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Right arrow Coronary disease
Asian Cardiovasc Thorac Ann 2006;14:75-82
© 2006 Asia Publishing EXchange Ltd

REVIEW PAPER

Update on Drug-Eluting Stents for Prevention of Restenosis

Chi-Hang Lee, MBBS, Huay-Cheem Tan, FACC, Yean-Teng Lim, FACC

Cardiac Department, National University Hospital, Singapore

For reprint information contact: Huay-Cheem Tan, FACC Tel: 65 6772 5213 Fax: 65 6777 1684 Email: tanhc{at}nuh.com.sg, Cardiac Department, National University Hospital, Level 3 Main Building, 5 Lower Kent Ridge Road , Singapore 119074.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATHOPHYSIOLOGY OF RESTENOSIS
 DRUG-ELUTING STENTS
 IMMOBILIZED DRUGS
 DRUG-RELEASING COATINGS
 ANTI-NEOPLASTIC DRUGS
 IMMUNOSUPPRESSIVE AGENTS
 INHIBITORS OF THE EXTRACELLULAR...
 CONCLUSION
 REFERENCES
 
Despite the success of coronary stent implantations in the last decade, in-stent restenosis due to neointimal hyperplasia remains a problem to overcome. Neointimal hyperplasia is a vascular response to stent injury and mainly consists of proliferation of smooth muscle cells and deposition of extracellular matrix. Recently, local drug delivery has been advocated as a potential strategy to prevent in-stent restenosis. Unprecedented results have been obtained in early clinical studies on sirolimus-eluting and paclitaxel-eluting stents. Trials using various pharmaceutical coatings on different coronary stents are ongoing. More types of drug-eluting stents are expected on the market in the near future. Meanwhile, the evaluation of drug-eluting stents is entering the second phase in which the safety and efficacy in more complex lesion subsets and different clinical presentations are being investigated. Results including cost-benefit analyses are expected to have a tremendous impact on the practice of interventional cardiology in the next decade.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATHOPHYSIOLOGY OF RESTENOSIS
 DRUG-ELUTING STENTS
 IMMOBILIZED DRUGS
 DRUG-RELEASING COATINGS
 ANTI-NEOPLASTIC DRUGS
 IMMUNOSUPPRESSIVE AGENTS
 INHIBITORS OF THE EXTRACELLULAR...
 CONCLUSION
 REFERENCES
 
Restenosis, defined as luminal re-narrowing of a treated vascular segment, has been the most important hurdle limiting the success of percutaneous transluminal coronary angioplasty (PTCA) since its introduction more than 25 years ago.1–2 Restenosis occurs in approximately one third of patients at 6 months after the procedure, and often leads to repeated hospitalization and coronary re-intervention. Several clinical and angiographic risk factors that may contribute to the development of restenosis have been identified. Before the stent era, a number of different pharmacological agents to reduce the risk of restenosis had been investigated, but none proved successful. The development of the coronary stent in the late 1980s shed some light on solving this Achilles’ heel of PTCA. The coronary stent was initially employed as a bailout device for threatened closure, but its potential as an anti-restenotic device emerged from its scaffolding effect, and thus a superior angiographic outcome. The efficacy of the coronary stent in reducing restenosis has been well proven in subsequent randomized studies.3–4 This technology has been rapidly accepted by the cardiology community. However, it was soon recognized that although the coronary stent effectively prevents vessel recoil and shrinkage, the incidence of restenosis is only moderately reduced. This is attributed to the higher degree of endothelial injury and exaggerated neointimal hyperplasia associated with stent implantation.


   PATHOPHYSIOLOGY OF RESTENOSIS
TOP
 ABSTRACT
 INTRODUCTION
 PATHOPHYSIOLOGY OF RESTENOSIS
DRUG-ELUTING STENTS
 IMMOBILIZED DRUGS
 DRUG-RELEASING COATINGS
 ANTI-NEOPLASTIC DRUGS
 IMMUNOSUPPRESSIVE AGENTS
 INHIBITORS OF THE EXTRACELLULAR...
 CONCLUSION
 REFERENCES
 
