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A Brief Overview of Stenting

Percutaneous coronary intervention (PCI) has become the most widely used strategy for the treatment of patients with coronary artery disease since its introduction by Grüntzig et al. in 1977 [1]. Angioplasty was plagued with multiple problems in the balloon catheter era, including acute collapse and dissection of the treated artery and recurrent luminal obstruction (restenosis), a pathological process that forced target vessel revascularization in 25–50% of cases, typically within 2–12 months post-PCI. A second revolution in the field of interventional cardiology materialized with the introduction of balloon-mounted stents, which consist of a self-expandable stainless-steel mesh that acts as a scaffold that maintains radial support to neutralize elastic recoil. Palmaz and colleagues introduced in 1985 the use of bare metal stents in peripheral arteries of dogs [2]. Schatz et al. then developed the first commercially successful stent, the Palmaz-Schatz stent [3]. In 1987, Sigwart et al. provided the first evidence that implantation of bare metal stents in patients with iliac, femoral, and coronary artery disease may offer a safe and useful way to prevent subacute occlusion and dissections and limit the occurrence of restenosis [4]. Following these pilot studies, the first Palmaz-Schatz stent was approved for use in the USA, and different bare metal stents platforms developed over the next decade confirmed the benefits of stenting compared with conventional transluminal balloon angioplasty, leading to the era of elective stenting. However, restenosis after base metal stents implantation still affected about 15–30% of patients, causing in the Western world an estimated annual cost exceeding $1 billion USD. After the identification of excessive proliferation of vascular smooth muscle cells (VSMCs) as a key feature of experimental and clinical neointimal thickening postangioplasty and the results of numerous animal studies demonstrating the utility of antiproliferative strategies to prevent this pathological process (reviewed in [5, 6]), a new era in interventional cardiology began nearly a decade ago with the advent of drug-eluting stents (also referred to as “coated” or “medicated” stents) that locally deliver high doses of antiproliferative drugs. Pilot studies using the sirolimus-eluting Bx Velocity™ stent demonstrated negligible neointimal thickening at follow-up [7, 8]. The superior performance of several drug-eluting stents platforms versus bare metal stents has been irrefutably confirmed in large multicenter clinical trials demonstrating dramatic reductions in restenosis rates, in target lesion revascularization, and in major adverse cardiac events [9]. Although the initial clinical trials with drug-eluting stents did not report significant adverse effects, recent case reports in real life patients have recognized an increased risk of late stent thrombosis potentially due to a mismatch between the vessels and the stent (late stent malapposition), hypersensitivity, or incomplete reendothelialization consider changing to “due to” to the cytostatic and cytotoxic effects that the active drugs exert on the underlying and neighboring ECs or the proinflammatory effects of the biostable polymeric coatings (Table 8.1) [9, 14]. The current clinical guidelines therefore recommend prolonged potent antiplatelet and antithrombotic adjunctive therapies in patients receiving drug-eluting stents. Because of these shortcomings, further research is essential in order to improve the long-term safety and efficacy of drug-eluting stents.

Table 8.1 Current limitations and adverse events attributed to drug-eluting stents
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Etiopathogenesis of In-Stent Restenosis and Cell Cycle Control in Mammalian Cells

