The future of drug eluting stents

Abstract

In‐stent restenosis (ISR) is the major drawback of percutaneous coronary interventions, occurring in 10–40% of patients. Drug eluting stents (DES) are successful in a large majority of patients in preventing restenosis for the first year after implantation. Recently, new stents have emerged that are loaded with anti‐inflammatory, antimigratory, antiproliferative, or pro‐healing drugs. These drugs are supposed to inhibit inflammation and neointimal growth and subsequently ISR. The future of DES lies in the development of better stents with new stent designs, better polymers including biological polymers and biological biodissolvable stent coatings, and new, better drugs.

In‐stent restenosis (ISR) is the major drawback of percutaneous coronary interventions, occurring in 10–40% of patients.¹ Drug eluting stents (DES) are successful in a large majority of patients in preventing restenosis for the first year after implantation. Recently, new stents have emerged that are loaded with anti‐inflammatory, antimigratory, antiproliferative, or pro‐healing drugs. These drugs are supposed to inhibit inflammation and neointimal growth and subsequently ISR. One problem with current DES is that as many as 40% of patients receiving DES require very long stented segments to provide adequate coverage. Further, when the coronary tree is excessively tortuous or heavily calcified, delivery of long DES is technically difficult.

Newer stent designs, innovations in drug delivery, and newer drugs are likely to emerge to prevent ISR; however, only limited results with new DES are available. The future of DES lies in innovation of better stents with new stent design, better polymers with the emergence of biological polymers and biological biodissolvable stent coatings, and new, better drugs.

STATUS OF DES

Some DES are effective in preventing ISR, although long term results from large studies are lacking. The longest clinical study follow up period is two years in the case of the RAVEL (randomized study with sirolimus coated BX velocity balloon expandable stent in the treatment of patients with de novo native coronary lesions), SIRIUS (sirolimus eluting balloon expandable stent in the treatment of patients with de novo native coronary artery lesions), and TAXUS‐I (treatment of de novo coronary disease with a single paclitaxel eluting stent) studies. Of interest is that target lesion revascularisation rates do not increase greatly between one and two years of follow up.² In some animal models a delayed healing between 90 and 180 days after implantation has been observed.³ The long term pathobiology of the interference of locally delivered drugs with the complex process that leads to vascular injury associated with stent implantation is uncertain; thus, long term clinical and angiographic follow up is mandatory.

THE FUTURE OF DES

The future of DES lies in the advances and new technology of new stent design, polymer (coating) with emergence of biological polymers and biological biodissolvable stent coating, and new drugs including stent based gene delivery by antibody tethered viruses.

The stent

The ideal DES is flexible and has a good radial strength and a large surface area on which to load one or more drugs. The gaps between the struts have to be small to distribute the drug optimally and equally over the target lesion. Stent material, electrophysiological properties, and biocompatibility of the stent surface also influence neointimal proliferation.⁴

Theoretically, a drug eluting biodegradable stent may be the ideal solution to prevent ISR. The drug can suppress the vessel wall's early response to injury, whereas the stent can prevent elastic recoil and negative remodelling. Eventually, the stent will be degraded over time and chronic vessel wall injury will be prevented. The future of DES will lie in delivery of multiple drugs at timed intervals through newer stent designs.

Conor stent

Conor's stent (Conor Medsystems, Menlo Park, California, USA) design incorporates hundreds of small holes, each acting as a reservoir into which drug‐polymer compositions can be loaded.⁵ This design has the potential to deliver multiple drugs, enhance control of the rate and direction of drug delivery, enable a wider range of drugs, and potentially increase the range of clinical applications of DES.

The design allows for greater control of release kinetics or control over the rate of drug release over time. Since drug release kinetics are controllable by selecting the pattern in which polymers and drugs are loaded into the holes, a wide range of release kinetics can be achieved. Because of Conor's ability to vary the structure of the drug inlay within the reservoirs, it can deliver a broad range of compounds, including fat soluble drugs, water soluble drugs, proteins, peptides, and oligonucleotides. The deep reservoirs provide greater dose capacity than thin surface coatings, allowing more drug to be delivered for a longer time.

Janus Sorin stent

Another design directly blasts the drug on to the stent.⁶ The stent has multiple grooves (reservoirs) on its medial side into which the drug is loaded inside sculptures on the stent's external surface, so there is no need for a polymeric coating. Moreover, the drug load is delivered to the vessel wall without drug loss in the blood stream. The sculpted design reduces the early and late thrombosis risk and is important in the early endothelialisation of the stent; this design also protects the drug during the implantation procedure.