The underlying mechanisms of restenosis comprise a combination of effects from vessel recoil, negative vascular remodeling, and neointimal hyperplasia. Endothelial denudation, intimal disruption, and medial layer damage occur in response to intervention procedures, irrespective of balloon dilatation, atherectomy devices, or stent implantation. This vascular injury leads to platelet aggregation and thrombus formation, which have been suggested as the foremost processes leading to restenosis after coronary intervention.5 The aggregated platelets represent a source of attractants and mitogens for smooth muscle cells. In addition, the platelet-derived growth factor secreted by endothelial cells and macrophages has been considered the major promoter of smooth muscle cell migration. The hypothesis that a thrombus represents the core of the restenosis process has been supported by angioscopic studies that provide clinical evidence of early thrombus formation after PTCA.6 Inflammation has also been implicated in restenosis as leukocytes have been found early and in abundance at the site of vascular injury.5

Smooth muscle cells play a pivotal role in the process of restenosis, due to their ability to migrate, proliferate, and synthesize extracellular matrix upon stimulation. At the injured vessel, they enter a proliferative phase from 24 hours to 3 months, and migrate into the intima through the disrupted internal elastic membrane.7 Metalloproteinases play an important role in this process. Thereafter, the smooth muscle cells continue to proliferate and synthesize extracellular matrix that ultimately constitutes the bulk of the restenotic lesion.7 Neointimal hyperplasia has been shown to be predominantly low-cellular tissue. Constituents of the extracellular matrix, such as hyaluronan, fibronectin, osteopontin and vitronectin, also facilitate smooth muscle cell migration. In addition, reorganization of the extracellular matrix, replacing molecules with collagen, may result in retraction of the vessel wall. Recent experiments have suggested that adventitial myofibroblasts also proliferate and migrate into the neointima and play an important role in supplying the intimal layer with proliferative cellular elements for lesion formation.8 Furthermore, the adventitia has been implicated in vascular remodeling because myofibroblasts are capable of collagen synthesis and tissue contraction, as seen in wound healing.

Elastic recoil, a consequence of the natural elastic property of blood vessels in response to stretch, has been recognized to occur instantly after PTCA. The rationale for the use of a stent as a scaffolding device became more apparent after experimental and clinical studies identified early elastic vascular recoil and late vascular shrinkage as important contributors to the process of restenosis.9,10 With the advent of intravascular ultrasound technology, it is now recognized that less than half of late lumen loss following PTCA is due to intimal hyperplasia, and vascular remodeling contributes significantly to the restenosis phenomenon. The relative contributions of vascular remodeling and neointimal hyperplasia to restenosis may vary considerably from one patient to another, and even from one site to another in the same vessel. Nevertheless, the ultimate clinical consequence of these puzzling processes is late lumen re-narrowing. Previous studies of systemic therapy (e.g., lipid-lowering agents, antioxidants, and antithrombotic drugs) to prevent restenosis after balloon angioplasty have been largely disappointing.11 Anti-restenosis therapy offered by drug-eluting stents has obvious merits in the ability to target therapy locally.


   DRUG-ELUTING STENTS
TOP
 ABSTRACT
 INTRODUCTION
 PATHOPHYSIOLOGY OF RESTENOSIS
 DRUG-ELUTING STENTS
IMMOBILIZED DRUGS
 DRUG-RELEASING COATINGS
 ANTI-NEOPLASTIC DRUGS
 IMMUNOSUPPRESSIVE AGENTS
 INHIBITORS OF THE EXTRACELLULAR...
 CONCLUSION
 REFERENCES
 
The idea of combining the principle of mechanical scaffolding with that of local pharmacological action emerged early in the stent era. The goal is controlled-release of an efficient drug from an inert coating. Initially, the polymer matrices containing the drug proved nonbiocompatible.12 Recently, the engineering of micrometer-thick coatings that can release adequate doses of drugs has proven feasible. Issues such as which stent, how to load the drug onto the stent, and what drug to use to inhibit the unwanted pathobiological response are ongoing.


   IMMOBILIZED DRUGS
TOP
 ABSTRACT
 INTRODUCTION
 PATHOPHYSIOLOGY OF RESTENOSIS
 DRUG-ELUTING STENTS
 IMMOBILIZED DRUGS
DRUG-RELEASING COATINGS
 ANTI-NEOPLASTIC DRUGS
 IMMUNOSUPPRESSIVE AGENTS
 INHIBITORS OF THE EXTRACELLULAR...
 CONCLUSION
 REFERENCES
 