Stenting can result in acute damage to the endothelial cell (EC) monolayer, triggering a chronic inflammatory response that may promote exuberant neointimal hyperplasia (Fig. 8.1) [5, 15]. Localized platelet activation and thrombosis accompanied by recruitment of circulating monocytes, neutrophils, and lymphocytes into the intimal area characterize the acute early phase of restenosis. Numerous chemotactic and mitogenic factors produced by neointimal cells provoke a first hyperplastic response of medial VSMCs, which migrate toward the growing neointimal lesion where they maintain high proliferative activity. Compared with VSMCs in normal adult arteries, which are fusiform and display a differentiated so-called contractile phenotype characterized by reduced proliferative activity and motility, activated VSMCs within the injured vessel wall exhibit an undifferentiated “synthetic” phenotype characterized by broader and flatter shape, expression of embryonic isoforms of contractile proteins, high responsiveness to growth and chemotactic stimuli, and abundant synthesis of extracellular matrix components. Accumulating evidence indicates that recruitment of bone marrow-derived and adventitial VSMC progenitors and adventitial myofibroblasts also plays a role in neointimal lesion development, but the relative contribution of this phenomenon to restenosis remains unclear [15]. At later stages, resolution of inflammation is associated with restoration of the “contractile” phenotype of neointimal VSMCs and normalization of the composition of the extracellular matrix, which more closely resembles the undamaged vessel wall. Consistent with the complexity of restenosis, numerous animal and human studies have identified a plethora of candidate regulators of neointimal hyperplasia, including signal transduction pathways (e.g., MEK/ERK and PI3K/Akt signaling cascades), transcription factors (e.g., AP-1, YY1, Gax, NF-κB, E2F, c-myb, c-myc), growth factors (e.g., PDGF, FGF, TGFβ, VEGF, IGF, EGF), inflammatory cytokines (e.g., TNFα), chemotactic factors (e.g., MCP-1, CCR2), thrombogenic factors (e.g., thrombin receptor, tissue factor), cell adhesion molecules (e.g., VCAM, ICAM, Mac-1, LFA-1), metalloproteases (e.g., MMP-2, MMP-9), and cell cycle regulatory proteins (e.g., CDK2, CDC2, cyclin B1, PCNA, pRb, p27, p21).

Fig. 8.1
figure 1

Mechanisms of in-stent restenosis. The left and right images show cross sections through a stented artery immediately after intervention and at a late time point showing excessive neointimal lesion development, respectively. The scheme between both images represents a longitudinal section through the vessel wall (for simplicity, neither the native atherosclerotic plaque that compromised blood flow before performing angioplasty nor the stent struts are depicted). Platelets are recruited into the damaged vessel wall and provoke thrombi formation. Blood-borne leukocytes adhere to thrombi via selectins and integrins and, driven by locally produced chemokines, they migrate across the fibrin-platelet layer toward the intimal area. Medial VSMCs exhibiting a differentiated so-called contractile phenotype revert to a “synthetic” less-differentiated phenotype characterized by abundant extracellular matrix protein synthesis and high responsiveness to mitogenic and migratory stimuli. Activated VSMCs migrate toward the growing neointimal lesion and proliferate very actively, thus contributing to neointimal thickening

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Neointimal hyperplasia following PCI can thus be viewed as the arterial wall’s healing response to acute mechanical injury, which encompasses excessive hyperplastic growth of VSMCs. The proliferation of mammalian cells requires a series of sequential events that constitute the mitotic cell cycle (Fig. 8.2). Under normal conditions, most differentiated cells are maintained in a nonproliferative state (G0 phase). After stimulation with growth factors, cells enter the first gap phase (G1), during which proteins necessary for DNA replication are synthesized and/or activated. In the subsequent synthesis phase (S) the DNA is replicated, then cells enter a second gap phase (G2) that allows the synthesis and activation of proteins required for mitosis (M phase). Cell cycle progression is orchestrated by the activation of various holoenzymes composed of the regulatory subunit cyclin and a catalytic cyclin-dependent protein kinase (CDK). Several mechanisms sequentially activate distinct CDK/cyclin complexes during different phases of the cell cycle, including the periodic synthesis and degradation of cyclins and the phosphorylation/dephosphorylation of CDKs and cyclins. Another important level of cell cycle regulation is the inhibition of CDK/cyclin holoenzymes through their interaction with CDK inhibitory proteins (CKIs) of two families: Cip/Kip (CDK interacting protein/kinase inhibitory protein: p21Cip1, p27Kip1, p57Kip2) and Ink4 (inhibitor of CDK4: p16Ink4a, p15Ink4b, p18Ink4c, p19Ink4d) [16]. Cip/Kip proteins bind to and inhibit many CDK/cyclin complexes, while Ink4 proteins specifically interact with and inhibit cyclin D-associated CDKs (Fig. 8.2). The rates of synthesis and degradation of CKIs, as well as their redistribution among different CDK/cyclin heterodimers are modulated by mitogenic and antimitogenic stimuli. The tumor suppressor p53 and other proteins modulate CKI expression and function to ensure that cell cycle progression is halted if environmental conditions are not appropriate and/or cells accumulate genetic damage. CDK/cyclin activity regulates E2F/DP- and retinoblastoma protein (pRb)-dependent transcription of target genes involved in cell cycle control and DNA biosynthesis (Fig. 8.2). In nonproliferating cells, low CDK/cyclin activity keeps pRb in its hypophosphorylated form, which binds to and inactivates the dimeric transcription factor E2F/DP. In contrast, high CDK/cyclin activity in proliferating cells causes the accumulation of hyperphosphorylated pRb during late G1-phase, thus leading to the release of E2F/DP and transactivation of various target genes necessary for cell cycle progression.

