravel study, a randomized trial, has enrolled 238 patients treated with sirolimus coated stent vs a control group: the results confirm the previous data with a complete suppression of intimal hyperproliferation and restenosis at six months follow-up. The first 400 patients treated in the Sirius trial a similar study which will randomize 1100 pts show a low, but not a complete inhibition of the restenotic process probably due to a more complexity of the lesions treated in comparison to Ravel trial (9.2% of restenosis). Another very promising drug is taxol (paclitaxel). It is an antiproliferative and antinflammatory molecule tested in a series of clinical trials called Taxus. The still unpublished data of TAXUS I and TAXUS II randomized trial show extremely low restenosis rate. Other drugs (actinomycin D, estradiol, tacrolimus, dexamethazone) show to have a potential effect on restenosis and neointimal proliferation and are under investigation. Is very important to maintain lessons learned from the past. The design, the type, the smooth surface of the stent still remains very important as it is a good expansion and a full coverage of th

Topics: Angiogenesis Inhibitors; Angioplasty, Balloon, Coronary; Clinical Trials as Topic; Coated Materials, Biocompatible; Coronary Restenosis; Estradiol; Graft Occlusion, Vascular; Immunosuppressive Agents; Multicenter Studies as Topic; Paclitaxel; Pharmaceutical Preparations; Pilot Projects; Randomized Controlled Trials as Topic; Stents; Tacrolimus; Time Factors

The aim of this study was to compare, in a randomized multicenter trial, paclitaxel-eluting stents (CoStar, Conor Medsystems, Menlo Park, California) versus pimecrolimus-eluting stents (Corio, Conor Medsystems) versus stents with dual elution of both drugs (SymBio, Conor Medsystems) in native coronary arteries.. The CoStar cobalt-chromium reservoir-based stent platform, eluting paclitaxel in a controlled way via a bioresorbable polymer, reduces restenosis versus its respective bare-metal stent. The reservoir system allows the use of other drugs targeted to different mechanisms involved in the process of vascular restenosis and simultaneous loading of multiple, synergistic drugs.. Patients with single de novo lesions were asymmetrically randomized to 1 of the 3 types of stent (1:2:2). Six-month coronary angiography was planned in all. The primary analysis was a noninferiority test for the primary end point of 6-month angiographic in-stent late lumen loss of Corio versus CoStar and SymBio versus CoStar. Secondary end points included binary angiographic restenosis and major adverse clinical events (cardiac death, myocardial infarction, target vessel revascularization).. The trial was prematurely suspended after 246 patients were enrolled (planned enrollment: 375 patients): 49 patients received CoStar, 97 received SymBio, and 100 received Corio. In-stent late loss was significantly reduced with CoStar versus either SymBio or Corio (0.58 +/- 0.58 mm vs. 0.96 +/- 0.73 mm and 0.58 +/- 0.58 mm vs. 1.40 +/- 0.67 mm, p < 0.001 for both comparisons). Binary in-stent restenosis rates were, 7.1%, 20%, and 40.9%, respectively (p < 0.001 for both comparisons); 6-month major adverse cardiac event rates were, 2.0%, 14.4%, and 39.0%, respectively (p < 0.001 for both comparisons).. Stents eluting pimecrolimus or the dual combination of pimecrolimus and paclitaxel failed to show angiographic noninferiority when compared with paclitaxel-eluting stents. (A Randomized, Multi-Center Study of the Pimecrolimus-Eluting and Pimecrolimus/Paclitaxel-Eluting Coronary Stent Systems; NCT00322569).

Topics: Angioplasty, Balloon, Coronary; Antineoplastic Agents, Phytogenic; Coronary Angiography; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Drug-Eluting Stents; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Paclitaxel; Survival Analysis; Tacrolimus