The pharmacokinetics of the tacrolimus eluting Janus stent (Sorin Biomedica, Saluggia, Italy) were evaluated in vivo evaluation. Short and long term pharmacokinetic studies were performed and tissue drug concentration was measured. The tacrolimus concentration in the artery wall peaked a few days after implantation and then declined to steady values over the following weeks. About 50% of the drug was released from the stent one month after implantation and no drug was released into the blood stream. In a porcine model, neointimal proliferation was significantly reduced with the Janus stent.

The JUPITER (Janus tacrolimus‐eluting stent) I study was divided into two phases. In phase I, 30 patients with native de novo coronary lesions were enrolled.⁷ Event‐free survival at one month's follow up was 100%. Phase II of the JUPITER I study was designed to complete phase I (“safety” evaluation). JUPITER II is a double blind randomised clinical trial of the treatment of stenosis of coronary lesions with the Janus Sorin stent involving 331 patients in 16 European centres.

The polymer

Polymer coatings are needed for most drugs because they do not adhere to the metallic stent surface. The polymer coating also modifies drug elution kinetics, which can be varied by using multiple polymer layers to achieve optimal drug release over time. Initially, all biodegradable or non‐biodegradable polymers induced an increased inflammatory reaction and enhanced neointimal proliferation.⁸ Later some polymers were found to be biologically inert and stable for at least six months.⁹,¹⁰

New developments in this area are biocompatible and inorganic coatings. Biocompatible coatings mimic the surface of normal tissue or cells. Phosphorylcholine coating does not interfere with re‐endothelialisation and the degree of neointimal formation and thus is one of the platforms particularly suited for stent based drug delivery.¹¹ Inorganic substances are used to coat stents so as to improve the electromechanical properties. This has to result in reduced platelet activation and inflammatory response. Ceramic stents with nanocavities containing tacrolimus are among the promising new devices under investigation.

Drug eluting poly(ε caprolactone) stent

A perivascular cuff to reduce ISR is constructed of a poly(ε caprolactone) (PCL) formulation suitable for the controlled delivery of drugs.¹² Placing the PCL cuff around the femoral artery in vivo resulted in restenosis‐like lesions containing predominantly smooth muscle actin positive cells. Loading the cuff with the anti‐restenotic compounds paclitaxel and rapamycin resulted in vitro in a sustained and dose dependent release for at least three weeks. Paclitaxel and rapamycin eluting PCL cuffs placed around the femoral artery of mice resulted in reduced intimal thickening at 21 days. Perivascular sustained release of both anti‐restenotic agents is restricted to the cuffed vessel segment with no systemic adverse effects.

Phosphorylcholine coated stents

Phosphorylcholine coated (PC) stents have been approved for the treatment of native coronary arterial lesions.¹³,¹⁴ Several studies have shown the durability and stability of the PC stent surface coating.¹⁵,¹⁶ In experimental models, PC coating of the strut surface has been shown to reduce thrombus formation on metallic stents.¹⁷ The PC coating has been employed as a drug delivery matrix for stent based delivery of the potent antiproliferative compound ABT‐578, which inhibits smooth muscle cell proliferation by blocking the cell cycle regulatory protein mTOR.

Experimental studies have shown that at 28 days the mean injury score for the control, PC, and PC with ABT‐578 coated stents was similar and the mean neointimal area was significantly reduced by ABT‐578 eluting stents. Further studies are necessary to determine the dose response and long term effects. The ENDEAVOR (randomised, controlled trial of the Medtronic Endeavor drug (ABT‐578) eluting coronary stent system versus the Taxus paclitaxel‐eluting coronary stent system in de novo native coronary artery lesions) I, II, and III clinical trials evaluated a PC coated ABT‐578 eluting stent for the prevention of ISR. Angiographic analysis at four months in 100 patients with focal de novo lesion (ENDEAVOR I) showed a mean in‐stent diameter stenosis of about 14% and a late lumen loss of 0.3 mm with a low frequency of target lesion revascularisation (1%).¹⁸ The clinical outcomes from the ENDEAVOR II (1500 patients randomly assigned to ABT‐578 or bare metal stent) and the ENDEAVOR III (436 patients randomly assigned to ABT‐578 or sirolimus DES) trials will determine the efficacy of the PC coated ABT‐578 eluting stent.¹⁹

Biodegradable polymer

Biodegradable polymers are increasingly being used in drug delivery systems, as the body hydrolyses these polymers into low molecular degradation products that are metabolised. Biodegradable delivery systems do not have to be removed after completion of release. In vitro studies showed that biodegradable polymer was highly biocompatible in a porcine coronary artery model and the histopathological evaluation showed only a mild inflammatory response. The extent of ISR of polymer‐only coated stents was comparable with that of bare metal stents.