Fig. 8.2
figure 2

Cell cycle regulation in mammalian cells. Activation of specific CDK/cyclin complexes drives progression through the different phases of the mammalian cell cycle (G1 Gap 1, S synthesis of DNA, G2 Gap 2, M mitosis). Advance through G1/S is orchestrated by CDK/cyclin-dependent hyperphosphorylation of pRb, which allows the transcriptional activation of E2F/DP target genes that are required for cell proliferation. CDK inhibitory proteins (CKIs) of the Cip/Kip and Ink4 families interact with and inhibit the activity of CDK/cyclin holoenzymes. Cip/Kip proteins bind to and inhibit a wide spectrum of CDK/cyclins, while Ink4 proteins are specific for cyclinD-associated CDKs. CDK1 is also known as CDC2

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MicroRNAs (miRNAs) represent an additional layer of the complex regulatory network that controls cell cycle progression, and evidence is accumulating that they may be of particular therapeutic interest in the context of pathological vascular remodeling [17]. For instance, miRNA-221 and miRNA-222 have been shown to limit VSMC proliferation by targeting the CKIs p27Kip1 and p57Kip2, and the growth-factor receptor c-Kit [18, 19]. Importantly, knockdown of these microRNAs inhibits arterial cell proliferation and neointimal formation in the rat carotid artery injury model [19].

Pharmacological Antiproliferative Strategies to Limit Neointimal Thickening After Mechanical Injury of the Vessel Wall

The recognition that excessive VSMC proliferation is a hallmark of restenosis postangioplasty in animal models and humans has fueled extensive research into the molecular mechanisms that control the cell cycle in these cells in vitro and in vivo. Moreover, numerous preclinical studies have been conducted to assess whether antiproliferative strategies are efficient at limiting neointimal lesion development, including gene therapy and drug-based approaches. Although gene therapy targeting cell cycle regulatory factors (e.g., inhibition of positive cell cycle regulators and overexpression of growth suppressors) has shown undisputable therapeutic efficacy in animal models of restenosis [5, 6], its clinical use awaits the overcoming of current limitations of gene therapy in humans. We have therefore focused our discussion on drug-based strategies that limited neointimal lesion development in animal models of angioplasty, some of which have demonstrated clinical benefits when administered in drug-eluting stent platforms.

Animal models are critical to provide mechanistic insight into neointimal thickening associated with balloon angioplasty and stenting, and to establish safety margins, efficacy, and toxicity [20–22]. The rat carotid model of balloon angioplasty has been extensively used to gain insight into the molecular mechanisms that provoke neointimal thickening induced by mechanical injury; however, the porcine and the rabbit models are considered standard for the evaluation of drug-eluting stents prior to human use [20–22]. Nevertheless, there are shortcomings associated with animal models that limit their biological significance. Ideally, drug-eluting stents should be tested in atherosclerotic arteries to more closely resemble the clinical situation; however, preclinical studies are generally performed in atherosclerosis -free vessels. Moreover, neointimal responses associated with stent deployment are exaggerated in pigs and rabbits, and the time course of healing is reduced compared to humans (about 4–6 weeks in swine and rabbits compared to roughly 6–9 months in humans). It is also noteworthy that the rabbit model does not offer the possibility of coronary stenting due to its anatomical size; thus, the aorta or the iliac arteries are used for stent placement in rabbits. Albeit the site of stenting can be considered as a critical limitation of the rabbit model, it resembles more closely than the pig the healing process observed in humans and is therefore widely used to examine inflammatory, proliferative, and thrombotic processes subsequent to vascular injury and stenting [20].

