Biolimus A9 Research Articles

TCT-625 Three Year Follow up of a Randomized Comparison of Nobori, Biolimus A9 Eluting Stent(BES) with Cypher, Sirolimus Eluting Stent(SES) for Coronary Revascularization in Japanese Population

Nobori stent (Terumo Co., Tokyo Japan), is the new concept Drug Eluting Stent which has unique bioabsorbable polymer (Poly-Lactic Acid) and the anti-proliferative agent Biolimus A9. We investigated the safety and the efficacy of Nobori stent comparing to Cypher stent in Japanese population by a

VERY LONG-TERM (1 AND 2-YEAR) COMPARISON OF BIORESORBABLE VS. PERMANENT POLYMER LIMUS-ELUTING STENTS IN A PORCINE CORONARY ARTERY MODEL

A Biolimus A9 self-expandable nitinol stent (BA9SES) stent was engineered with a permanent primer layer consisting of parylene and a bioabsorbable abluminal layer of polylactic acid (PLA) and Biolimus A9 (∼22 μg/mm of stent length), in contrast to the permanent polymer-based, sirolimus-

Favorable pharmacokinetics of biolimus A9 after deployment of Nobori stent for coronary artery disease: insights from Nobori PK study in Japanese subjects

The Nobori stent is a new drug-eluting stent (DES) with biodegradable polymer coating limited to the abluminal side of stents. Biolimus A9 is a novel sirolimus derivative specifically developed for DES, and polymer load 15.6 μg of biolimus A9 per 1 mm of stent. A non-randomized multicenter trial was conducted in Japan. Twenty-two de novo lesions were treated by Nobori stents and biolimus A9 concentration in whole blood was serially measured at 14 predetermined time points using a validated chromatography-tandem mass spectrometry (LC-MS/MS) assay. The C max was 85.3 ± 37.9 pg/mL (min-max 46.7-169 pg/mL) in the 18 mm cohort and 198 ± 81 pg/mL (min-max 82.5-365 pg/mL) in the ≥ 28 mm cohort and no early or late bursts of biolimus A9 release were documented. After 4 weeks, no measurable concentration of biolimus A9 was observed in any patient. Estimated AUC0-t was 1.12 ± 1.16 ng/mL h in the 18 mm group, and 5.93 ± 4.41 ng/mL h for the ≥ 28 mm group. A significant association between loaded biolimus A9 dose adjusted by patient weight and pharmacokinetic parameters was observed. The systemic exposure of biolimus A9 eluting from the Nobori stent was low and proportional to the loaded amount of biolimus A9, and clearance from the blood was rapid. These findings suggest that the Nobori stent is feasible and safe. Systemic lower exposure of biolimus A9 after Nobori stent implantation may have beneficial effects on stent endothelialization.

In vivo comparison of a polymer‐free Biolimus A9‐eluting stent with a biodegradable polymer‐based Biolimus A9 eluting stent and a bare metal stent in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries

To evaluate the effect of a polymer-free Biolimus A9-eluting stent [BioFreedom (BF)], compared with that of a biodegradable polymer-based Biolimus A9-eluting stent [BioMatrix Flex (BMF)] and a bare metal stent (BMS) in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries. Rabbits were fed with 1% cholesterol diet (n = 14) for 14 days, both iliac arteries were balloon denuded and radiated, and then rabbits were switched to 0.15% cholesterol diet. After 4 weeks, BF (n = 8), BMF (n = 8), and BMS (n = 8) were deployed in denuded and radiated areas. Four weeks later animals were euthanized, arterial segments were processed for morphometry. The neointimal area in vessels implanted with BF stents was significantly less than that seen in vessels implanted with BMS (0.90 mm(2) ± 0.14 vs. 1.29 mm(2) ± 0.23, P <0.01). Percent fibrin and fibrin score were higher with BMF stents compared to BMS (P <0.03 and <0.04) and giant cell number was significantly higher with both BMF and BF stents (P < 0.01 for both). Percent endothelialization was significantly higher and % uncovered struts were lower with BMS compared to either BMF or BF stents (P < 0.05 for both). This study demonstrates that compared to BMS, BF stents significantly decreased neointimal hyperplasia.