The EuroSTAR (European collaborators registry on stent‐graft techniques for abdominal aortic aneurysm repair) trial is designed to evaluate the safety, performance, and efficacy of a different stent in de novo native coronary artery lesions with paclitaxel and a bioresorbable polymer matrix poly(dl‐lactide‐co‐glycolide) (PLGA). It is prospective, multicentre, and designed to enrol up to 320 patients. Results for the use of this stent in the treatment of de novo lesions in native coronary arteries are promising.⁶

Amorphous oxide DES

Amorphous oxide has unique chemical and physical properties. Amorphous oxide coating on 316LVM stainless steel wires and heparin loaded on to amorphous oxide of 316LVM stainless steel wire surfaces have been studied.²⁰ Evidence shows that amorphous oxide can be an ideal substitute for the polymer coating of drug loaded stents to minimise metallic corrosion, inflammation, late thrombosis, and restenosis. The feasibility of loading heparin on to an amorphous oxide layer and the efficacy of a heparinised 316LVM stainless steel wire were confirmed by various experimental studies.²⁰

Plasmid DNA eluting biodegradable polymer coated metallic stent

The plasmid DNA in the stent coating mixture is dispersed within microemulsion droplets. This preparation forms a uniform film over the outer surface of the Crown stent (Cordis Cardiology, Miami, Florida, USA) with a thin polymeric web between the struts.²¹ On balloon expansion, deployment of the stent results in stretching of the polymer without fragmentation. Sustained release of DNA from coated stents in vitro is characterised by an early burst of DNA with more than 50% eluted during the first hour of incubation. Seven days later neointimal formation was found to be comparable in arteries stented with and without a DNA polymer stent coating. PLGA coated stents, whether DNA is present or not, show no early (seven days) evidence of inflammatory activity in response to the polymer coating. Further long term studies will be of great importance for future implementation of plasmid DNA eluting stents.

The drug

The drug is the biologically active agent that has to inhibit the formation of neointimal hyperplasia by suppression of platelet activation and of the inflammatory response, and by inhibition of smooth muscle cell migration and proliferation. Ideally, the drug should have an outstanding overall safety profile and a broad therapeutic window. Besides the biological effects, the drug has its own chemical properties that influence achieving optimal tissue concentrations and the possibilities for loading on a stent. Tissue concentrations depend on lipophilic or lipophobic characteristics, molecular weight, and the degree of protein binding of the used drug.²²,²³ Some drugs can be loaded directly on to the metallic surface of the stent, but most drugs need a polymer coating, which forms a reservoir for the drug.

Tyrphostin AGL‐2043 eluting stent

Tyrphostin AGL‐2043 is a potent tricyclic quinoxaline inhibitor of PDGF β receptor tyrosine kinase (protein tyrosine kinase). Selective inhibition of PDGF β receptor protein tyrosine kinase by tyrphostins reduces smooth muscle cell proliferation and migration and reduces neointimal formation. A study was designed to determine the effect of AGL‐2043 delivered from a stent based, biodegradable polymeric coating on neointima formation in the porcine coronary artery model.²⁴ Stents coated with biodegradable PLGA polymer, with or without AGL‐2043, were implanted into the left anterior descending artery of a porcine coronary model. After 28 days, histomorphometric analysis showed that ISR in animals treated with AGL‐2043 was reduced by 50%, absolute neointimal area was reduced by 44%, and absolute luminal area was increased by 57%. Long term studies should be the next step in testing the applicability of this coating in the human interventional setting.

Stent based delivery of adenovirus tissue inhibitor of metalloproteinase‐3

A recent study at Bristol Heart Institute has shown that stent based antiproliferative treatments incorporating adenovirus appear to decrease ISR, express the tissue inhibitor of metalloproteinase‐3 (which inhibits neointima formation), decrease smooth muscle cell migration, stabilise the extracellular matrix, and uniquely promote apoptosis.²⁵

THE FUTURE HAS STARTED

DES have been shown to be beneficial in the treatment of atherosclerotic coronary artery disease; however, the biocompatibility of current synthetic polymer stent coatings that serve as a vehicle for local stent mediated drug delivery remains a concern. Biological coatings based on biological substances such as fibrin, collagen, hyaluronic acid, and biological oils can serve as valid alternative stent coatings. Gene eluting stents, biological biodissolvable stent coating, and bioabsorbable magnesium stents have all been studied with promising results, although more long term and in vivo studies are needed.

Gene eluting stents

The hypothesis that naked plasmid DNA encoding human vascular endothelial growth factor (VEGF) 2 can be delivered locally by gene eluting stents to reduce neointima formation has been tested. Plasmid encoding human VEGF‐2 coated BiodivYsio phosphorylcholine polymer stents have been deployed and compared with uncoated stents in a randomised, blinded fashion in iliac arteries of normocholesterolaemic and hypercholesterolaemic rabbits.²⁶ Re‐endothelialisation was nearly complete in the VEGF stent group after 10 days and was significantly greater than in control stents. At three months, intravascular ultrasound analysis showed that the lumen cross sectional area was significantly greater and the percentage cross sectional narrowing was significantly lower in VEGF stents than in control stents. Acceleration of re‐endothelialisation by VEGF‐2 gene eluting stents provides an alternative treatment strategy for the prevention of restenosis. VEGF‐2 gene eluting stents may be considered for stand alone or combination treatment. More extensive studies with long term follow up are essential.