Inhibitors of Mammalian Target of Rapamycin

The mammalian target of rapamycin (mTOR) protein is a member of the phosphoinositide 3-kinase (PI3K)-related proteins kinases (PIKK) family that forms the catalytic subunit of two different complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [23, 24]. Signaling through the mTOR pathway links cell cycle activity with energy and nutrient availability and therefore plays a key role in maintaining homeostasis. A potent inhibitor of mTOR is rapamycin (also known as rapamune, sirolimus), a fungal macrolide produced by Streptomyces hygroscopicus that impairs mTOR complex assembly via sequestration of the intracellular receptor FKBP12 [23, 24]. Treatment of VSMCs with sirolimus upregulates p27kip1, inhibits pRb phosphorylation, and limits cell proliferation and migration in vitro [25–29]. These findings are in agreement with the observation that the p27kip1/CDK/pRb pathway regulates VSMC proliferation and migration in a coordinated manner [30, 31].

Preclinical studies in different animal models have demonstrated the utility of sirolimus to limit neointimal thickening induced by arterial injury. Oral or intramuscular application of sirolimus reduces neointimal thickening in porcine and rat balloon injury models [32–34]. As in cultured VSMCs [28, 29], the reduction in neointimal proliferation observed in the porcine coronary model is associated with increased p27kip expression and reduced pRB phosphorylation [33]. Sirolimus eluting-stents have also demonstrated protection against neointimal thickening in porcine [35–37], rabbit [38], and rat [39] models. Likewise, Pires and colleagues reported that sirolimus-eluting cuffs placed around the femoral artery significantly reduce intimal thickening in both normocholesterolemic wild-type mice [40] and atherosclerotic hypercholesterolemic apoE*3-Leiden transgenic mice [41] with no systemic adverse effects or effect on cuffed contralateral femoral arteries. However, evidence has been presented demonstrating that sirolimus has unfavorable in vitro and in vivo effects on ECs. Barilli et al. demonstrated that prolonged treatment of human ECs with sirolimus impairs cell viability (increased apoptosis and necrosis) and function (reduced proliferation and mobility and increased actin stress fiber formation), possibly through mTORC2 inhibition [42]. Suppression of reendothelialization and revascularization by sirolimus also correlates with increased EC mortality via apoptosis and autophagy [43], a process activated in response to cellular damage and nutrient deprivation that mediates the degradation of cellular components in lysosomes [44]. Using a porcine model of epicardial coronary artery stenting, Frey and colleagues noted delayed vascular healing (endothelialization) with slow-release sirolimus-eluting stents compared with bare metal stents and extended-release sirolimus-eluting stents [45]. Sirolimus treatment might also delay reendothelization through induction of endothelial progenitor cell senescence, possibly due to increased expression of p27kip and inactivation of telomerase [46]. Moreover, sirolimus suppresses the coordinated proadhesive and proinflammatory gene expression that normally occurs in renal artery segments subjected to mechanical injury, which in turn may reduce the recruitment of leukocytes and hematopoetic progenitor cells that participate in vascular healing [47]. These adverse effects of sirolimus on mature ECs and endothelial progenitors might contribute to increased risk of late stent thrombosis in patients receiving sirolimus-eluting stents.

Several sirolimus derivatives have been developed with the goal of optimizing mTOR inhibitory therapies. Everolimus exhibits a shorter half-life and reduced unwanted side-effects compared with sirolimus if delivered systemically, yet both drugs elicit similar protection against neointimal formation in a porcine coronary artery model [48, 49]. Zotarolimus exhibits increased retention in the arterial wall and reduces neointima development after stent deployment in a porcine coronary artery model [50]. Finally, compared with sirolimus-eluting stents, a polymer-free stent coated with the sirolimus analog biolimus A9 has demonstrated equivalent early and superior late reduction of intimal proliferation in a porcine model [51]. Remarkably, delayed arterial healing with biolimus A9 was minimal, and there was no increased inflammation at 180 days compared with implantation of sirolimus-eluting stents.

