Objectives: This study sought to compare the efficacy and safety results after coronary implantation of a combined sirolimus-eluting CD34 antibody coated Combo stent (OrbusNeich Medical, Ft. Lauder...

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The REMEDEE Trial: A Randomized Comparison of a Combination Sirolimus-Eluting Endothelial Progenitor Cell Capture Stent With a Paclitaxel-Eluting Stent

The techniques and materials used during percutaneous coronary intervention have advanced considerably over the past 3 decades, yet restenosis remains one of the major drawbacks of this procedure. Many innovative technologies, including drug-eluting stents, with or without specific polymers, and fully biodegradable stents have been and continue to be developed in the search for a safe and effective antirestenosis therapy. Remarkable advances in stent design and nanoparticle delivery systems ('nanovehicles') have already fueled revolutionary changes in the prevention and treatment of in-stent restenosis. In this Review we provide an overview of the latest innovations for optimizing outcomes of coronary stenting, and up-to-date information about prevention and treatment of in-stent restenosis.

Restenosis after PCI. Part 2: prevention and therapy

Biodegradable stent coatings were recently introduced as a potential solution to overcome sustained inflammatory responses observed with permanent polymer-based drug-eluting stents. In a preliminary study, selected biodegradable or permanent polymer-based sirolimus-eluting stent (SES) formulations were screened for effectiveness in comparison to bare metal stents (BMS) at 28 days. Subsequently, the most favourable SES formulation was compared to commercially available SES (Cypher™) at 28, 90 and 180 days to investigate the histopathologic response as well as tissue, blood and organ pharmacokinetics. Overlapping SES implantation was conducted to evaluate vascular healing at 28 days in this particular setting. SES with biodegradable poly (L-lactide) polymer (PLLA) or poly(lactide-co-glycolide) showed the most favourable outcome with regards to reductions in neointimal area in comparison to BMS at 28 days. The PLLA SES showed a similar reduction in neointimal area compared to Cypher™ at 28 days, with significant greater reductions at 90 and 180 days (1.7 ± 0.7 mm² vs. 3.1 ± 1.5 mm², p=0.03 and 1.8 ± 1.2 mm² vs. 3.0 ± 1.5 mm², p=0.01, respectively). Sirolimus vascular tissue concentrations were detectable up to 90 days following implantation. Overlapping stented segments showed favourable histopathologic results with respect to fibrin deposition and endothelialisation at 28 days. In conclusion, the use of PLLA as drug-eluting matrix resulted in mild inflammatory responses in the presence of effective sirolimus tissue concentrations. The greater efficacy observed at long-term follow-up in PLLA SES compared to Cypher™ may be a multifactorial result of stent design, polymer biocompatibility and improved release kinetics.

Histopathological comparison of biodegradable polymer and permanent polymer based sirolimus eluting stents in a porcine model of coronary stent implantation.

Objectives Dissolution testing is a powerful tool for the characterization of dosage form performance in vitro under standardized conditions. In spite of the increasing number of parenterally administered medicinal products, currently there are no compendial dissolution test methods designed especially for these types of dosage forms. In addition to classical drug delivery systems, drug/device combination products, such as drug-eluting stents, are being used increasingly.

Key findings  This review describes the current methods that are used most often for in-vitro dissolution testing of parenteral dosage forms, i.e. the ‘sample and separate’ methods, the ‘dialysis’ methods, and the ‘flow-through’ methods, with a special emphasis on whether these methods can be used for drug-eluting stent testing. In the light of current regulatory requirements and with the exploding costs of preclinical and clinical development, test systems that include biorelevant parameters and are predictive of in-vivo performance are increasingly important. Published attempts to take biorelevant conditions into consideration in the design of dissolution test apparatus developed for parenteral dosage forms, including a method that was designed to emulate the embedding and flow-conditions at the site of stent implantation, have been outlined in this review.

Summary  In spite of the large quantity of highly potent controlled release parenteral products marketed today, there is still a lack of suitable methods for in vitro dissolution testing for these dosage forms especially with regard to biorelevant testing conditions. For dosage forms implanted into tissues it seems of major importance to reproduce the transport forces which are predominant in vivo (diffusive versus convective) in the in-vitro experimental setup.

In-vitro dissolution methods for controlled release parenterals and their applicability to drug-eluting stent testing.

