Current Pharmaceutical Design - Volume 16, Issue 36, 2010

Coronary stent implantation has become a well-established therapy in the management of coronary artery disease. Although the STRESS (Stent Restenosis Study) and BENESTENT (Belgium-Netherlands Stent) trials demonstrated convincingly that stenting is superior to PTCA with respect to restenosis in de novo lesions, there is however a still high incidence (10 to 50%) of restenosis following stent implantation depending on lesion and patient characteristics. Improvements in stent design and implantation techniques resulted in an increase in the use of coronary stents and today in most centers in USA and Europe stenting has become the predominant form of nonsurgical revascularization and accounts for about 90% of all procedures. Coronary stents provide luminal scaffolding that virtually eliminates elastic recoil and remodeling. Stents, however, do not decrease neointimal hyperplasia and in fact lead to an increase in the proliferative component of restenosis. Agents that inhibit cell-cycle progression indirectly have also have been tested as inhibitors of vascular proliferation. Sirolimus (Rapamune, Rapamycin), a macrolide antibiotic with immunosuppressive properties and its analogues, Paclitaxel (Taxol) inhibit neointimal formation in animal models when loaded onto coated stents. Preliminary clinical studies with drug eluting stents (DES) produced dramatic results eventually eliminating restenosis in large and midsize arteries. This was later confirmed in large randomized clinical trials and demonstrated the benefit of DES in patients with a high risk for restenosis. There is no doubt that DES dramatically reduces the rate of angiographic restenosis and the clinical need for repeat revascularization procedures. DES enables cardiologists to perform procedures in complex lesions, in which surgery would have been the only option before the advent of DES. However, so far no beneficial effect on death and re-infarction was observed in any of the randomized clinical trials. There are still concerns regarding an increase in the rate of late stent thrombosis. Certainly DES technology is a definitive step forward to optimize the results of PCI. However, before we can recommend a DES for every patient, the long-term safety and efficacy issues have to be solved. In this issue, a multidisciplinary team of international experts discuss all the most relevant topics on stent-based treatment techniques including polymer coating designs [1], mechanism of action of different pharmaceuticals on restenosis [2,3] comprehensive reviews of major clinical studies [4,5], new stents for vulnerable plague [6], next generation DES developments including biodegradable and bioabsorbable stents [7], discussion of duration of dual antiplatelet therapy [8] alongside with pathobiology of stent thrombosis [9].

Currently approved drug eluting stents (DES) consist of a metallic scaffold and an elutable drug dispersed in a polymer matrix that conformally surrounds the struts. These primarily biostable polymers bind the drug to the stent and modulate the elution of the drug into the arterial tissue. This chapter summarizes the key requirements for polymers used in the DES, including physical properties, stability, compatibility with drugs, biocompatibility with vascular tissue and control of drug release. An in-depth analysis of polymer structure, coating design, drug-polymer morphology and drug elution profile is provided for the four currently marketed DES: CYPHER® Sirolimus- eluting Coronary Stent, Taxus® / Taxus Liberte®, XIENCE V™ / Promus® and Endeavor®. A new generation of DES is being developed using bioabsorbable polymers which degrade over time and leave behind a bare metal stent. This includes the RES TECHNOLOGY™ platform employed in the NEVO™ Sirolimus-eluting Coronary Stent which is explored with respect to polymer composition, degradation profile and drug release kinetics.