Taxanes

Taxol (paclitaxel) is a microtubule stabilizing drug that impairs centrosomal function, induces abnormal mitotic spindles, and suppresses spindle microtubule dynamics during mitosis causing G2/M-phase arrest [52]. In vitro treatment of VSMCs with paclitaxel upregulates both p53 and its downstream target p21Cip1, and also disorganizes cytoskeleton structures and increases apoptosis. These effects are associated with a significant inhibition of processes that promote restenosis, including cell proliferation and migration and extracellular matrix production [27, 53–55]. Accordingly, oral paclitaxel treatment markedly reduces neointimal lesion formation after rat balloon angioplasty without causing significant toxicity [53, 56], and local delivery of paclitaxel to the balloon angioplasty site in rabbit carotid artery disorganizes microtubules and inhibits neointimal thickening [57]. Likewise, studies in the porcine coronary artery model have demonstrated long-term effects of paclitaxel-eluting stents [58, 59]. However, the cytotoxic effects of paclitaxel may partly explain its reduced long-term efficacy and safety compared with sirolimus [60]. Wessely and colleagues demonstrated that both drugs efficiently block VSMC proliferation, but paclitaxel has more deleterious effects on ECs, such as more potent antiproliferative and proapoptotic activities [27]. Moreover, paclitaxel-eluting cuffs placed around the femoral artery effectively prevent neointimal thickening on the atherosclerotic plaques of hypercholesterolemic apoE*3-Leiden transgenic mice, but high concentration demonstrated adverse vascular pathology and transcriptional responses (e.g., increased mRNA level of the proapoptotic factors FAS, BAX, and caspase 3), suggesting a narrower therapeutic range of this drug [41]. Given the high cytotoxicity of paclitaxel, major efforts are underway to improve the safety of this drug while maintaining therapeutic benefits. Such strategies include programmable drug release [61], addition of paclitaxel to contrast media [62], or drug coating of the angioplasty balloon rather than the stent [63].

Estradiol

Estradiol, the most abundant sex hormone in humans, has numerous effects in vascular cells, including modulation of cell proliferation and migration, which are for the most part mediated by its binding to the estrogen receptors α and β [64, 65]. Upon binding of estradiol, these intracellular receptors act as transcription factors that modulate the expression of a large number of genes [64]. In cultured cells, estradiol inhibits VSMC proliferation and migration and, conversely, promotes EC proliferation [66]. Mechanistically, the effects of estradiol appear to be mediated by changes in the activity of various signaling proteins, including the mitogen-activated protein kinases p38 and ERK1/2 [66–68] or the GTPase Rac1 [69]. Therefore, estradiol may be effective at preventing vascular restenosis after arterial injury with low risk of late stent thrombosis, as it would be predicted to enhance reendothelialization. Supporting this notion, a number of preclinical studies have demonstrated the protective function of this hormone against vascular injury. For example, systemic delivery of estradiol in rodents and rabbits accelerates reendothelization after vessel denudation [70–73], reduces neointimal thickening in the injured carotid artery [74–81] and aorta [82], and inhibits VSMC proliferation in vivo [75, 76, 82, 83]. Similarly, cathether-mediated local delivery of estradiol in balloon-injured porcine coronary artery reduces VSMC proliferation and neointimal thickening [84], and estrogen-coated stent implantation reduces neointimal formation in a similar porcine model [85]. These preclinical studies demonstrate that both systemic and local delivery of estradiol prevent adverse vascular remodeling after arterial injury and provide rationale for the assessment of the therapeutic potential of estradiol-eluting stents in humans.

Other Drugs

Based on reported capacity to inhibit VSMC proliferation and neointima formation in different animal models of vascular injury, other drugs might prove effective at inhibiting clinical restenosis. For example, the 3-hydroxi-3-methilylglutaryl-CoA (HMG CoA) reductase inhibitor cerivastatin is one of the most promising compounds owing to its pleiotropic effects, which include inhibition of cell proliferation and improvement of EC function [86]. Preclinical assessment in a rat carotid model has revealed that cerivastatin-eluting stent deployment limits neointima formation [87]. Treatment of VSMC cultures with cerivastatin increases p21Cip1 and p27Kip1 levels, downregulates cyclin A and D1, and decreases CDK2 activity and pRb phosphorylation, leading to reduced cell proliferation, and all these effects of cerivastatin are less pronounced in ECs [87]. Therefore, local application of statins might limit restenosis while decreasing the risk of late stent thrombosis associated with defective reendothelialization.

