Drug-eluting stents

Cardiovascular Radiation Medicine 3 (2002) 226 – 241

Drug-eluting stents From bench to bed Ron Waksman* Division of Cardiology, Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010, USA Received 24 March 2003; accepted 25 March 2003

Abstract

The introduction of stents to clinical practice in 1987 was the major breakthrough in the field of percutaneous coronary intervention (PCI). The use of stenting has drastically improved the outcomes of traditional PCI. First stents were approved for bailout and treatment of dissections, reducing dramatically the need for emergent coronary artery bypass grafting (CABG) as a result of vessel closure during PCI. Later stents were proven to reduce the restenosis rate of PCI from 30% – 40% with balloon angioplasty to 15% – 20% with stents, primarily by eliminating elastic recoil and vascular remodeling as shown by intravascular ultrasound (IVUS) studies. These outcomes have led to a wide acceptance of stenting as the strategy of choice for more than 80% of all PCI procedures performed. The current review focuses on the following topics: (1) strategies in drug selection to reduce neointimal proliferation, (2) stent designs and polymer selection as a platform for drugeluting stents, (3) review of major preclinical and clinical experimental work performed in the field, and (4) a discussion of the potential and limitations of the technology. D 2003 Elsevier Inc. All rights reserved.

Keywords:

Stents; Restenosis; Radiation

1. Introduction The introduction of stents to clinical practice in 1987 was the major breakthrough in the field of percutaneous coronary intervention (PCI) [1]. The use of stenting has drastically improved the outcomes of traditional PCI. First, stents were approved for bailout and treatment of dissections, reducing dramatically the need for emergent coronary artery bypass grafting (CABG) as a result of vessel closure during PCI [2]. Later, stents were proven to reduce the restenosis rate of PCI from 30 –40% with balloon angioplasty to 15 – 20% with stents, primarily by eliminating elastic recoil and vascular remodeling as shown by intravascular ultrasound (IVUS) studies [3 –6]. These outcomes have led to a wide acceptance of stenting as the strategy of choice for more than 80% of all PCI procedures performed. The introduction of stents was associated with two serious complications, however. The first was an increase

* Tel.: +1-202-877-8575; fax: +1-202-877-2715. E-mail address: [email protected] (R. Waksman). 1522-1865/02/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1522-1865(03)00115-X

in subacute thrombosis within the first 30 days of stent implantation later controlled with the use of antiplatelet therapy [7], and the second was the phenomenon of in-stent restenosis that was primarily caused by smooth muscle proliferation and matrix synthesis, treated today with the use of vascular brachytherapy [8– 18]. The goal to eliminate restenosis, or at least to reduce its rate to a single digit, has stimulated researchers to explore new technologies and adjunct therapy modalities to restore and preserve the acute and long-term outcomes following stenting. The three major components of restenosis following PCI that should be targeted include the following: (1) an exuberant cellular proliferation and matrix synthesis (intimal hyperplasia) triggered by injury to the vessel wall [12]; (2) an acute elastic recoil immediately following balloon deflation; and (3) a late vascular contraction (remodeling) resulting in a decrease in total vessel diameter [6]. While coronary stenting eliminates elastic recoil and vessel contracture by acting as a mechanical scaffold within the vessel, it is unable to inhibit excessive neointimal formation. Stents were associated with an increase of neointimal formation compared to balloon angioplasty as a result of excessive injury

R. Waksman / Cardiovascular Radiation Medicine 3 (2002) 226–241

to the vessel wall, and the inflammatory process resulted from the interaction of the metal with the vessel wall. Furthermore, platelet activation, cytokines release and matrix production contribute to the process of restenosis following stenting [13 – 15]. While radiation therapy demonstrated success in the reduction of in-stent restenosis, it failed to obtain a singledigit restenosis rate for de novo lesions especially when coupled with stents, either as a platform of the radioactive stent or a catheter-based system [16 – 18]. Nevertheless, the experimental work with vascular brachytherapy guided the direction for prevention of restenosis by focusing primarily on antiproliferative therapy and by intervening in the cell cycle; although the potential of other strategies such as antiinflammatory, antimigratory and proendothelial are being examined with the drug-eluting stent technology [19]. The failure of systemic drug therapy to inhibit restenosis was explained by underdosing to the treated target vessel. Effective systemic doses were toxic and could not be tolerated by the patients. Thus, local delivery of the potential agents for inhibition of neointimal formation to the site of the lesion was considered the desired approach. However, local drug delivery utilizing a catheter-based system was associated with lack of drug retention at the target site, and in some instances, it enhanced the injury at the injected site. Thus, the concept of drug-eluting stents is attractive if the desired drugs can be loaded on the stents and released homogenously across the target vessel over