Drugs can be immobilized on a stent surface by using priming layers. Heparin-immobilization has been applied to several stents. Initially the aim of this coating was reduction of stent thrombosis during a period when (sub)acute thrombotic stent occlusion still proved a problem. However, demonstrating statistical proof of reduction of stent thrombosis with the current incidence rate of about 1% in uncoated stents requires an expensive large-scale randomized trial. Reduction of in-stent restenosis has thus far not been accomplished by heparin coating. In the randomized COAST (COAted STent) trial, the uncoated Jomed stent was compared with the Corline heparin-coated Jomed stent in a randomized study of 300 patients. Results, however, did not demonstrate superiority of the active coating.13


   DRUG-RELEASING COATINGS
TOP
 ABSTRACT
 INTRODUCTION
 PATHOPHYSIOLOGY OF RESTENOSIS
 DRUG-ELUTING STENTS
 IMMOBILIZED DRUGS
 DRUG-RELEASING COATINGS
ANTI-NEOPLASTIC DRUGS
 IMMUNOSUPPRESSIVE AGENTS
 INHIBITORS OF THE EXTRACELLULAR...
 CONCLUSION
 REFERENCES
 
A drug-releasing coated stent consists typically of: the metal stent backbone; a layer of drug which is bound, absorbed, or blended; and sometimes, a superficial polymer layer that serves as a diffusion barrier to prevent early drug dose dumping. The delivery layer must fulfill biocompatibility, pharmacokinetic, and mechanical requirements. This means that apart from being nontoxic, the delivery layer must be suitable for sterilization, it must follow the geometric change of configuration during stent expansion, and resist mechanical injury caused by inflation of the balloon. Furthermore, the release of the drug into the recipient vessel must take place in a manner that is consistent with the drug’s mode of action. Drug release must be predictable and in controllable concentrations and time-spans.14–15 Current technology is able to address these problems, guaranteeing an intact coating during clinical application.

Complying with prevailing theories about the restenosis process, drugs are released in days to weeks. Special precautions include dose control to minimize toxicity. Delivery to the underlying vascular tissue generally favors lipophilic drugs that bind to vascular structures. The ultimate selection of the candidate drug is typically based on favorable effects in the following model systems: cell culture, systemic administration in rodent models of vascular damage, and a final eluting stent design in the porcine coronary model. In cell culture, the tested drugs have to elicit more anti-proliferative effects on vascular smooth muscle cells than on endothelial cells.16 If positive, the next step is systemic administration in a rodent model after vascular injury, usually endothelial damage or deeper vascular damage. Finally, biocompatibility and efficacy are studied in larger animals, preferably swine, to determine the extent of reduction of neointimal hyperplasia in the stent and to demonstrate the lack of proinflammatory features, lack of delay in general vascular wound healing, and re-endothelialization, which are the targets for improvement of stent biocompatibility outlined above. Once these phases have been completed successfully, initial clinical testing is warranted.


   ANTI-NEOPLASTIC DRUGS
TOP
 ABSTRACT
 INTRODUCTION
 PATHOPHYSIOLOGY OF RESTENOSIS
 DRUG-ELUTING STENTS
 IMMOBILIZED DRUGS
 DRUG-RELEASING COATINGS
 ANTI-NEOPLASTIC DRUGS
IMMUNOSUPPRESSIVE AGENTS
 INHIBITORS OF THE EXTRACELLULAR...
 CONCLUSION
 REFERENCES
 