The aim of this multicentre, non-randomised trial was to evaluate the safety and efficacy at 180+/-14 days of a pimecrolimus eluting coronary stent based on a cobalt-chromium platform and a poly-L-lactic acid (PLLA) bioresorbable polymer.. Sixty-one patients, with single de novo coronary lesions <14 mm in length and a reference vessel diameter of 3.0 to 3.5 mm, were enrolled in five centres (Germany and Belgium). Angiography and IVUS were performed at baseline, post-procedure and 180+/-14 days later. The primary endpoint was a composite of major adverse cardiac events (MACE) at 180+/-14 days and expected to be below 20%. Patients had single vessel disease in 59%, 2-vessel disease in 28% and 3-vessel disease in 13% of cases. MACE rate at 180+/-14 days was 18.0%. Binary in-stent restenosis was 32.7% due to in-stent late lumen loss of 1.11+/-0.65 mm by QCA. Stent thrombosis rate at 30+/-7 and 180+/-14 days was 1.6% and 3.3%, respectively. Overall TLR rate at 30+/-7, 180+/-14 days and 12+/-1 months was 1.6%, 27.9% and 32.8% respectively.. The primary endpoint was met at 180+/-14 days. However, the anti-restenotic effect of the pimecrolimus eluting stent did not reach levels similar to clinically established DES.

Topics: Aged; Angioplasty, Balloon, Coronary; Belgium; Cardiovascular Agents; Chromium Alloys; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Female; Germany; Humans; Lactic Acid; Male; Middle Aged; Myocardial Infarction; Polyesters; Polymers; Prospective Studies; Prosthesis Design; Severity of Illness Index; Tacrolimus; Thrombosis; Time Factors; Treatment Outcome; Ultrasonography, Interventional

The aim of this study was to determine the safety and efficacy of a novel pimecrolimus-eluting stent in a porcine coronary model and in a phase I clinical trial.. Rapamycin- and paclitaxel-eluting stents reduce the need for repeat intervention by limiting neointimal hyperplasia but might cause delayed healing, pre-disposing patients to late stent thrombosis. Because inflammation plays a key role in restenosis, pimecrolimus, an anti-inflammatory drug, might reduce restenosis without adversely affecting re-endothelialization.. We evaluated a novel polymeric pimecrolimus-eluting stent covered with a thin parylene C diffusion barrier in a porcine coronary model and in a phase I human clinical trial. The clinical study was a prospective, nonrandomized, first-in-human hypothesis-generating study that enrolled 15 patients who had a single de novo native coronary stenosis.. At 28 days and 3 months in the porcine model, histopathologic indicators predicted safety and biocompatibility when stents coated with polymer only, drug only, and 2 drug-polymer formulations were compared with bare-metal stents (BMS). In the phase I clinical trial, 15 patients had successful implantation of pimecrolimus-eluting stents. By 6 months, no patient suffered death, myocardial infarction, or stent thrombosis. However, the angiographic restenosis (61%), mean late loss (1.44 mm), and repeat target lesion revascularization (53%) were significantly higher than historical BMS controls. Whereas the primary end point was percent volume obstruction, restenosis was so severe that operators performed intravascular ultrasound examination in only 6 patients.. Pimecrolimus-eluting stents induced an exaggerated neointimal hyperplasia at 6 months in comparison with historical controls.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Animals; Cardiovascular Agents; Coated Materials, Biocompatible; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Disease Models, Animal; Drug-Eluting Stents; Feasibility Studies; Female; Humans; Hyperplasia; Male; Middle Aged; New Zealand; Polymers; Prospective Studies; Prosthesis Design; Registries; Risk Assessment; Severity of Illness Index; Swine; Tacrolimus; Time Factors; Treatment Outcome; Ultrasonography, Interventional; Xylenes