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time to obtain a sustained biological effect that will prevent the restenosis process. The current review focuses on the following topics: (1) strategies in drug selection to reduce neointimal proliferation; (2) stent designs and polymer selection as a platform for drugeluting stents; (3) review of major preclinical and clinical experimental work performed in the field; and (4) a discussion of the potential and limitations of the technology.

2. Drug selection and mechanisms of action to reduce neointimal proliferation Detailed understanding of the biological events that follow stent implantation has led to a selection of agents for drug-eluting stents that target specific elements of this biologic process. Furthermore, agents have been selected based on physicochemical properties that optimize deposition and retention in the vessel wall following delivery. Most agents proposed for this technology carry broad biological actions and act on different phases of the cell cycle (Fig. 1). For example, sirolimus and taxol are antiproliferative, but also carry antiinflammatory properties and possess immunoregulatory function, despite the classification of several drugs by its main mechanism of action, as shown in Table 1. There are multibiological mechanisms that determine efficacy and toxicity of these agents. For example, antiproliferative agents that inhibit smooth muscle cell

Fig. 1. Mechanisms of action.

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Table 1 Drug selection for restenosis prevention Antiinflammatory immunomodulators

Antiproliferative

Antimigratory ECM inhibition

Dexamethasone M-prednisolone Interferon g-1b Sirolimus Tacrolimus Cyclosporine Everolimus Tranilast Mycophenolic acid Mizoribine Lefunomide

Taxane QP Paclitaxel Actinomycin Methothrexate Angiopeptin Vincristine Mitromycine c-myc-antisense Abbott ABT 578 RestenASE 2-Chloro-deoxyadenosine

Batimastat Prolyl hydroxylase inhibitors Halofuginone C-proteinase inhibitors Probucol

proliferation can potentially slow endothelial regrowth and increase the prevalence of late thrombosis. Such a phenomenon was seen with vascular brachytherapy and controlled with prolonged antiplatelet therapy [20,21]. Another approach is to classify the drugs by their physicochemical properties such as solubility, diffusivity, partitioning coefficients, as well as protein binding. For example, hydrophilic drugs such as heparin readily permeate into tissue but are also rapidly cleared. In contrast, hydrophobic drugs diffuse poorly following delivery, thereby allowing higher doses to be maintained in blood vessels. Sirolimus and paclitaxel are highly hydrophobic and would, therefore, predictably reside longer in the blood vessel, while drugs that are more water-soluble or have greater diffusivity might well require prolonged delivery in order to achieve prolonged vessel wall exposure. Although both hydrophilic and hydrophobic drugs show large spatial concentration gradients in the arterial wall, hydrophobic agents appear to distribute better and more homogenously into the arterial wall than hydrophilic agents.

3. Antiproliferative and immunomodular agents

Healing and reendothelialization promoters BCP671 Statins VEGF Estradiol

Wyeth-Ayerst Laboratories (Philadelphia, PA) and approved by the Food and Drug Administration for the prophylaxis of renal transplant rejection in 1999 [22,23]. Sirolimus has its roots in Easter Island, where an actinomycete streptomyces hygroscopicus that produced a novel macrolide antibiotic with potent antibiotic, potent antifungal, immunosuppressive and antimitotic activities was found. Sirolimus binds to an intracellular receptor protein and elevates p27 levels, which leads to the inhibition of cyclin/ CDK complexes and ultimately induces cell-cycle arrest late in the G1 phase. It inhibits proliferation of both rat and human smooth muscle cells in vitro and reduces intimal thickening in models of vascular injury [23 –25]. Sirolimus inhibits T lymphocyte activation and proliferation, which occurs in response to antigenic and cytokine stimulation; however, its mechanism is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK binding protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the phase progression of the cell cycle [24,25]. Sirolimus embedded on the stent allows local drug levels in the vessel wall to 4 Ag/mg of the artery, while the blood levels are almost nil.