Coronary artery disease is commonly characterized by atherosclerotic obstruction of vessels responsible for providing adequate blood supply to the myocardium. Disruption of atheromatous plaques can promote thrombosis, significant reductions in cardiac perfusion, and devastating acute (i.e, death) or chronic (i.e., congestive heart failure) consequences. Minimally invasive, catheter-based techniques have been implemented throughout the past three decades and include balloon angioplasty and stent implantation, to alleviate occlusive plaque burden in coronary vessels. Yet, these techniques have not come without complication, namely the tendency for vessels to re-occlude, or undergo restenosis. This manifestation is characterized by acute physical and longer-lasting cellular/biochemical components. To maximize clinical effectiveness, researchers and clinicians have exploited recognition that use of a rigid bare metal stent bound to a drug-bearing polymer, or so-called drug-eluting stent (DES), is best to combat the mechanical and biological contributors to restenosis. In this report, we review restenosis factors in detail, the corresponding rationale for drug choice for DES, and the results of trials conducted with such DES agents. Particular emphasis is given to paclitaxel, a natural compound included in a first-generation DES (Taxus® Express2®) made available for clinical use by Boston Scientific Corporation. We use paclitaxel as a model to illustrate alternatives for drug delivery to coronary vessels, broad concerns about DES use in the context of disease backgrounds, such as diabetes, and suggestions related to the continuing evolution of DES.

Sirolimus (rapamycin), a macrolide antibiotic approved for use as an immunosuppressive agent in the prevention of organ rejection, is a cell proliferation inhibitor and regulator of the immune response which acts through inhibition of TOR (target of rapamycin), a kinase essential to cell cycle progression. Recent studies suggest that the TOR pathway is critical to overall cell function, and at a basic mechanistic level, may be a regulator and potential therapeutic target involved in many of the major (and minor) disorders seen in man today. Cardiovascular diseases including restenosis following percutaneous coronary intervention as well as the more widespread condition of atherosclerosis, share this common involvement of TOR. The present report addresses the current state of intervention in cardiovascular disorders with Sirolimus and similar inhibitors of TOR, including the rationale for this approach and the successes observed to date. Success of the first drug-eluting stent to locally treat restenosis in the clinic is discussed, as are preclinical studies addressing a role in overall atherosclerosis in animal models. In addition, due to the known toxicities when given systemically, an approach for targeted delivery to local areas of vascular disease is discussed.

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 Everolimuseluting 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.

Coronary artery stents mechanically buttress the arterial wall and prevent negative remodeling, leading to increased lumen gain and less angiographic and clinical restenosis when compared to balloon angioplasty alone. Although stents prevent negative remodeling, they do not eliminate restenosis, as they cause complex arterial injury, triggering responses that culminate in the induction of neointimal hyperplasia. For many years after the development of balloon angioplasty and stenting, many unsuccessful attempts were made to find methods to prevent neointimal hyperplasia. In 1995, Sollott and colleagues were the first to recognize the ability of the antineoplastic compound paclitaxel to limit neointimal hyperplasia formation. In 1997, Axel and colleagues were the first to demonstrate that paclitaxel locally delivered to the artery wall limited neointimal hyperplasia in an animal model. After success in preclinical and human trials, the FDA approved the use of paclitaxel-eluting coronary stents in 2004 on the strength of the pivotal TAXUS trials, which demonstrated that stents utilizing a polymer coating as a paclitaxel delivery vector were effective in the prevention of restenosis. Subsequent trials have confirmed the effectiveness of paclitaxel in restenosis prevention. In these trials, paclitaxel was delivered using both polymer-coated stents and stents directly impregnated with drug, and on different stent platforms by different manufacturers. Paclitaxel- eluting stents have been shown to be effective in a variety of cardiovascular lesion and patient subsets in randomized trial and registry data sets. Although there are concerns that locally delivered paclitaxel and/or its polymer delivery vehicle may lead to impaired vascular healing that may predispose to the development of stent thrombosis, pooled data analyses have confirmed an acceptable safety profile for paclitaxel-eluting coronary stents. The current generation of paclitaxel eluting stents have distinctly different performance profiles when compared to first generation and second generation coronary stents eluting sirolimus or related compounds, especially in regard to target lesion revascularization rates. However, whether these differences translate into clinically relevant benefits remains debatable. In addition, newer paclitaxel elution techniques and newer paclitaxel-eluting stent architecture may improve the performance of paclitaxel-eluting stents. As the only approved non-limus based antiproliferative agent currently available, paclitaxel is uniquely positioned in the future of interventional vascular medicine.