Drug eluting stents (DES) have been shown to reduce restenosis compared with bare metal stents in bifurcated lesions. The aim of this study was to evaluate the long-term clinical outcomes of patients with bifurcated lesions treated by 3 different DES.. Consecutive patients with symptomatic coronary artery disease on one bifurcated lesion with SB>2.25 mm (on visual estimation) undergoing at the Department of Cardiology of the Catholic University of Rome, Italy were screened. Patients treated with Sirolimus-eluting stent (Cypher Select; SES Group), Tacrolimus-eluting stent (Taxus-Libertè; TA Group) and Zotarolimus-eluting stent (Endeavor Driver; ZOT Group) were enrolled in the study. Clinical and angiographic characteristics of all patients were prospectively recorded. Major adverse clinical events (MACE), including death, acute myocardial infarction (MI) or target lesion revascularization (TVR) by either percutaneous coronary intervention (PCI) or coronary surgery were recorded during the follow-up. Incidence of definite or probable stent thrombosis was calculated according to the ARC criteria.. Two hundred and forty-one consecutive patients were enrolled (89 Group CY, 98 Group TA and 54 Group EN). Length of follow-up was 235+/-60 days. Baseline clinical and angiographic characteristic were similar across the groups. The adopted technique for stent implantation was provisional stenting (73.4%), T-stenting technique (7%), crush (7%) and V-stenting (2.6%). The rate of patients finally treated with two stents was similar among groups. The cumulative rate of MACE (9% SES, 12% TA, 11% ZOT: P=0.7) and of TVR (2% SES, 9% TA, 7% ZOT) was similar among groups. No definite stent thrombosis was observed during follow-up, while 1 probable stent thrombosis was observed in TA group.. The clinical outcome of bifurcated lesions using DES and mainly a technique of single stent implantation is good. In the present observational study, clinical adverse events did not differ in patients with bifurcated lesions treated by Cypher, Taxus or Endeavor stent implantation.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Drug Therapy, Combination; Drug-Eluting Stents; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Prospective Studies; Risk Factors; Rome; Sirolimus; Tacrolimus; Treatment Outcome

The Janus stent releases Tacrolimus from reservoirs located at the abluminal stent surface without any polymer. In stable coronary lesions the stent did not show relevant antiproliferative effects. Since Tacrolimus provides antiproliferative and antiinflammatory properties, we sought to investigate the efficacy of the Tacrolimus eluting Janus stent in acute coronary syndrome lesions with a more pronounced inflammatory cell reaction compared to stable coronary artery lesions.. Patients with acute coronary syndrome (STEMI or NSTEMI) undergoing cardiac catheterization and stent implantation were enrolled in this prospective registry. Primary outcome measure was in-stent late lumen loss at 6 months. There were two pre-specified subgroups based on presence or absence of high-pressure post-dilation (HPPD) with a balloon >or= 0.25 mm larger than the delivery balloon.. Sixty patients were enrolled. In 34 patients HPPD was performed. Reference diameter was 2.85+/-0.57 mm. Stented length was 30.8+/-23.8 mm in HPPD and 19.7+/-7.3 mm in non-HPPD group. For the total population in-stent late loss was 0.92+/-0.80 mm and binary restenosis rate 32.6%. Late loss (1.09+/-0.74 mm Vs. 0.64+/-0.83 mm) and binary restenosis rate (37.0% Vs. 25.0%) were higher in the HPPD subgroup compared to lesions in non-HPPD. The angiographic evidence of thrombus was associated with a higher late loss. Restenotic pattern was occlusive in 40%, diffuse in 33% and focal in 27%.. The use of the Tacrolimus eluting Janus stent in acute coronary syndrome lesions was associated with a high late lumen loss, a high angiographic restenosis rate and a mainly occlusive or diffuse pattern of restenosis.

Topics: Acute Coronary Syndrome; Aged; Angioplasty, Balloon, Coronary; Coronary Restenosis; Drug-Eluting Stents; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Radiography; Risk Factors; Tacrolimus; Treatment Outcome

We sought to evaluate the safety and performance of the Janus Tacrolimus-Eluting stent (TES) in an unselected population of patients, without application of restrictive clinical or angiographic criteria.. Continued attention to the safety, efficacy, and deliverability of first-generation drug eluting stents has led to the development of new antiproliferative agents with alternative stent platforms and different drug carrier vehicles.. The TEST (Tacrolimus Eluting STent) registry is a prospective, nonrandomized single-center registry in which 140 consecutive patients who underwent single- or multi-vessel percutaneous coronary intervention between February 2005 and August 2005 were enrolled.. The composite rate of major adverse cardiac events (MACE) at 22 months clinical follow-up was 40.9%. The rate of mortality, myocardial infarction, and target lesion revascularization (TLR) were 5.5%, 11%, and 31.5%, respectively. Angiographic follow-up at 8 months was achieved in 74% of patients; binary restenosis occurred in 39.4% of lesions. Most restenosis lesions (94.6%) had a diffuse pattern, while focal restenosis was observed in 5.4% of cases. Definite or probable stent thrombosis was observed in 2.4% of patients.. The present prospective, nonrandomized, TEST registry indicated high MACE and restenosis rates, and thereby rather discouraging long-term outcomes with use of the Janus TES in an unselected "real world" population of patients who underwent single- or multi-vessel percutaneous coronary intervention.