Two different strategies to control the neointimal proliferation after vascular injury are proposed. First is the cytostatic approach, which aims to control the regulation and expression of cell cycle-modulating proteins at any level along the pathway-modulating cell proliferation. Second, the cytotoxic approach—killing proliferating cells— has the disadvantage of induction of necrosis, which may contribute to vessel wall weakening. Among the antiproliferative agents proposed for this application are the following: sirolimus and its analogues, taxol derivatives, tacrolimus and a variety of antineoplastic drugs such as actinomycin D, vincristine, doxorubicin, vinblastine, suramin and so on.

The initial success with sirolimus has led to the search of sirolimus analogs. Among these are everolimus (a new macrocylic triene derivative) [26], ABT 578 and other antiimmunosuppressive compounds such as mycophenolic acid, cyclosporine and tacrolimus, which inhibit proliferation via G1 arrest and reduce the immune response.

3.1. Sirolimus (rapamycin)

3.3. Paclitaxel

Sirolimus (rapamycin, Rapamune), a natural macrocyclic lactone, is a potent immunosuppressive agent developed by

Paclitaxel is an antimicrotubule agent initially isolated from the Pacific yew tree (Taxus brevifolia) [27]. Paclitaxel

3.2. Sirolimus analogues

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is the active ingredient in the drug Taxol (Bristol-Myers Squibb). It is a diterpenoid with a characteristic taxane skeleton of 20 carbon atoms and a molecular weight of 853.9 Da. Paclitaxel has been used in the treatment of cancer primarily in the breast and ovaries [28]. Systemic paclitaxel effectively inhibited vascular smooth muscle migration and proliferation in animal models [29,30]. It is primarily an antiproliferative agent selected for stent-based application with and without polymer to inhibit neointimal proliferation. It is inhibiting cell replication predominantly in the G0/G1 and G2/M phases of the cell cycle. Paclitaxel is a highly lipophilic agent. It alters microtubular dynamics and prevents microtubule deconstruction during cellular mitosis that interferes with cell division, motility, activation, secretion and signal transduction. High-dose (HD) application leads to inflammation cell loss, medial thinning and increased risk of stent thrombosis, whereas moderate dosages are supposed to enable biocompatible responses, reendothelialization and positive remodeling. 3.4. Matrix metalloproteinase inhibitors Batimastat is a matrix metalloproteinase (MMP) inhibitor, which acts by chelating zinc and inhibiting the MMP enzymes [31]. These enzymes can degrade all compounds of the extracellular matrix including cell migration and proliferation. Studies with batimastat loaded into phosphorylcholine-coated stents failed to reduce restenosis in clinical trials. 3.5. Antiinflammatory agents The inflammatory component of restenosis, seen primarily with stents, led to the investigation of whether antiinflammatory agents loaded onto stents can be effective in the reduction of neointimal proliferation following stent implantation. The targets are leukocytes, monocytes, macrophages and a variety of cytokines seen after vascular injury. Among the antiinflammatory agents proposed are the anti-P-selectin, M1/70, and interleukin-10, which have shown significant reduction of neointimal hyperplasia in animal models [32]. Corticosteroids have a broad range of antiinflammatory and immunosuppressive activities [33]. They also have been shown to inhibit the formation of platelet activating factor. Steroids were tested systemically and locally for the prevention of restenosis [34 – 36]. Several approaches were used with coated stents utilizing different polymers. Recently, dexamethasone was loaded onto stents with PC coating and was tested in humans. The preliminary results have demonstrated lower binary restenosis and late loss and initiated a dose-finding study. Other antiinflammatory agents tested are ibuprofen, colchicines, estrogen, angiopeptin, tranilast, antioxidants including probucol and lipidlowering agents (Table 1).