Biological biodissolvable stent coating (Ziscoat)

Ziscoat and Lubbeek (personal communication, 2005) have studied the biocompatibility of biological oil based stent coatings in a porcine coronary model. At five days mural thrombus formation and inflammatory response were comparable in bare stents. At four weeks' follow up, the stented arterial segments were completely healed and the inflammation score was even slightly lower in the coated stent group than in the bare stent group. Neointimal hyperplasia at that time was similar in the coated stent group and the bare stent group. Results suggest a very good short term outcome of these totally biosoluble biological oil based stent coatings, although long term follow up is needed. These coatings are very interesting to use for stent mediated local drug delivery.

Bioabsorbable magnesium stent

Stenting technology has moved towards the development of temporary implants composed of biocompatible materials that mechanically support the vessel during the period of high risk of recoil and then completely biodegrade later. Degradable implants offer better physiological repair and reconstitution of local vascular compliance. This stent has a better radial straightening effect and higher possibility of late positive remodelling. Experimental data have shown promising results with magnesium in ischaemia reperfusion injury, both in reducing infarct size and in reversing myocardial stunning. Preliminary data three months after implantation of a bioabsorbable magnesium stent show a primary clinical patency of nearly 90%.²⁷ Preclinical work has shown that absorbable metal stents based on magnesium offer a real possibility of improving both acute and long term results of percutaneous coronary revascularisation.

CONCLUSION

While several drugs have been tested in animal models and human trials, the recent advances of DES have concerned the reduction and prevention of ISR. As efficacy and safety of DES differ depending on the drug and stent delivery system, recent studies have focused on the various constituents of DES, including the stent backbone, polymers used for drug delivery, and the pharmacokinetic properties of the pharmacological agents themselves. Although an altered stent surface may be able to carry drugs, the most difficult questions are how much drug should be used, how uniformly it should be distributed, and over what period the drug should be delivered. While the mid term clinical results with sirolimus and paclitaxel eluting stents are promising, post‐DES restenosis remains a concern. In the case of sirolimus eluting stents up to 5% of patients require a repeat revascularisation. Subacute thrombosis, hypersensitivity reactions to sirolimus eluting stents, drug resistance to sirolimus, and paclitaxel and aneurysmal dilatation of the stented segment have been reported. With more understanding of restenosis mechanisms, new treatments with high potency and less toxic effects are under evaluation to overcome these remaining problems.

The future lies in delivery of multiple drugs at timed intervals through new stent designs (the Conor stent has the potential to deliver multiple drugs and the Janus Sorin stent has reservoirs for drug delivery with no polymer). The advantages of biodegradable polymers include high drug loading capacity, controlled long term drug release, and full degradation of the polymer over a certain time resulting in full release of the drug during a well controlled time interval. Gene eluting stents are undergoing experimental and clinical trials and we expect that gene eluting stents alone or in conjunction with other DES will be available in the near future with a lower ISR rate. In the future, DES may be used for the prevention of acute coronary syndrome (through the plaque sealing concept). It is believed that acute coronary syndrome is caused by unstable plaques of mild to moderate stenosis (< 50%) that do not result in angina symptoms.²⁸ Given the high event‐free survival rate achieved with DES, one could argue for treating these lesions with stents. The effect of DES on other difficult lesions such as left main coronary artery disease, bifurcation disease, and chronic total occlusions is under investigation. However, it is important to keep in mind that the efficacy of DES is based on avoiding recurrent angina and additional revascularisation procedures. With the recent development of DES an even more spectacular evolution is taking place that will forever change the landscape of interventional cardiology.

Abbreviations

DES - drug eluting stents

ENDEAVOR - randomised, controlled trial of the Medtronic Endeavor drug (ABT‐578) eluting coronary stent system versus the Taxus paclitaxel‐eluting coronary stent system in de novo native coronary artery lesions

EuroSTAR - European collaborators registry on stent‐graft techniques for abdominal aortic aneurysm repair

ISR - in‐stent restenosis

PC - phosphorylcholine coated

PCL - poly(ε caprolactone)

PLGA - poly(dl‐lactide‐co‐glycolide)

RAVEL - randomized study with sirolimus coated BX velocity balloon expandable stent in the treatment of patients with de novo native coronary lesions

SIRIUS - sirolimus eluting balloon expandable stent in the treatment of patients with de novo native coronary artery lesions

TAXUS - treatment of de novo coronary disease with a single paclitaxel eluting stent

VEGF‐2 - vascular endothelial growth factor 2