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Prosthesis Design; Registries; Risk Assessment; Tacrolimus; Time Factors; Treatment Outcome

Topics: Angioplasty, Balloon, Coronary; Cardiovascular Agents; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Humans; Myocardial Infarction; Prosthesis Design; Risk Assessment; Tacrolimus; Time Factors; Treatment Outcome

To evaluate the degree of endothelialization of the nonapposed struts located at the ostia of side branches.. Endothelialization of coronary stents has got considerable relevance because of the phenomenon of late thrombosis. Bifurcation location and incomplete stent apposition have been linked to this complication.. Domestic pigs (n = 11; weight: 25 +/- 3 kg) were anesthetized and had one stent per coronary artery implanted: one stainless steel (Tecnic), one cobalt-chromium (Chrono), and one tacrolimus-eluting stent (Janus), all of them being Carbofilm-coated (Sorin). One, three, or seven days postprocedure, the pigs were sacrificed, the hearts explanted, and longitudinal sections examined by surface electron microscopy to quantify the percentage of the strut endothelialized over the branches and in the total surface.. Forty-four side branches (25 stents) that had stent struts over their origin were evaluated. Different patterns of endothelialization were observed, from the total absence to the complete endothelialization. There were no significant differences in relation to type of stent or to the artery treated. The predictors of higher percentage of endothelialization were the ratio of metal to branch diameter (P = 0.04) and better endothelialization in the rest of the stent (P = 0.0002), only this parameter maintaining significant correlation (P = 0.03) in multivariate analysis.. Carbofilm-coated stent struts located over the origin of side branches follow the pattern of endothelialization for the rest of the stent, even in the case of tacrolimus-eluting stent.

Topics: Analysis of Variance; Animals; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Drug-Eluting Stents; Endothelium; Humans; Immunosuppressive Agents; Risk Factors; Statistics as Topic; Swine; Tacrolimus; Thrombosis

Topics: Angioplasty, Balloon, Coronary; Animals; Cardiovascular Agents; Coated Materials, Biocompatible; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Humans; Hyperplasia; Polymers; Prosthesis Design; Risk Assessment; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome; Xylenes

To characterize in-stent restenosis after the implantation of sirolimus-eluting stents (SES), paclitaxel-eluting stents (PES), tacrolimus-eluting stents (TES), and zotarolimus-eluting stents (ZES), 25 patients treated with drug-eluting stents (DES; 9 PES, 10 SES, 4 TES, and 2 ZES) and 19 with bare-metal stents (BMS) underwent directional coronary atherectomy for in-stent restenosis 4 to 36 months after implantation. Restenosis after DES implantation was more frequently focal and associated with smaller specimens compared to that after BMS implantation. Light and confocal microscopy were used. Histologic features were similar in DES and BMS. In-stent restenotic lesions were composed mainly of neointima containing proteoglycan-rich smooth muscle cells and fibrolipidic regions. Small inflammatory infiltrates were observed, mostly in patients with unstable angina; CD18- and/or CD3(+) cells were detected in patients with BMS and DES. Different smooth muscle cell phenotypes were observed: synthetic was more frequent with BMS and PES, intermediate with ZES, contractile or intermediate with SES, and contractile with TES. The mean proliferation index was low and comparable among stent types; cyclins B1 and D1 were expressed in all DES. In conclusion, intra-DES and intra-BMS restenotic tissue was composed mainly of smooth muscle cells with different phenotypes, proliferating at a low rate. The different smooth muscle cell phenotypes within the stent types might suggest different mechanisms of restenosis.