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3.6. Antisense Local intracoronary administration of antisense oligonucleotide against c-myc for the prevention of in-stent restenosis has been evaluated in clinical trials [37,38]. The drug is a chimeric DNA/RNA ribosome-based molecule engineered for better stability of the ribosome’s substrate binding sequence—specifically bindings—and cleaves the PCNA target sequence. PCNA is involved in the initiation of the cell proliferation. An approach to load the antisense on a stent has been attempted with mixed results in preclinical evaluation. 3.7. Strategies to promote healing and reendothelialization In contrast to the agents outlined earlier in this section, which primarily inhibit biological activity, a strategy to promote healing and reendothelialization may indirectly reduce the trigger for proliferation and inflammation by rapidly restoring the injured endothelium and its functions. A number of studies have shown the role of endothelial growth factors (EGF), fibroblast growth factors (FGF) and vascular endothelial growth factors (VEGF) in modulating the reendothelialization process [39 – 41]. Other strategies to promote endothelial regeneration are the incorporation of circulating endothelial progenitor cells, which can be implanted on the stents to enhance healing, and other healing promoters such as 17-h-estradiol [42]. The latter have led to clinical trials using the BiodivYsio matrix platform, with reports on lower restenosis rates. Other drugs have been claimed to potentially enhance healing and minimize the neointimal formation by various mechanisms such as antioxidants with vitamins, probucol and statins [43,44]; antiinflammatory drugs with tranilast [45,46]; or antihormonal drugs with angiopeptin [47,48]. Some showed promising results in preclinical and Phase I clinical trials when given systemically and are now being tested on a stent platform.

4. Impact of stent design and polymer technology A drug-eluting stent is a device that presents or releases one or more bioactive agents to tissue at and near implant. The agents may be released into the blood stream and into the blood vessel wall, its cells, plaque or tissues adjacent to the stent or at a distance from it. Drugs can be embedded and released from within (matrix type) or surrounded by and released through (reservoir type) polymer materials that coat (strut adherent) or span (strut spanning) the stent struts. In other formulations, the drug may be linked to the stent surface without the need for a coating by means of detachable bonds that release with time. They can be removed by active mechanical or chemical processes or can be in a permanently immobilized form that presents the drug to flowing blood. The stent

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Fig. 2. Vascular compatibility with BSC polymer.

platform may be a simple modification of clinically available devices or may be specially designed for drug elution. Endoluminal stents may prove to be the ideal platform for local delivery, because they are deployed in direct contact with the vessel wall. Stent design and geometry should play a role in the reduction of restenosis with and without drugs [49,50]. Bare stents with various strut thickness and stent design or passive coating, as well as surface texture, may determine the degree of injury and may influence the degree of neointimal formation [51 – 58]. It would be essential to enable homogenous drug distribution through the entire vessel surface in contact with the stent. Special care should be attributed to handling the edges with minimum trauma and a sufficient amount of the drug. It is possible that stents for drug elution will be customized in configuration to control drug diffusion to the vessel wall for restenosis and other potential indications. Stent-based drug delivery has been accomplished via several approaches: (1) bare stents dipped or sprayed with the selected drug; (2) metal stents coated with degradable or nondegradable polymers, which may be loaded with a drug, permitting gradual and sustained local delivery, and control the release with and without top coating; and (3) polymeric stents, constructed entirely of biodegradable substances that elute therapeutic agents over time. The key feature of these

polymers is their compatibility with the vessel wall as shown in Fig. 2. Although some drugs such as Taxol, due to its lypophilic properties, may be loaded on a bare stent, there could potentially be a lack of control of the pharmacodynamics. Another potential concern is the amount of drug that will elute from the stent prior to the stent implantation. However, preclinical studies in the porcine model and the pilot clinical trials using Taxol loaded on a bare stent demonstrated safety and efficacy. Stent coating and polymers have an important role in the coordination of drug release to the vessel wall, either via degradable or nondegradable polymers. The majority of the polymers utilized for stent coating have induced substantial inflammation in experimental models. However, other polymers were associated with less inflammatory response. Among those are poly-L-lactic acid (PLLA) and tyrosine kinase inhibitor. Among other materials being tested for potential coating are the following: duraflex, urethane, silicone, acryl, styrene, ceramic and carbofilm [59 –66]. The polymers can serve as a depot for drug elution and control diffusion either by a top coat, by self-erosion with the drug or by serving as a barrier between the drug and the vessel wall. For example, the sirolimus-eluting stent used the BX Velocity stent as a platform in various lengths and diameters. The stent contains 140 g/cm2 of sirolimus. The