Comparison of pharmacokinetics of the limus‐eluting stents in Japanese patients

The aim of this study was to compare the pharmacokinetics of the four limus-eluting stents used in Japanese patients. There are presently no reports comparing human pharmacokinetics among drug-eluting stents (DESs). We retrospectively analyzed data from pharmacokinetic studies of patients implanted with an 18-mm DES: Cypher stent (sirolimus, n = 10), Endeavor stent (zotarolimus, n = 7), Xience V stent (everolimus, n = 6), and Nobori stent (biolimus A9, n = 10), in multicenter trials of Japan. Total drug doses of the Cypher stent, Endeavor stent, Xience V stent, and Nobori stent were 150, 180, 88, and 293 μg, respectively. Drug concentrations were measured in serial whole blood samples after implantation and the pharmacokinetics were analyzed. Mean peak drug levels were 0.86 ng mL(-1) for Cypher, 1.80 ng mL(-1) for Endeavor, 0.50 ng mL(-1) for Xience V, and 0.09 ng mL(-1) for Nobori. After adjustment for the loaded dose, mean peak drug levels of the Cypher and Xience V stents were similar (0.0057 ng mL(-1) μg(-1) each) while the Endeavor (0.0100 ng mL(-1) μg(-1)) was higher, and the Nobori (0.0003 ng mL(-1) μg(-1)) was lower, compared with the Cypher and Xience V stents. The other pharmacokinetic parameters of four DESs differed according to characteristics of the coated drug. The systemic exposure of biolimus A9 was much lower than that of the other DESs studied. In Japanese patients, systemic exposure was low, regardless of the type of limus drug eluted from the stents; but specific pharmacokinetic activities were varied according to the drug characteristics, concentration, and DES design.

TCT-48: Very Long Term Clinical Outcomes of Patients with Coronary Bifurcation Lesions Treated with the Biolimus A9 Coated Dedicated Axxess Stent: Results from the Prospective, Multicenter AXXESS Plus Trial (Final Report of the Study)

TCT-48: Very Long Term Clinical Outcomes of Patients with Coronary Bifurcation Lesions Treated with the Biolimus A9 Coated Dedicated Axxess Stent: Results from the Prospective, Multicenter AXXESS Plus Trial (Final Report of the Study)

Randomized comparison of the nobori biolimus A9‐eluting stent with the sirolimus‐eluting stent in patients with stenosis in native coronary arteries

The aim of this randomized-controlled trial is to compare biolimus A9-eluting stent (Nobori) to sirolimus eluting stent (Cypher). The Nobori coronary stent is coated only abluminally with a biodegradable polymer, poly-lactic acid, and the antiproliferative agent biolimus A9. This stent has been studied in randomized trials versus Taxus Express and Taxus Liberte and showed noninferiority and superiority for in-stent late loss. This is the first randomized trial of Nobori stent versus Cypher stent. We conducted a randomized (3:2), controlled trial comparing Nobori and Cypher, in 335 patients (198 Nobori and 137 Cypher) at 15 centers in Japan. Patients with de-novo lesions in up to two native coronary arteries were considered for enrollment. The primary endpoint was freedom from target vessel failure (TVF), a composite of cardiac death, myocardial infarction, and target vessel revascularization at 9 months. At 9 months, the primary endpoint of freedom from TVF was 92.6% in Nobori and 93.8% in Cypher arm (noninferiority test P < 0.001). As main secondary endpoints, the in-stent late loss was 0.12 ± 0.30 mm and 0.14 ± 0.34 mm in Nobori and Cypher stents, respectively. Target lesion revascularization was 0.5% in Nobori and 3.9% in Cypher treated patients (P = 0.04). Definite and probable stent thromboses were not recorded in any patient. Despite the relatively small number of patients, this well controlled clinical trial confirmed the primary hypothesis of non-inferiority of the Nobori biolimus A9-eluting stent to the Cypher sirolimus-eluting stent for freedom from TVF. Both stents showed excellent midterm results.