Topics: Aged; Coronary Artery Disease; Coronary Restenosis; Coronary Vessels; Drug-Eluting Stents; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Muscle, Smooth, Vascular; Paclitaxel; Sirolimus; Tacrolimus; Treatment Outcome

Stent-based delivery of tacrolimus has shown neointimal hyperplasia and restenosis reduction; FK506 is a water insoluble macrolide immunosuppressant. The purpose of this study was to evaluate acute and chronic tissue response to a polymer-free FK506 drug-eluting stent implantation in a porcine coronary artery model. Seventy-eight nonatherosclerotic minipigs underwent successful placement of 134 stents (control n = 56; FK506 (1.5 microg/mm(2)) n = 44; FK506 (2.6 microg/mm(2)) n = 34) at 7, 15, 30, 90, or 180 days. Endothelialisation was almost complete at 7 days, complete at 15 days. At 30 and 90 days, mean neointimal thickness, neointimal area, and % stenosis was significantly less for drug-eluting stents compared with controls. At 180 days, histomorphometric values were similar for eluting and control stents. The FK506-eluting stent allows for a complete re-endothelialisation at 15 days and favorably moderate neointimal hyperplasia at 30 and 90 days in the porcine coronary model. Because of a possible limited bioavailability of FK506, long-term inhibition of neointimal formation was not sustained at the considered follow-up.

Topics: Angioplasty, Balloon, Coronary; Animals; Coated Materials, Biocompatible; Coronary Restenosis; Coronary Vessels; Drug-Eluting Stents; Hyperplasia; Immunosuppressive Agents; Materials Testing; Surface Properties; Swine; Swine, Miniature; Tacrolimus; Tunica Intima

The long-term effectiveness of drug-eluting stents (DES) in unselected diabetics in routine practice is currently unclear.. To evaluate the long-term effectiveness of bare metal stents and DES in a real-world setting of diabetic patients, we analyzed 2-year follow-up data from all diabetic patients with de novo lesions enrolled in a prospective Web-based multicenter registry (Registro Regionale Angioplastiche dell'Emilia-Romagna; study period, 2002 to 2004) comprising all 13 hospitals performing percutaneous coronary interventions in the Emilia-Romagna region of Italy. Among the 1648 eligible patients treated with either bare metal stents alone (n=1089) or DES alone (n=559), 27% were insulin dependent and 83% had multivessel coronary disease. At 2 years, use of DES was associated with lower crude incidence of major adverse cardiac advents (all-cause mortality, nonfatal myocardial infarction, and target vessel revascularization) compared with bare metal stents (22.5% versus 28.1%; P=0.01). After propensity score adjustment, only target vessel revascularization appeared significantly lower in the DES group (11.6% versus 15.0%; hazard ratio, 0.66; 95% confidence interval, 0.46 to 0.96; P=0.041). Two-year angiographic stent thrombosis occurred in 1.5% DES patients and 0.7% of the bare-metal-stents patients (P=0.18). At Cox regression analysis, predictors of 2-year major adverse cardiac advents were left ventricular ejection fraction <35%, Charlson comorbidity index, insulin-dependent diabetes, and total lesion length.. In this large, real-world, diabetic population, the use of DES was associated with a moderate reduction in the 2-year risk of target vessel revascularization, a benefit that was limited to non-insulin-dependent diabetic patients. Larger long-term studies are needed to clarify the long-term effectiveness and safety of such devices in diabetic patients.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Combined Modality Therapy; Comorbidity; Coronary Restenosis; Coronary Stenosis; Coronary Thrombosis; Diabetes Mellitus; Diabetic Angiopathies; Female; Humans; Insulin; Italy; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Registries; Risk Factors; Sirolimus; Stents; Tacrolimus; Treatment Outcome