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coating formulation consists of 30% sirolimus by weight in a 50:50 mixture of the polymers polyethylenevinyllacetate (PEVA) and polybutylmethcrylate (PMBA). The thickness of the two layers on the stent is 5 – 10 Am. To prolong the drug release, drug-free polymer is applied on the top of the drug – polymer matrix, introducing the barrier (Fig. 3). However, major potential hazards can occur by coating stents with polymers including chronic inflammation, especially when the drug is gone, direct local toxicity to the vascular tissue, polymer incompatibility with circulating humoral factors and, finally, polymer breakdown and erosion. The polymer must deliver the antirestenotic therapy in a fashion that assures that it reaches the desired target at the physiologically appropriate time, while remaining truly biologically inert. In addition, an effective polymer coating must be nonthrombogenic and be able to tolerate the mechanical stresses involved in stent deployment without altering its physical or biologic properties. In an experimental model, fibrin-coated tantalum stents permitted local delivery of heparin to porcine coronary arteries. These experimental stents reduced thrombosis, inflammation and death when compared with polyurethane-coated control stents. Furthermore, inert polymeric coatings, including phosphorylcholine (a highly hydrophilic molecule), have been introduced into clinical usage, with potential beneficial effects on thrombus deposition and no adverse effects on late vessel healing. Further plans are to use this coating as the sole platform for drugs such as estrogen, dexamethasone, antisense and ABT 587 (a rapamycin analog). The BiodiviYsio stent employs a phosphorylcholine coating of 50 –100 nm thickness and can serve as a depot for drug elution. An added layer of complexity lies in determining drug concentrations following local stent-based delivery.

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Use of tracer compounds as markers or models of bioactive compounds is limited because the pharmacokinetics and pharmacodynamics within vessels can vary markedly, depending on the agent and the state of the vessel (diseased, atherosclerotic or normal). Polymers can also serve as a barrier between the stent and the vessel wall. Polymeric gel paving demonstrated in experimental models show the potential to serve as a barrier to circulating mitogens.

5. Preclinical data The porcine coronary model was utilized to detect in vivo pharmacokinetics and drug concentration in blood, in the coronary artery wall at the immediate implant site and in tissue directly juxtaposed to the stent, which should be measured at multiple time points. These times should cover the range of elution, from immediately after implantation, until the time when most of the drug is eluted. Drug concentrations were also measured in distal tissue supplied by the stented artery segment in short-term, acute (hours to days) studies. The rabbit iliac model is also utilized to examine the effectiveness of drug-eluting stents. Fig. 4 demonstrates the dose response of actinomycin D in rabbit iliac arteries. The porcine model is also utilized to determine the safety and efficacy of various drugs and polymers for different time points, varying from 30 days to 6 months. The intent of these studies is to demonstrate reduction of neointimal formation vs. control at 30 days without an increase in vessel toxicity (e.g., fibrin deposition, thrombosis and vessel necrosis). The degree of reendothelialization is examined via electron microscopy. The durability of the effect is examined at 90 and 180 days. Although animal studies

Fig. 3. Control of drug release from the stent.

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Fig. 4. Dose response of actinomycin D in rabbit iliac arteries.

are mandatory prior to clinical trials, they are not always predictive of the clinical outcome, especially with dichotomy in the recurrence rate at 6 months in preclinical evaluation and longevity of the results over a period of 2 years in humans (Fig. 5). Interesting examples, when the

clinical results did not mimic the preclinical results, were demonstrated with actinomycin D [67], tacrolimus and batimastat. They all showed promising results at 30 days in the porcine coronary model, with lack of efficacy and some toxicity in the clinical trials.

Fig. 5. Long-term efficacy of a sirolimus-eluting stent (preclinical vs. clinical experience).

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5.1. The sirolimus-eluting stents In vivo pharmacokinetic studies in the porcine coronary model demonstrated that whole blood concentration of sirolimus peaks at 1 h to 2.63F0.74 ng/ml after stent deployment, and then declines below the lower limit of detection to 0.4 ng/ml by 3 days. In contrast, with oral rapamycin, the measured chronic blood levels are between 6 and 17 ng/ml. The drug is almost completely eluted by 15 days after implantation in fast release formulation, and a modification of the release by the topcoat polymer extends the release to within similar tissue levels at 28 days. The efficacy studies in the porcine coronary model demonstrated 50% reduction in the neointima with sirolimus, when compared to bare stent at 28 days. However, at 90 and 180 days, the degree of neointima was similar for the control vs. the sirolimus stent. Although reendothelialization was similar in both groups, there was detection of less inflammation in the sirolimus group. In addition, the evaluation of arterial wall protein documented a 70% reduction in the inflammatory cytokine MCP-1 for the sirolimus stent [68 – 71].