Paclitaxel is a microtubule-stabilizing agent with anti-proliferative activity that interferes with the mitotic spindle in the M-phase, thereby preventing progression to anaphase and subsequent proliferation. Furthermore, it can inhibit migration of cells. Paclitaxel-eluting stents showed dose-related anti-restenotic efficacy in animal models.17–19 At high doses, however, fibrin deposition was enhanced and vascular wound healing impaired.20 A number of clinical studies in Asia, Europe, and the United States have been completed. The ASPECT trial was a dose-finding study comparing stents with two doses of paclitaxel with conventional stents.21 Paclitaxel was directly bonded to the metal surface, without the use of a polymer layer. High-dose paclitaxel reduced angiographic late loss to 0.29 mm compared to 1.04 mm in the control group. The binary angiographic restenosis rate was reduced from 27% to 4%. A sub-study using intravascular ultrasound to examine the stents at follow-up showed a dose-dependent reduction of in-stent tissue from 31 ± 22 mm3 in non-coated, to 18 ± 15 mm3 with the low-dose, and 13 ± 14 mm3 with the high-dose.22 In the ELUTES trial, 4 incremental dosages (0.2, 0.7, 1.4, and 2.7 µg·mm–2 stent surface area) of paclitaxel directly attached to the abluminal surface of V-Flex Plus coronary stents were compared with non-coated control stents.23 In the 190 patients recruited, there was a dose-dependent decrease in angiographic diameter stenosis (34% in controls vs. 14% in the highest paclitaxel-coating group; p = 0.006) and restenosis rate (21% in the controls vs. 3% in the highest paclitaxel-coating group; p = 0.056). In the small but randomized TAXUS I trial, the polymer-based paclitaxel-eluting NIR-stent (n = 31) reduced angiographic late loss at 6 months to 0.35 mm vs. 0.71 mm (p = 0.007) in 30 non-coated controls.24 This resulted in a reduction of the 6-month angiographic restenosis rate from 10% to 0% (p = 0.11). Six-month major adverse cardiac event rates were 6.7% in the bare-stent group and 0% in the drug-eluting stent group (p = 0.24), primarily due to a difference in the need for revascularization (p = 0.24).24 In animal studies, a similar paclitaxel dose did not interfere with vascular healing and endothelialization. The results of the TAXUS II study, which recruited 536 patients, showed that the binary restenosis rate was significantly lower in both the slow-release formulation (2.3% vs. 17.9%; p = 0.0002) and moderate-release formulation (4.7% vs. 20.2%; p < 0.0001) than the bare-stent group.25 These preliminary findings were confirmed in the recently reported TAXUS IV study, which was a large scale (n = 1,314) prospective double-blind randomized multicenter trial to examine the safety and efficacy of a slow-release polymer-based paclitaxel-eluting Express2 stent.26 The primary endpoint, target vessel revascularization at 9 months, was significantly reduced from 12% in the bare-metal stent to 4.7% in the paclitaxel-eluting stent groups (p = 0.001).26 The corresponding values at 1-year follow-up released at the American Heart Association Scientific Congress in 2003 were: 16.7% and 6.8%, respectively (p < 0.001). The binary restenosis rates were 26.6% and 7.9%, respectively. A pilot-study (TAXUS III) enrolled 28 patients with in-stent restenosis. At 6-month follow-up, there was one late total occlusion, and 3 other patients showed angiographic restenosis.27

A different slow-release microtubule inhibitor (QP2) was studied with a seamless ensheathed nonbiodegradable-polymer-loaded stent containing 4 mg of the drug.28 At the 3- to 8-month follow-up, a lower restenosis rate was seen in the drug-releasing stent group (n = 31). The subsequent SCORES trial, however, showed an increased rate of adverse events, mainly due to stent thrombosis (12%) occurring later than 30 days, and 4% cardiac-related mortality.29 After enrollment of 266 of the intended 400 patients, this trial was stopped. Actinomycin-D is effective against proliferating cells in all phases of the cell cycle. Animal studies showed a dose-dependent inhibition of in-stent restenosis. A randomized clinical trial (ACTION), studying stents releasing 2 doses versus a bare-metal stent, was put on hold prematurely because of lack of efficacy after interim analysis. Follow-up was continued to determine safety. The restenosis rates reported at the 2002 Congress of the European Society of Cardiology were 11% for the controls and 25% for the actinomycin-coated stents, respectively. The main feature of stent failure appeared to be restenosis at the stent edges, which appeared in 17 of the first 39 enrolled patients, and was the main reason for discontinuation of the trial.


   IMMUNOSUPPRESSIVE AGENTS
TOP
 ABSTRACT
 INTRODUCTION
 PATHOPHYSIOLOGY OF RESTENOSIS
 DRUG-ELUTING STENTS
 IMMOBILIZED DRUGS
 DRUG-RELEASING COATINGS
 ANTI-NEOPLASTIC DRUGS
 IMMUNOSUPPRESSIVE AGENTS
INHIBITORS OF THE EXTRACELLULAR...
 CONCLUSION
 REFERENCES
 
Rapamycin (sirolimus), a potent immunosuppressive agent that inhibits cellular proliferation by blocking cell cycle progression in G1-phase, showed a significant reduction of the arterial proliferative response after systemic administration in the porcine coronary model.30 Interestingly, in a small series of atherectomy specimens obtained from patients with in-stent restenosis, gene expression was compared with normal arterial tissue and revealed an over-expression of thrombospondin, heat-shock protein 70, and most pronounced: the binding protein of tacrolimus and sirolimus.31–32 Stent-based sirolimus delivery showed up to 45% dose-dependent reduction in the neointimal area in animal models.33 Clinical studies with implantations performed in 30 patients in South America and 15 in Europe showed angiographic and intravascular ultrasound results with minimal neointima formation.34