Another compound of potential therapeutic interest in the setting of restenosis is flavopiridol, a synthetic CDK inhibitor that induces VSMC growth arrest in parallel with increased levels of the growth suppressors p21Cip1, p27Kip1, and p53 and decreased accumulation of hyperphosphorylated pRb [88, 89]. Accordingly, both oral and stent-mediated administration of flavopiridol significantly reduce neointima formation after rat carotid injury [88, 89].

Some antioxidants, such as carvedilol and probucol, have also demonstrated strong antiproliferative properties in the arterial wall. Oral treatment with carvedilol inhibits VSMC proliferation and blunts neointima formation in the rat carotid injury model [90, 91], and carvedilol-coated stents inhibit neointima hyperplasia in pigs [92]. In contrast, the results with the related antioxidant probucol are conflicting. On one hand, oral administration of probucol in rabbits decreases neointima formation and the number of lesional proliferating VSMCs in balloon-injured carotid artery [93] or abdominal aorta [94], and some studies suggest that probucol also promotes reendothelization [94, 95]. However, other studies do not find any protective effect of probucol against neointimal thickening following balloon angioplasty in the rat carotid artery [96] or stent deployment in porcine coronary artery [97]. Similarly, probucol-coated stents fail to demonstrate beneficial effects in lumen area, neointimal area, or arterial cell proliferation in a porcine coronary injury model [92].

Cilostazol is a novel and potent inhibitor of phosphodiesterase in platelets and VSMCs that exerts both antithrombotic and antiproliferative properties, and is therefore a promising therapeutic candidate in the setting of restenosis. Cilostazol inhibits mitogen-induced VSMC proliferation by increasing the concentration of cyclic adenosine monophosphate [98], resulting in activation of the p53-p21Cip1 axis [99]. Notably, oral cilostazol treatment inhibits neointima formation in the rat carotid balloon angioplasty model [100], and cilostazol-coated stents reduce neointimal thickening in porcine coronary arteries [101].

Some antidiabetic drugs have also demonstrated their effectiveness at reducing adverse vascular remodeling. Thiazolidinediones (e.g., rosiglitazone, pioglitazone) are peroxisome proliferator-activated receptor γ [PPAR-γ] agonists originally developed as insulin sensitizers, but also exhibit vascular protective properties. For example, among other beneficial effects in the arterial wall, thiazolidinediones inhibit VSMC proliferation via ERK inactivation and induction of GSK-3β-dependent signaling [102]. Studies in rodents have demonstrated that rosiglitazone treatment prevents neointimal thickening after mechanical injury of the carotid artery [102–104]. Similar beneficial effects of thiazolidinediones have been observed in balloon injury [105] or stent implantation [106] rabbit models, and stenting in porcine coronary arteries [107].

Tranilast is an inhibitor of TGF-β-dependent signaling that attenuates VSMC proliferation in vitro [108–111] by a complex mechanism that involves inhibition of ERK1/2 [110], downregulation of the transcription factor c-myc [109], and upregulation of p21Cip1 [112]. Studies in rabbits and rodents have demonstrated that oral administration of tranilast reduces neointimal growth after photochemical or balloon injury of the arterial wall [113–116], and similar results have been obtained in pigs after coronary artery stenting [117, 118].