Randomized, Double-Blind, Placebo-Controlled, Single Intravenous Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of the Novel Coronary Smooth Muscle Cell Proliferation Inhibitor Biolimus A9 in Healthy Individuals

Biolimus A9 (BA9) is a novel proliferation inhibitor of coronary smooth muscle cells that has been specifically designed for coating drug-eluting stents. The goals of this study were to identify the highest safe intravenous dose of BA9, to evaluate the dose-dependent pharmacokinetics of BA9 after intravenous administration in humans, and to characterize early clinical symptoms of BA9 toxicity in healthy subjects. This phase 1 trial in healthy subjects was designed as a double-blind, placebo-controlled, randomized, ascending single-dose study. After screening and randomization, 28 volunteers received either placebo (n = 7) or BA9 (n = 21) in a double-blinded fashion. Doses from 0.0075 mg/kg were escalated to 0.25 mg/kg in 4 cohorts. BA9 concentrations were measured using liquid chromatography-tandem mass spectrometry. BA9 doses up to 0.075 mg/kg were well tolerated. Only the highest BA9 dose of 0.25 mg/kg produced reversible drug-related adverse events. The most frequent adverse events were headache, nausea, and mouth ulcers, most likely due to immunosuppression. Exposure to BA9 did not result in electrocardiographic or clinical laboratory changes. BA9 had a terminal half-life of 90.0 ± 40.0 hours (all n = 21, mean ± standard deviation), an apparent clearance from blood of 0.96 ± 1.07 L/kg/h, and a volume of distribution of 96.5 ± 72.6 L/kg.

Clinical Studies with Sirolimus, Zotarolimus, Everolimus and Biolimus A9 Drug- Eluting Stent Systems

The introduction of the drug-eluting stent (DES) has revolutionized the field of interventional cardiology during the past decade. Initial pivotal randomized clinical trials showed a large reduction in restenosis rates and the need for repeat intervention with DES compared with bare-metal stents. The three main components of a DES are 1) the stent platform, 2) a coating facilitating elution of the drug (mostly a polymer), and 3) a antiproliferative/anti-inflammatory drug. Currently, two classes of drugs are widely used in DES, Taxanes, including its best-known member Paclitaxel, and Rapamycins, which include Sirolimus and its analogues such as Everolimus, Zotarolimus and Biolimus A9. The first DES to receive United States Food and Drug Administration approval was the Sirolimus-eluting stent. Recently, two other stent types eluting a Sirolimus-analogue were approved; the Zotarolimus-eluting stent and the Everolimus-eluting stent. Biolimus A9-eluting stents, using biodegradable polymers, are currently approved and marketed outside of the United States. This review article focusses on the clinical studies that have been performed with DES eluting Sirolimus or its analogues.

The pharmacokinetics of Biolimus A9 after elution from the BioMatrix II stent in patients with coronary artery disease: The Stealth PK Study

This prospective, open-label multicenter study was conducted to assess the pharmacokinetics of Biolimus A9 after elution from BioMatrix II coronary stents. Recent clinical trials have demonstrated the efficacy and safety of Biolimus A9 eluted from different stent platforms. To date, the pharmacokinetics of Biolimus A9 in patients following the deployment of BioMatrix II stents has not yet been studied BioMatrix II stents were implanted into 27 patients with coronary artery disease. The primary endpoints of the study were the systemic concentrations of Biolimus A9 after 28 days and 6 months as measured using a sensitive validated liquid chromatography-tandem mass spectrometry assay. The highest measured blood concentration at any time point was 394 pg/mL. At 28 days and 6 months following stent placement, 51.8 and 100% of patients, respectively, had Biolimus A9 concentrations <10 pg/mL. After 9 months, 100% of the patients were free of major cardiac adverse events (MACE). There was no Biolimus A9 toxicity, no cardiac or non-cardiac deaths, no myocardial infarctions, nor target vessel or target lesion revascularizations during the 9 months of follow-up. No case of acute, subacute, or late stent thrombosis was detected. Compared to other drug-eluting stents, such as Cypher, BioMatrix II results in relatively low systemic exposure, which may be explained by the ablominal coating of the Biomatrix II stent in combination with Biolimus A9's high lipophilicity.