Follow-up studies of up to 2 years proved that the results could be sustained.35 The first 30 patients completed their 2-year follow-up in February 2002; between 1 and 2 years, there was no death or target vessel revascularization.36 One patient experienced a myocardial infarction due to occlusion of the target vessel at the proximal stent edge.36 Anecdotal reports suggest that neointimal hyperplasia remains suppressed up to 18 months after the procedure.37

The Randomized Study with the Sirolimus-Eluting Velocity Balloon Expandable Stent (RAVEL), a 238-patient randomized clinical trial comparing the rapamycin-coated stent with bare stents in 19 medical centers was conducted from August 2000 to August 2001.38 Patients with single-vessel disease were randomized to receive either a bare-metal BX Velocity stent or a similar stent coated with sirolimus. The angiographic results after 210 days of follow-up were extremely positive. The sirolimus group had an angiographic late loss of –0.01 mm compared to 0.80 mm, and a restenosis rate of 0% compared to 27% in the conventional stent group (p < 0.0001). Event-free survival was 94% vs. 71% in the conventional stent group. Intravascular ultrasound examination at 6 months demonstrated that intimal hyperplasia expressed as a percentage of the stent volume was 1.4% ± 2.8% in the sirolimus group vs. 28.8% ± 19.7% in the bare-stent group (p < 0.0001).39 The pivotal randomized SIRIUS trial enrolled 1,101 patients in the USA to receive either a sirolimus-eluting or a bare control stent.40 The primary endpoint, the rate of target vessel failure at 9 months, was significantly reduced from 21% with a standard stent to 8.6% with a sirolimus-eluting stent (p < 0.001). The corresponding binary restenosis rate (36.3% vs. 8.9%) and target lesion revascularization rate (16.6% vs. 4.1%) were also significantly reduced. Intravascular ultrasound, which was performed in a subgroup of 250 patients, showed that the sirolimus-eluting stent was associated with a reduction of in-stent obstruction as a percentage of volume (33.4% vs. 3.1%; p < 0.001). Notably, in addition to the reduction in the rate of restenosis, the pattern of post-stenting restenosis also differed with the sirolimus-eluting stent. Whereas the restenotic lesions in bare-metal stents were diffuse, those in sirolimus-eluting stents were more often focal. In this regard, focal restenotic lesions can be easily treated with simple balloon angioplasty, thus avoiding the need for brachytherapy or coronary bypass grafting. In both the RAVEL and SIRIUS trials, the risk of stent thrombosis was not increased.38,40 Two-year results were presented at the American Heart Association Scientific Congress in 2003 and showed sustained benefit in event-free survival (87% vs. 73.4%).

Building on the US SIRIUS experience, 2 additional clinical trials were simultaneously begun in Europe (E-SIRIUS) and Canada (C-SIRIUS).41–42 E-SIRIUS and C-SIRIUS (together called New SIRIUS) were double-blind randomized clinical trials comparing sirolimus-eluting stents with bare-stent controls, with identical inclusion criteria. With the lesson learned from the SIRIUS trial, New SIRIUS used an optimal stent-deployment technique; an in-segment binary restenosis rate of 5.1% in the sirolimus-eluting stent group vs. 44.2% in the bare-metal stent group was obtained. Sirolimus-eluting stent implantation was evaluated as the default strategy for all percutaneous procedures as part of the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry; 508 consecutive patients with de novo lesions treated exclusively with sirolimus-eluting stents (SES group) were compared with 450 patients who received bare stents in the preceding period. At 1 year, the cumulative rate of major adverse cardiac events was 9.7% in the sirolimus group and 14.8% in the control group (p = 0.008); the risk of clinically-driven target-vessel revascularization was 3.7% vs. 10.9%, respectively (p < 0.001). Therefore, unrestricted utilization of sirolimus-eluting stents in the "real world" seems to be safe and effective in reducing both repeat revascularization and major adverse cardiac events at 1 year, compared with bare-stent implantation.43