Antiproliferative Strategies for the Treatment of Clinical Restenosis Using Drug-Eluting Stents

PCI is the preferred therapeutic option to treat symptomatic coronary artery disease in the majority of cases. Interventional cardiology, as well as special areas of interventional angiography such as stent- or balloon-based treatment of complex lesions of the superficial femoral artery or below-the-knee arteries that inevitably carry a high risk of restenosis, have greatly benefited from the introduction of drug-eluting interventional devices. The use of drug-eluting stents has now even paved the road to safely and reliably treat complex coronary artery disease even in cases that had been previously considered to be a domain of bypass surgery, such as left main coronary artery and multivessel disease, including in diabetic patients [119]. To date, numerous lesion and patient characteristics have been identified to benefit from the usage of drug-eluting stents (Table 8.2). Predictors of restenosis include stent length and the number of stents per lesion, lesion length and complexity, small vessel diameter (≤2.75 mm), residual diameter stenosis, and certain clinical scenarios (e.g., previous restenosis and diabetes mellitus), while premature antiplatelet therapy discontinuation, renal failure, bifurcation lesions, diabetes, and low ejection fraction have been identified as predictors of thrombotic events associated with drug-eluting stents deployment [14]. The diagnostic gold standard for restenosis is coronary angiography, but noninvasive diagnostic tools are being developed (e.g., computerized tomography, cardiac magnetic resonance tomography).

Table 8.2 Indications for drug-eluting stents—current evidence
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To date, the two major classes of pharmacological compounds used in clinical interventional cardiology are the mTOR inhibitors (referred to as “limus drugs”) and paclitaxel, which inhibit VSMC proliferation and migration, two key processes that contribute to neointimal thickening during in-stent restenosis (Fig. 8.3). The term “limus drugs” is confusing since pimecrolimus and tacrolimus are calcineurin inhibitors that only exhibit immunosuppressive activities and have yielded unsatisfactory results when used in drug-eluting stent platforms to prevent restenosis [129, 130]. By contrast, pivotal studies a decade ago using sirolimus- and paclitaxel-coated stents have shown a dramatic decrease of late lumen loss, the pathoanatomical correlate of angiographic and clinical restenosis, compared to uncoated bare metal stents [131]. Meta-analysis and recent clinical head-to-head trials have implicated superior performance of mTOR-inhibitor-eluting stents [132]. Interestingly, the first clinically available drug-eluting stents, Cordis’ sirolimus-eluting stent, has been unsurpassed in terms of clinical safety and efficacy as is becoming evident in recent randomized comparisons presented at large international meetings as well as peer-reviewed publications [133]. However, due to potential improvements in stent design, Abbott’s everolimus-eluting Xience V stent is the most frequently used stent in contemporary interventional cardiology.

Fig. 8.3
figure 3

Overview of drugs currently used on the vast majority of drug-eluting stents approved for human use. The name of the stent platform is provided in parenthesis. A large reduction in restenosis and need for target vessel revascularization has been conclusively demonstrated with drug-eluting stents that deliver mTOR inhibitors and paclitaxel, two unrelated families of drugs which cause cell cycle arrest in G0/G1-phase and M-phase, respectively. Tacrolimus and pimecrolimus are calcineurin inhibitors which only exhibit immunosuppressive properties and have yielded unsatisfactory clinical results in drug-eluting stents platforms

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Several studies investigated the use of dual drug-eluting stents to inhibit the rate of restenosis. Most of the combinatorial approaches revealed no beneficial effect. Examples include the combination of paclitaxel and pimecrolimus [130] or sirolimus and estradiol [134]. Interestingly, a combination of sirolimus and probucol on the ISAR platform revealed a positive effect [135]. However, replication of clinical results by independent groups is not yet available.

Current Limitations of Drug-Eluting Stents and Optimization

As in many instances, medical devices such as drug-eluting stents do not exclusively alleviate clinical problems such as restenosis but are associated with limitations that merit further optimization. The major shortcomings associated with current FDA-approved drug-eluting stent platforms that can be associated with the development of late (between 1 and 12 months after stent placement) and very late (12 months and later) stent thrombosis are listed in Table 8.1. Since cell cycle inhibitors do not selectively inhibit proliferation of their main target cells, namely VSMCs, but also inhibit proliferation of other cells, most importantly ECs, cell cycle inhibitors can delay healing processes and thus precipitate acute and subacute, life-threatening events, in particular stent thrombosis. Whereas early stent thrombosis that occurs during the first 30 days after stent placement is generally associated with problems linked with PCI itself or shortcomings attributable to concomitant antithrombotic pharmacotherapy such as drug resistance or patient incompliance, late/very late stent thrombosis is often related to risks associated with ongoing local inflammatory processes and delayed arterial healing, thus leading to a prothrombotic milieu (Table 8.1). Since stent thrombosis is associated with considerable mortality, it has been the focus of many clinical investigations. Thus, current guidelines recommend prolonged dual antithrombotic therapy of at least 12 months after drug-eluting stent implantation, exceeding the 4-week recommendation for bare metal stents [136].