TCT-243: Two Years Follow Up of a Randomized Comparison of Nobori Biolimus A9 Eluting Stent with Cypher Sirolimus Eluting Stent for Coronary Revascularization in Japanese Population

TCT-243: Two Years Follow Up of a Randomized Comparison of Nobori Biolimus A9 Eluting Stent with Cypher Sirolimus Eluting Stent for Coronary Revascularization in Japanese Population

102 Clinical outcome in patients treated with Nobori, a new generation drug eluting stents in a real life setting: Abstract 102 Table 1

Purpose The use of drug eluting stents (DES) in every day clinical practice is not restricted to approved indications. The safety of this approach is not fully established. Therefore we initiated a large study to assess, in a real life setting, the usage practice and outcomes of patients treated with Nobori®, a new generation DES, coated only abluminally with a matrix of biodegradable polymer and Biolimus A9. Methods As a part of the large NOBORI 2 study, one thousand consecutive patients treated with Nobori DES are enrolled in 125 centres across Europe and Asia. Patients were stratified in two pre-specified groups according to the risk factors and lesion characteristics. On-label, group 1 comprised patients with characteristics similar to pre-approval clinical trials; Off-label, group 2 was composed of patients with a higher complexity, which would be excluded from those trials. Primary endpoint was Target Lesion Failure (TLF), a composite of cardiac death, MI and target lesion revascularization (TLR) at 6 and 12 months, while secondary endpoints included Target Vessel Failure (TVF), stent thrombosis, death/MI, TLR, at 1, 6 and 12 months, 2, 3, 4 and 5 years. Data are entered in an electronic database and extensive on site and 100% on line monitoring for all patients are performed. Clinical events are adjudicated by an independent clinical event committee and all baseline angiograms are analysed by independent corelab. Results In this, real-world population, 68% of patients (n=680) were treated for off-label indications. The most frequent off label use was acute myocardial infarction (37%), bifurcation stenting (26%), restenosis (8.4%), CTO (4.2%) and SVG (3.5%). Patients with off label indications had significantly more lesions treated (1.6 vs 1.1; p 20 mm (52% vs 33% p Conclusion Preliminary results of this large multicentre registry confirm excellent safety and efficacy profile of the Nobori stent in both groups of patients. Long term follow-up data for a large patient population as in this study, will better determine safety of current practice with this particular device.

Polymer-Free Biolimus A9-Coated Stent Demonstrates More Sustained Intimal Inhibition, Improved Healing, and Reduced Inflammation Compared With a Polymer-Coated Sirolimus-Eluting Cypher Stent in a Porcine Model

Drug-eluting stents effectively reduce restenosis but may increase late thrombosis and delayed restenosis. Persistent polymer, the drug, or a combination of both could be responsible. Local delivery of Biolimus A9, a rapamycin derivative, from a polymer-free BioFreedom stent (Biosensors International) may prevent these complications. We compared high-dose (HD) (225 microg/14 mm Biolimus A9) and low-dose (LD) (112 microg/14 mm Biolimus A9) BioFreedom stents with a polymer-coated sirolimus-eluting Cypher stent (SES) and a bare-metal stent (BMS) at 28 days and 180 days in an overstretch coronary mini-swine model with histomorphometric and histological analysis. At 28 days, there was a reduction in neointimal proliferation by HD, LD, and SES compared with BMS (neointimal thickness: HD, 0.080+/-0.032; LD, 0.085+/-0.038; SES, 0.064+/-0.037; BMS, 0.19+/-0.111 mm; P<0.001; BMS > HD/LD/SES). At 180 days, both BioFreedom stents were associated with reduced neointimal proliferation, whereas SES exhibited increased neointima (neointimal thickness: HD, 0.12+/-0.034; LD, 0.10+/-0.040; SES, 0.20+/-0.111; BMS, 0.17+/-0.099 mm; P<0.001; SES > HD/LD; BMS > LD). At 180 days, BioFreedom stents showed decreased fibrin and inflammation, including granuloma and giant cells, compared with SES. The polymer-free Biolimus A9-coated stent demonstrates equivalent early and superior late reduction of intimal proliferation compared with SES in a porcine model. After implantation of BioFreedom stent, delayed arterial healing was minimal, and there was no increased inflammation at 180 days compared with SES implantation. The use of polymer-free stents may have a potential long-term benefit over traditional polymeric-coated drug-eluting stents.