Everolimus, 40-O-(2-hydroxyethyl)-rapamycin, an orally active immunosuppressive and anti-proliferative compound of the same family as sirolimus, has shown promise in preventing rejection in renal and heart transplantation. None of the 25 patients had restenosis in the small FUTURE I trial.44 In the FUTURE II trial, late loss at 6-month angiography was significantly reduced (0.85 vs. 0.12 mm, p < 0.001) with the everolimus-eluting stent compared to the bare-metal stent. The immunosuppressant dexamethasone was used on the Biodivysio PC-coated stent in a registry including 71 patients (STRIDE). There was one hospital death due to stent thrombosis, and 3 other patients experienced adverse events before 30 days.45 The primary endpoint of restenosis at 6 months was 13%. The sirolimus analogue ABT-578 is a tetrazole-containing macrocyclic immunosuppressant believed to be a potent anti-proliferative agent due to binding to the target molecule FKBP-12. Administered systemically, ABT-578 has been shown to significantly prevent restenosis after balloon angioplasty.46 In vitro, ABT-578 inhibited growth-factor-induced proliferation of coronary artery smooth muscle cells. Preliminary data in the porcine coronary model of stent-induced injury demonstrated that the ABT-578-coated stent appeared to significantly inhibit neointimal response in coronary vessels. Clinical studies on the ABT-578 eluting stent (ENDEAVOUR 1 and 2) have been recently completed. Mycophenolic acid coating on the Duraflex stent also showed positive efficacy results in a porcine model.46 However, the IMPACT registry presented at EuroPCR 2003 failed to show any positive results in reducing restenosis.


   INHIBITORS OF THE EXTRACELLULAR MATRIX AND MISCELLANEOUS
TOP
 ABSTRACT
 INTRODUCTION
 PATHOPHYSIOLOGY OF RESTENOSIS
 DRUG-ELUTING STENTS
 IMMOBILIZED DRUGS
 DRUG-RELEASING COATINGS
 ANTI-NEOPLASTIC DRUGS
 IMMUNOSUPPRESSIVE AGENTS
 INHIBITORS OF THE EXTRACELLULAR...
CONCLUSION
 REFERENCES
 
Drugs in these categories have thus far been studied in preclinical experiments with variable results. An earlier study with DNA encoding for vascular endothelial growth factor showed reduced neointima formation in rabbits, but a recent study with the vascular endothelial growth factor protein was negative.47–48 Batimastat, in a dose that effectively inhibited negative vascular remodeling, proved of only limited efficacy in reducing neointimal thickness by 14% in a stent model in atherosclerotic swine.49 Due to the lack of efficacy in the interim analysis, the first clinical trial with stents loaded with batimastat (BRILLIANT) was prematurely stopped. A preliminary trial involving 30 patients showed that the 17-ß-estradiol-eluting stent was safe. Clinical, angiographic, and intravascular ultrasound analysis was performed at the 6-month follow-up. Two patients exceeded 50% intra-stent narrowing by angiography, whereas no patient experienced edge restenosis, and none experienced a major adverse cardiac event.50

Drug-eluting stents for the prevention of restenosis are currently attracting great interest among scientists in industry and in the medical community. This is due to the promising clinical results reported from studies with the sirolimus- and paclitaxel-eluting stents. Enthusiasm has been further nourished by positive results from laboratory studies with other stents and drugs. Potential problems, such as delayed but not definite neointimal suppression and incomplete vascular healing were, however, observed in high-dose experimental studies. It now becomes clear that not all drug-eluting stents are equally effective. Several projects have been stopped prematurely because of lack of efficacy or even excess adverse events. Anecdotal reports of late thrombotic occlusion were initially ascribed to specific stent configurations or individual drugs, but may now be regarded as an important safety issue for all drug-eluting stents until more and longer follow-up results become available. A substantial rate (20%) of late incomplete stent apposition (ISA) in sirolimus-coated stents compared to 4% in control stents was found in the RAVEL trial.39 Thus far, this observation has not been associated with an increase in clinical events.51 Careful observation of clinical results will show whether this phenomenon bears any clinical relevance. Both sirolimus-eluting stents and paclitaxel-eluting stents have received approval for use in Europe and the United States. The promise of the drug-releasing stents is that they may position percutaneous coronary intervention as first-line therapy in the management of patients with coronary artery disease. This promise has of course to be substantiated by evidence obtained in clinical trials that are currently studying the drug-eluting stent in anatomical subsets such as left main disease, bifurcation lesions, chronic total occlusions, and long lesions.