The purpose of this study was to determine the effectiveness and vascular response of a pimecrolimus drug eluting stent and a combination (pimecrolimus + paclitaxel) stent as compared with bare metal controls in the porcine coronary model.. In the first phase of the study, cobalt chromium stents were loaded with an erodible polymer and either a slow release or a fast release formulation of pimecrolimus. Thirty stents (metal, n = 10; pimecrolimus slow, n = 10; pimecrolimus fast, n = 10) were implanted in the coronary arteries of 10 pigs. At 30 days, neointimal proliferation and inflammation were both significantly less in the pimecrolimus fast release group as compared with the bare metal controls. Endothelialization was complete and equal in all three groups of stents. In the second phase of the study, stents were loaded with an erodible polymer with alternating reservoirs of paclitaxel and pimecrolimus. Twenty stents (8 control stents and 12 dual stents) were implanted in the coronary arteries of seven pigs. At 30 days, neointimal proliferation was significantly less in the dual drug group as compared with the bare metal controls. Endothelialization was complete in both groups of stents, suggesting complete healing of the arteries.. In a 30-day porcine stent model, pimecrolimus inhibits neointimal proliferation as compared with bare metal stents. Also, the proof of concept of a dual drug eluting stent was established showing both safety and efficacy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Blood Vessel Prosthesis Implantation; Calcineurin Inhibitors; Cell Proliferation; Coated Materials, Biocompatible; Coronary Angiography; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Drug Combinations; Follow-Up Studies; Graft Occlusion, Vascular; Immunosuppressive Agents; Paclitaxel; Stents; Swine; Tacrolimus; Treatment Outcome; Tunica Intima

Topics: Animals; Antineoplastic Agents, Phytogenic; Blood Vessel Prosthesis Implantation; Calcineurin Inhibitors; Cell Proliferation; Coated Materials, Biocompatible; Coronary Angiography; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Drug Combinations; Graft Occlusion, Vascular; Immunosuppressive Agents; Paclitaxel; Stents; Swine; Tacrolimus; Treatment Outcome

Cyclosporine is used routinely for prophylaxis for renal allograft rejection. In experimental animal studies, cyclosporine had been shown to inhibit smooth muscle cell proliferation during the arterial response to injury. We investigated whether systemic immunosuppression may inhibit in-stent restenosis in renal transplant patients undergoing coronary stenting.. From 1993 to 2003, 33 renal transplant patients with 45 coronary lesions and 37 dialysis patients with 52 lesions underwent coronary stenting using bare metal stents at our center. We followed all patients clinically for a mean period of 37 +/- 31 months and 40 patients angiographically at 14 +/- 15 months after coronary intervention. Cyclosporine was combined with corticosteroids in 32 patients and one patient received tacrolimus instead of cyclosporine.. The baseline clinical and angiographical characteristics were similar and the success rate of the procedure was 100% in both groups. In renal transplant group, the mean dose of cyclosporine was 192.5 +/- 68 mg/day and the blood cyclosporine level at the time of procedure was 152.9 +/- 51.5 ng/mL. The rate of in-stent restenosis was 7.1% in renal transplant group and 57.1% in dialysis group (P < 0.0001). The mean late loss was 0.47 +/- 0.57 mm in renal transplant group when compared with 1.51 +/- 1.09 mm in dialysis group (P = 0.004). The overall rate of major adverse cardiac events (MACEs) was 6.1% in renal transplant group and 35.1% in dialysis group (P < 0.0001).. Renal transplant patients receiving combined immunosuppressive agents showed markedly low rates of in-stent restenosis and MACE after coronary revascularization with stent. We consider that this result may be related to the ability of combined immunosuppressive therapy to inhibit inflammatory reaction and vascular smooth muscle cell proliferation induced by coronary stenting.

Topics: Coronary Angiography; Coronary Artery Bypass; Coronary Restenosis; Cyclosporins; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Prosthesis Failure; Retrospective Studies; Stents; Tacrolimus; Transplantation, Homologous; Treatment Outcome

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.

Topics: Aluminum Oxide; Animals; Coated Materials, Biocompatible; Coronary Restenosis; Graft Occlusion, Vascular; Hyperplasia; Immunosuppressive Agents; Prosthesis Design; Stents; Swine; Tacrolimus; Tunica Intima

In-stent restenosis remains an unresolved problem which occurs in 5-20% of patients undergoing coronary stenting within the first 3-6 months. Neointimal formation is the main contributor to in-stent restenosis. Stent-induced arterial injury and peri-strut inflammation are involved in the process of neointimal formation by activating cytokines and growth factors which induce smooth muscle cell dedifferentiation, migration, and proliferation. Histopathological studies found that neointimal hyperplasia is principally composed of smooth muscle cells, inflammatory cells, and extracellular matrix. Stent-based delivery of anti-proliferative and/or anti-inflammatory agents have shown beneficial effects on neointimal hyperplasia in experimental studies and clinical trials. Tacrolimus (FK506) is a water-insoluble macrolide immunosuppressant discovered in 1984. It has been widely used in reducing the incidence and severity of allograft rejection after organ transplantation. It has also been used to treat other inflammatory conditions such as atopic dermatitis. In this study, we evaluated the efficacy of stent-based delivery of tacrolimus on inflammation and neointimal formation in an overstretched coronary stent model.