The major components of a typical drug-eluting stent platform that can be optimized to increase efficacy and safety of drug-eluting stents include the polymer, the delivery system, stent design, and the drug itself (Fig. 8.4) [137]. All current FDA-approved drug-eluting stents carry a nonerodible polymer to avoid boost release and retard drug delivery to the vascular wall, since prolonged drug release of several weeks is considered to be of pivotal importance for effective inhibition of restenosis. Thus, the issue of polymeric coating is of integral importance for the development of novel drug-eluting stent platforms. Yet, virtually all polymers are able to precipitate proinflammatory processes in the vascular wall and are therefore considered to be a major cause for late and very late stent thrombosis. To circumvent this important clinical dilemma, several possible solutions have been proposed and are currently under investigation. The major focus is now on biodegradable polymers such as a polylactic acid polymer that biodegrades into carbon dioxide and water over time, as it is used on the biolimus A9-eluting Biomatrix and Nobori drug-eluting stents platforms. A fairly large clinical trial has shown noninferiority of this stent platform compared to the current gold standard, the sirolimus-eluting stent [138]. Other approaches to limit or abstain from surface polymer coating are microporous stents [139], reservoir-based drug delivery [137], and bioactive surface technology [140].

Fig. 8.4
figure 4

Major components of a typical drug-eluting stent platform. Research endeavors to improve the efficacy and safety of drug-eluting stents include the identification of new drugs, new stent design, optimization of delivery systems (e.g., use of bioabsorbable stent platforms), and improved biodegradable polymers

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Major attention has been recently drawn to bioabsorbable stent platforms. The rationale behind this intriguing approach is the limited presence of a vascular scaffold in the coronary artery. However, first-in-man clinical trials using these approaches revealed rather disappointing results, eventually leading, for example, to the cessation of the magnesium bioabsorbable stent program from Biotronik [141]. However, a polymer-based, fully erodible coronary stent that delivers everolimus has recently shown encouraging results in a limited number of patients [142]. Albeit widespread clinical use of this particular stent platform is not currently foreseeable, the interest and expectations regarding this technology remain high in the interventional cardiology community.

Conclusions

In the last two decades, numerous studies in animal models have conclusively demonstrated that inhibiting cell proliferation within the damaged vessel wall is a suitable strategy to limit neointimal thickening after angioplasty. Nowadays, the majority of coronary interventions utilize drug-eluting stents that deliver locally high doses of antiproliferative drugs, such as sirolimus (and derivatives) and paclitaxel. These medical devices have revolutionized the field of revascularization owing to a dramatic reduction in the incidence of restenosis, target lesion revascularization, and major adverse cardiac events. However, both efficacy and safety of drug-eluting stent platforms need to be improved to reduce the need for repeated revascularization and the development of late stent thrombosis due to delayed reendothelialization, which forces prolonged oral dual antiplatelet therapy. Major areas of drug-eluting stent research include the development of new drugs, approaches to limit or even avoid the presence of polymers (e.g., biodegradable polymers, microporous stents, reservoir-based drug delivery), use of antithrombotic coatings, bioactive surface technology to promote vascular healing (e.g., antibody-, peptide-, and nucleotide-coated stents), and development of bioabsorbable stent platforms. By combining different strategies, next-generation drug-eluting stent platforms may consist of polyvalent devices that embrace the three foundations of stent-based lesion therapy: antirestenotic, prohealing, and antithrombotic. Another goal will be to develop drug-eluting stents tailored to some patient or lesion subgroups (e.g., diabetics, patients presenting with acute myocardial infarction) and lesion characteristics. Achieving these ambitious objectives will certainly require the close interaction of specialists in different biomedical and medical disciplines.