TCT-487: Sustained Long-Term (1-Year) Structural Integrity and Biocompatibility of Biolimus A9 Eluting Self Expandable Designated Bifurcation Stent in a Porcine Coronary Model: Comparison to Overlapping Cypher Stents

TCT-487: Sustained Long-Term (1-Year) Structural Integrity and Biocompatibility of Biolimus A9 Eluting Self Expandable Designated Bifurcation Stent in a Porcine Coronary Model: Comparison to Overlapping Cypher Stents

TCT-393: Five-year Clinical Results of the Biolimus A9 Eluting Stent with Biodegradable Polymer

TCT-393: Five-year Clinical Results of the Biolimus A9 Eluting Stent with Biodegradable Polymer

TCT-483: Long-Term (1-Year) Biocompatibility of the Abluminally Coated Biolimus A9 Eluting Self Expandable Stent in a Porcine Coronary Artery Model

TCT-483: Long-Term (1-Year) Biocompatibility of the Abluminally Coated Biolimus A9 Eluting Self Expandable Stent in a Porcine Coronary Artery Model

Development and validation of a semi-automated assay for the highly sensitive quantification of Biolimus A9 in human whole blood using high-performance liquid chromatography–tandem mass spectrometry

Drug-eluting stents are sustained-release intra-coronary devices that are usually coated with a few hundred micrograms of drug. Measuring the drugs that are released over weeks in order to assess human pharmacokinetics is a challenge that requires assays with high sensitivity. We developed and validated a semi-automated LC–MS/MS assay for the quantification of Biolimus A9, a proliferation signal inhibitor that was specifically developed for coating on drug-eluting stents in human EDTA blood. The only manual step was the addition of a zinc sulfate/methanol protein precipitation solution which included the internal standard. Samples were injected into the HPLC and extracted online. The assay had the following performance characteristics: range of reliable response 0.01–100 ng/mL ( r 2 > 0.99), inter-day accuracy (0.033 ng/mL): 111.7%, and inter-day precision: 8.6%. There was no ion suppression, matrix interferences or carry-over. Extracted samples were stable in the autosampler at +4 °C for at least 24 h and could undergo three freeze–thaw cycles. The assay, with a lower limit of detection of 333 fg/mL and a lower limit of quantitation of 10 pg/mL, was sufficiently sensitive and robust for quantifying Biolimus A9 in clinical trials after IV injection and after stent implantation.

Randomized Comparison of the Nobori Biolimus A9-Eluting Coronary Stent With the Taxus Liberté Paclitaxel-Eluting Coronary Stent in Patients With Stenosis in Native Coronary Arteries