Aims: Different biodegradable-polymer drug-eluting stents have not yet been systematically analysed. We sought to; 1) evaluate the risk of target lesion revascularisation (TLR) and definite stent thrombosis (DST) among different groups of biodegradable-polymer (BioPol) DES, and 2) to compare them with permanent polymer (PermPol) DES. Methods and results: We searched PubMed and relevant sources from January 2005 until October 2010. Inclusion criteria were (a) Implantation of a drug-eluting stent with biodegradable polymer; (b) available follow-up data for at least one of the clinical end-points (TLR/DST) at short term (30 days) and/or mid-term (one year). A total of 22 studies, including randomised and observational studies, with 8264 patients met the selection criteria; nine studies (2042 patients) in whom biodegradable-polymer sirolimus eluting stents (BioPol-SES) were implanted, eight studies (1731 patients) in whom biodegradable-polymer paclitaxel eluting stents (BioPol-PES) were implanted, and seven studies (4491 patients) in whom biodegradable-polymer biolimus-A9 eluting stents (BioPol-BES) were implanted. At 30 days, there was a higher risk of DST (p=0.04) and subsequently TLR (p=0.006) in the BioPol-BES compared to BioPol-SES, with no significant difference in the other stent comparisons. At 1-year, there was higher risk of TLR in the BioPol-PES (p= 0.01), and the BioPol-SES (p=0.04) compared to BioPol-BES. One-year stent thrombosis was not statistically different between the studied groups (overall p= 0.2). In another analysis comprising seven randomised trials comparing BioPol-DES (3778 patients) and PermPol-DES (3291 patients), the risks of TLR and stent thrombosis at 1-year were not significantly different (p= 0.5 for both). Conclusions: Performance of different BioPol-DES seems to vary from each other. The short- and mid-term success rates may not be superimposable. Furthermore, they may not be necessarily better than PermPol-DES.

Clinical performance of drug-eluting stents with biodegradable polymeric coating : a meta-analysis and systematic review

We have used a series of in vitro and in vivo tests to assess the suitability of two new degradable polymers for application as coatings for drug-eluting stents. The first is a family of urethane-linked multi-block copolymers (MBCP) that comprise blocks of lactide, glycolide, epsilon-caprolactone and/or poly(ethylene glycol) chain-extended with 1,4-butanediisocyanate (SynBiosys polymers). The second is a family of maltodextrin (MD) modified with fatty acid sidechains to yield a hydrophobic polymer (Eureka() SOLO polymers). We coated stainless-steel stents with two representative urethane-linked MBCPs and one hydrophobic MD polymer alone or in combination with the anti-restenotic drug sirolimus. Urethane-linked MBCPs formed uniform coatings on the stent substrates, withstood crimping and expansion on balloon catheters, completely released sirolimus from the coating within 30 days, and degraded within 30-60 days in PBS. The hydrophobic MD polymer formed uniform coatings, exhibited somewhat slower release of sirolimus (approx. 85% within 30 days), degraded within 60 days in PBS when sirolimus was incorporated in the coating, but showed very slow degradation in the absence of drug. We implanted stents coated with urethane-linked MBCPs or hydrophobic MD polymers in a porcine coronary artery model and used histological analysis at 28- and 90-day end-points to assess the biological response to the materials. Measures of stenosis and inflammation for urethane-linked MBCP and hydrophobic MD polymer coatings were not statistically different from bare metal controls at 28 and 90 days, suggesting that the polymers show good vascular biocompatibility. Endothelialization was nearly complete at 28 days and complete at 90 days for all formulations. Urethane-linked MBCP polymer-only and drug-eluting coatings and hydrophobic MD drug-eluting coatings were nearly completely degraded within 90 days in vivo whereas roughly half of hydrophobic MD polymer-only coatings remained after 90 days. Taken together, our in vitro and in vivo results suggest that SynBiosys urethane-linked MBCP and Eureka SOLO hydrophobic MD polymer families possess the physical and chemical properties and vascular biocompatibility necessary for further investigation for use in the next generation of drug-eluting stents.

In vitro and in vivo characterization of novel biodegradable polymers for application as drug-eluting stent coatings.

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In vitro and in vivo characterization of novel biodegradable polymers for application as drug-eluting stent coatings.