In the RAVEL trial, ISA, as observed by intravascular ultrasound at the 6-month follow-up, was more frequent in the sirolimus-eluting stent patients than in the control arm.39 This implication was not clear initially due to the lack of post-procedural intravascular ultrasound in the RAVEL protocol. Nevertheless, in the SIRIUS trial, with both post-procedural and follow-up intravascular ultrasound, late-acquired ISA was more commonly observed in the sirolimus-eluting stent group.40 However, in the TAXUS II trial, patients treated with bare-metal stents or paclitaxel-eluting stents had similar rates of late-acquired ISA.52 Nevertheless, these observations by ultrasound of late ISA have not been associated with any adverse events throughout the follow-up period in any of these studies. Notably, late thrombotic stent occlusion was not seen to be more frequent in patients treated with a sirolimus- or paclitaxel-eluting stent, even after clopidogrel discontinuation.

The costs of the currently marketed drug-eluting stent have been perceived as a major limitation in more widespread use of these devices. In an analysis from the RAVEL trial, the utilization of sirolimus-eluting stents resulted in a mean additional procedural cost of 1,286 Euros, compared to the control group. In addition, data from the SIRIUS trial have shown that at one year, the costs of sirolimus-eluting stent implantation were approximately US$300 higher per patient.53 Obviously, the cost estimations derived from the RAVEL and SIRIUS trial cannot be directly extrapolated to other situations, and formal analyses from other clinical scenarios are warranted.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 PATHOPHYSIOLOGY OF RESTENOSIS
 DRUG-ELUTING STENTS
 IMMOBILIZED DRUGS
 DRUG-RELEASING COATINGS
 ANTI-NEOPLASTIC DRUGS
 IMMUNOSUPPRESSIVE AGENTS
 INHIBITORS OF THE EXTRACELLULAR...
 CONCLUSION
REFERENCES
 
While it was once recognized that there were a number of limitations to overcome in the site-specific drug delivery approach, the acceptance of coronary stent implantation as the state-of-the-art revascularization strategy has spread rapidly all over the world. As a direct consequence, exploration of the potential of stent-based local drug delivery has generated tremendous enthusiasm. Nowadays, delivering drugs that prevent restenosis with the coronary stent reflects the most elegant form of local drug delivery and clearly has a number of advantages. With the advent of bioengineering technology, various types of coronary stents coated with different antineoplastic and immunosuppressive agents have been developed. Current trials suggest that a carrier polymer coating on the stent surface would be necessary for effective drug delivery. Sirolimus and paclitaxel are the two drugs most extensively evaluated in early clinical trials (Table 1Go, Figure 1Go), and both have produced unprecedented results of less than 10% restenosis rates in randomized clinical trials. Meanwhile, the evaluation of the drug-eluting stent is entering the second phase, in which its safety and efficacy in more complex lesion subsets and different clinical presentations are being investigated. Long-term safety and efficacy of the sirolimus-coated stent is now available at 4 years. Results, including cost-benefit analyses are expected to have a tremendous impact on the practice of interventional cardiology in the next decade.


View this table:
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  		Table 1. Summary of Landmark Studies on Polymer-based Drug-eluting Stents
 

Figure 1
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  		Figure 1. Angiographic late loss of paclitaxel- and sirolimus-eluting stents.

 


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATHOPHYSIOLOGY OF RESTENOSIS
 DRUG-ELUTING STENTS
 IMMOBILIZED DRUGS
 DRUG-RELEASING COATINGS
 ANTI-NEOPLASTIC DRUGS
 IMMUNOSUPPRESSIVE AGENTS
 INHIBITORS OF THE EXTRACELLULAR...
 CONCLUSION
 REFERENCES
 

  1. Serruys PW, Luijten HE, Beatt KJ, Geuskens R, de Feyter PJ, van den Brand M, et al. Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon. A quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months. Circulation 1988;77:361–71.[Abstract/Free Full Text]

  2. Nobuyoshi M, Kimura T, Nosaka H, Mioka S, Ueno K, Yokoi H, et al. Restenosis after successful percutaneous transluminal coronary angioplasty: serial angiographic follow-up of 229 patients. J Am Coll Cardiol 1988;12:616–23.[Abstract]

  3. Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994;331:496–501.[Abstract/Free Full Text]

  4. Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med 1994;331:489–95.[Abstract/Free Full Text]

  5. McBride W, Lange RA, Hillis LD. Restenosis after successful coronary angioplasty. Pathophysiology and prevention. N Engl J Med 1988;318:1734–7.[Medline]

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