A vulnerable plaque is an atheromatic plaque with specific morphological characteristics, mainly presented as an unstable collection of white blood cells and lipids in the wall of an artery. It is of great importance to adequately recognize and treat this entity before its rupture, before the initiation of an acute coronary syndrome. The search of the location of future plaque ruptures or plaque erosions is an important area of cardiovascular research. Systemic therapy, including use of statins, targets the vulnerable patient. However, adverse events cannot be completely eliminated with the appropriate application of systemic therapies and this has given rise to efforts for evolution of local or regional therapies of the vulnerable plaques to prevent future events. Recently drug eluting stents dedicated to vulnerable plaques have been developed, aiming in the local stabilization of the vulnerable plaque.

Angioplasty of the coronary arteries has made significant headway in the past 20 years as a treatment for atherosclerotic vascular disease. Though drug-eluting stents are effective, they appear to invoke a thrombogenic response. Biodegradable stents are a promising alternative to permanent stents and may eventually be used to solve the lingering problem of in-stent restenosis. Additionally, fully degradable stents have the ability to deliver more drugs to the target site than a thin coating of drug on metallic stents. A variety of degradable materials have been studied for stent design, including polyesters, polycarbonates, bacterial-derived polymers, and corrodible metals. The ideal biodegradable stent would be reliably deployable under fluoroscopic guidance and situate into the target lesion with minimal endovascular trauma. The stent should degrade into nontoxic byproducts and invoke a minimal degree of inflammation at the target site. Finally, the stent itself should disappear within months (to years) without significant displacement from the deployment site. Although initial data from clinical trials have been sufficient to bring biodegradable materials into the realm of feasibility, future research is undoubtedly necessary to resolve the critical issues of inflammation and mechanical stability.

Stent thrombosis (ST) is a rare complication following coronary stenting; however given the associated serious consequences, in particular death and myocardial infarction, it remains a source of considerable concern for cardiologists. Although no differences have been found between drug-eluting stents (DES) and bare-metal stents (BMS) in terms of early ST, some studies have reported adverse outcomes associated with DES as compared to BMS at long-term follow-up. Delayed endothelial coverage of the stent struts, inflammation and local hypersensitivity due to the interaction between the drug and polymer coating have been characterized to be typical for DES compared to BMS and may prolong the window of vulnerability to ST. Consequently the recommended duration of dual antiplatelet therapy (DAT) was longer with DES than with BMS. Results from studies investigating the optimal duration of DAT remain inconclusive and the current recommendation seems to be that patients undergoing DES implantation should have DAT for at least 6-12 months. Our treatment strategy requires more detailed analysis and should improve as we understand more about the impact of the newer generation DES and variability in antiplatelet therapy response, in addition to the effects of novel therapeutic agents and the availability of more data on the optimum duration of DAT.

First generation drug-eluting stents (DES) have significantly improved the treatment options for patients with symptomatic coronary artery disease by decreasing rates of acute vessel closure and restenosis after percutaneous coronary revascularization procedures. However, early enthusiasm was temperd by reports of late stent thrombosis (LST), which raised concerns about safety. Since millions of DES have been implanted in patients worldwide, it is imperative to understand the pathology of DES in man. Autopsy studies from the CVPath DES registry documented that delayed arterial healing is accompanied by poor endothelialization of stent struts which is the single best predictor of late stent thrombosis. Arterial healing of DES is highly heterogeneous and is dependent on underlying plaque morphology as well as on the stent location. We identified several anatomical and pathological changes in man, which were associated with LST; these include hypersensitivity reaction to polymer, plaque rupture, bifurcation sites, malapposition and stent fracture. DES was also associated with premature atherosclerotic changes versus BMS.