The newly developed Nobori coronary stent coated with a bioresorbable polymer, polylactic acid, and the antiproliferative agent Biolimus A9 has the potential to reduce restenosis by suppressing neointima formation. We conducted a randomized (2:1), controlled trial comparing the Biolimus A9-eluting stent Nobori and the paclitaxel-eluting stent Taxus Liberté, in 243 patients (153 Nobori and 90 Taxus) at 29 centers in Europe, Asia, and Australia. Patients with previously untreated lesions in up to 2 native coronary arteries were considered for enrollment. The primary end point was in-stent late loss at 9 months, whereas secondary end points included other quantitative coronary angiography parameters, such as in-segment late loss and the rate of restenosis as well as key intravascular ultrasound parameters. Clinical secondary end points were stent thrombosis and composite of major adverse cardiac events comprising death, myocardial infarction, and target vessel revascularization. At 9 months, the in-stent late loss was significantly lower in the Nobori group compared with the Taxus group (0.11+/-0.30 mm versus 0.32+/-0.50 mm) reaching both the primary hypothesis of noninferiority of Nobori stent versus Taxus Liberté stent (P<0.001) and the secondary hypothesis of superiority (P=0.001). This finding was confirmed by a significant reduction in binary restenosis from 6.2% in Taxus to 0.7% in Nobori (P=0.02) and neointimal volume obstruction, detected by intravascular ultrasound, from 5.5+/-7.2% in Taxus to 1.8+/-5.2% in Nobori (P=0.01). The major adverse cardiac events rate was 4.6% in the Nobori and 5.6% in the Taxus cohort of patients. The stent thrombosis rate was 0% in the Nobori arm and 4.4% in the Taxus arm. The NOBORI 1 clinical trial confirmed its primary hypothesis--noninferiority of the Nobori Biolimus A9-eluting stent versus the Taxus Liberté stent in reducing neointimal proliferation. Both stents showed a low major adverse cardiac events rate in the studied population.

Letter by Brugaletta et al Regarding Article, “Interference of Drug-Eluting Stents and Endothelium-Dependent Coronary Vasomotion: Evidence for Device-Specific Responses”

To the Editor: We read with interest the article by Hamilos et al,1 demonstrating a variable endothelium-dependent coronary vasomotor response at coronary segments adjacent to different drug-eluting stents (DES) and bare metal stents. In particular, a better coronary vasodilatation induced by pacing was observed in patients receiving zotarolimus-eluting or biolimus A9–eluting stents when compared with patients receiving paclitaxel- or sirolimus-eluting stents. As discussed by the authors, endothelial dysfunction after first-generation DES may be induced by the effect of the drug, its release kinetics, the proinflammatory effect of the polymer, or the combination of these factors. However, before drawing easy conclusions, several …

In vivo evaluation of a biolimus eluting nickel titanium self expanding stent with overlapping balloon expandable drug eluting and bare metal stents in a porcine coronary model

Long lesions and complex vessel anatomy frequently require the use of overlapping stents to treat a lesion. The purpose of this study was to evaluate the long-term effects of overlapping the Axxess Biolimus A9 eluting stent (BES) with two of the most commonly used, commercially available drug eluting stents. These stents were compared to BxVelocity bare metal (BMS) stents in a porcine coronary stent-injury model. Nineteen juvenile farm swine, 25-35 kg in weight, 3-6 months in age were utilised. Each animal received an Axxess stent to their coronary artery as permitted by the individual animal's anatomy. A second stent, either a Cypher, sirolimus eluting stent (SES) or, a Taxus, paclitaxel eluting stent (PES), or a BxVelocity bare metal stent (BMS) were implanted in an overlapped fashion. The animals were then followed for either 28 or 180 days as specified by a randomisation scheme. At the end of each follow-up period, they were euthenised, and the vessels containing the overlapping stents were harvested, processed into histological sections, and analysed. Compared to bare metal stents, overlapped segments using DES exhibited delayed vascular healing compared to both the proximal and distal non-overlap sites at each of the follow-up time point. Overall, in the non-overlap stent segments, SES induced significantly more inflammation and neointimal hyperplasia compared to PES and BMS. In this study of BMS and two different types of DES overlapped with the Axxess Biolimus A9 eluting stent, we found that while there was a delay in the degree of vascular healing with DES compared to BMS, the specific type of DES that was overlapped with BES did not affect the behaviour of the overlap zone in terms of most of the histomorphometric measures at 28 or 180 days. This was true whether the stent was drug eluting or bare metal. More inflammation with delayed healing was seen in the SES compared to PES and BMS.