Topics: Animals; Cell Survival; Coated Materials, Biocompatible; Coronary Restenosis; Coronary Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Immunohistochemistry; Immunosuppressive Agents; Male; Paclitaxel; Stents; Swine; Tacrolimus; Tunica Intima

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.. 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 microg/mm(2) coating produced tacrolimus tissue levels of 20 mumol/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 microg/mm(2)) 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.. 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.

Topics: Animals; Blood Vessel Prosthesis; Coated Materials, Biocompatible; Coronary Restenosis; Coronary Vessels; Delayed-Action Preparations; Disease Models, Animal; Graft Occlusion, Vascular; Immunosuppressive Agents; Paclitaxel; Swine; Swine, Miniature; Tacrolimus; Treatment Outcome

To avoid in-stent restenosis, a new technologic approach with "coated" stents may deliver local cytostatic products (sirolimus, paclitaxel, tacrolimus...). At this time, present clinical studies validate the importance of these active coated stents in sub-groups of patients with diabetes, long lesions, small vessels and proximal left anterior descending coronary lesions.

Topics: Coronary Restenosis; Humans; Paclitaxel; Sirolimus; Stents; Tacrolimus

Local delivery of immunosuppressive or antiproliferative agents using a drug-eluting stent is a new technology meant to inhibit in-stent restenosis providing both a biological and mechanical solution and has recently emerged as a very promising approach. Up to now several agents have been in use: Paclitaxel, Rapamycin, Actinomycin D or Tacrolimus. Evaluating these drugs regarding their release kinetics, effective dosage, safety in clinical practice and benefit, several studies have been published or are still ongoing: SCORE (Paclitaxel-derivative), TAXUS I, II, III, IV (Paclitaxel), ELUTE, ASPECT (Paclitaxel), RAVEL, SIRIUS (Sirolimus), ACTION (Actinomycin), EVIDENT, PRESENT (Tacrolimus). Paclitaxel was the first stent-based antiproliferative agent under clinical investigation providing profound inhibition of neointimal thickening, depending on delivery duration and drug dosage. The randomized multicenter SCORE trail (Quanam stent, Paclitaxel coated) enrolled 266 patients at 17 sites. At 6 month follow-up, a drop of 83% in stent restenosis using the drug-eluting stent could be achieved (6.4% drug-eluting stent vs. 36.9% control group) attributable to a remarkable decrease in intimal proliferation. Unfortunately, due to both frequent stent thrombosis and side-branch occlusions the reported 30-day MACE rate was 10.2%. The randomized TAXUS I safety trail (NIRx, Paclitaxel coated) also demonstrated beneficial reduction of restenotic lesions at 6-month FU (0% vs. 11%) but, this time, associated with the absence of thrombotic events presumably due to the lower drug dosage. The ongoing TAXUS II, III and IV trails are aimed at providing additional insight regarding the efficacy of the TAXUS Paclitaxel-eluting stent. Both the RAVEL and the SIRIUS trial have been conducted to evaluate a Sirolimus-coated stent (Bx VELOCITY stent). From the results available, the beneficial findings regarding reduction of renarrowing using a drug-eluting stent have been confirmed without any adverse effects. Although parameters like drug toxicity, optimal drug dosage or delayed endothelial healing need to be further evaluated, summarizing the today's clinical experience the strategy of drug-coated stents promises a striking benefit in interventional treatment of coronary lesions.

Topics: Angiogenesis Inhibitors; Angioplasty, Balloon, Coronary; Animals; Coated Materials, Biocompatible; Coronary Restenosis; Dactinomycin; Drug Delivery Systems; Follow-Up Studies; Humans; Immunosuppressive Agents; Multicenter Studies as Topic; Paclitaxel; Pilot Projects; Protein Synthesis Inhibitors; Randomized Controlled Trials as Topic; Safety; Sirolimus; Stents; Swine; Tacrolimus; Time Factors