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this drug. Also, the dip-coating technique without the use of polymers has demonstrated dose response in porcine coronary arteries. Other interesting observations with the paclitaxel drug were as follows: thinning of the media, excess of fibrin, medial wall hemorrhage and cell necrosis. As with sirolimus, the efficacy in reduction of neointima formation was shown at 28 days. Additionally, in one study of rabbit iliac arteries, the use of polymer-coated stents releasing 200 Ag effectively suppressed neointimal proliferation at 90 days [72,73]. Heldman et al. [74] and Farb et al. [75] also reported delayed healing and increase of local inflammation and fibrin deposition with these stents. In the porcine model of dip-coated stents, a dose response for inhibition of neointima formation was demonstrated. Finally, the elution of various doses of paclitaxel (42.0, 20.2, 8.6, 1.5 and 0 Ag per stent) from a biodegradable polymer (chondroitin sulfate and gelatin) was addressed in rabbit iliac. After 28 days, the two high doses were associated with a significant reduction of neointimal proliferation. However, with the same dose, there was incomplete healing with intimal hemorrhage and increased adventitial inflammation.

5.2. The paclitaxel-eluting stent 6. The clinical trials Preclinical trials were reported utilizing Taxol, both with and without polymers. The initial studies with nonbiodegradable polymeric stent coating were associated with high degrees of inflammation, thrombosis and necrosis. A dose response experimental work detected the optimal dose for

Most compounds were tested initially in small pilot trials, after demonstrating safety and efficacy. Pivotal studies have been initiated. Table 2 outlines the status of the clinical trials with drug-eluting stents up to January 2003.

Table 2 Comparison of completed randomized drug-eluting stent trials RAVEL

SIRIUS

Taxus II SR

Taxus II MR

ASPECT a

ELUTESb

DELIVER

No. of patients Drug Stent Lesion length (mm) RVD (mm) Diabetes mellitus (%) MACE at 30 days (%)

238 Sirolimus BX Velocity <15 (9.56) 2.5 – 3.5 18 2.5

1058 Sirolimus BX Velocity 15 – 30 (14.4F6) 2.5 – 3.5 26 2.4

261 Paclitaxel Express <12 (10.6F4) 3.0 – 3.5 11 2.0

264 Paclitaxel Express <12 (10.7F4) 3.0 – 3.5 17 2.0

177 Paclitaxel Supra G (nonpolymer) <15 (10.9F4) 3.0 – 3.5 20 1.0

140 Paclitaxel V Flex P nonpolymer) <15 (11.1F1) 3.0 – 3.5 16 8.0

1042 Paclitaxel Penta (nonpolymer) <25 (11.7F5) 2.5 – 4.0 29 1.2

Restenosis (%) Control Active

26 0

32 9

22 5

22 9

27 4a

21 3b

21 – 22 16 – 17

Late loss Control (mm) Active (mm)

0.8 0.01

0.81 0.24

0.79F0.45 0.31F0.38

0.77F0.50 0.30F0.39

1.04F0.83 0.29F0.72

0.73F0.12 0.10F0.12

N/A N/A

TVR/TVF (%) Control Active

22.9 0.8

19.2/21 6.4/8.6

14.3 7.7

17.7 6.2

3.4 3.4

10.2 3.4

14 – 15 11 – 12

MACE (%) Control Active

17.1 3.3

18.9 7.1

19.5 8.5

20 7.8

4 – 10 4 – 33

11 11

N/A N/A

a b

ASPECT: Only the high dose and the control are presented in the table. ELUTES: Only the high dose (2.7Ag/mm2) and the control are presented in the table.

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6.1. First in humans The first studies in humans with the sirolimus stent were performed in two centers and were reported by Sousa et al. [76] Two types of drug release formulations were evaluated: fast release, which releases 100% of the drug (140 Ag/cm2) in the first 15 days in 30 patients; and a slow release of 100% of the drug, which releases 20% of the drug in the first 15 days in 15 patients. Overall in the study, 45 patients were enrolled—30 in Sa˜o Paulo, Brazil, and 15 in Rotterdam, The Netherlands. Patients were evaluated at 4 months, 1 year and 2 years. There was minimal neointima formation measured by QCA and IVUS, with minimal late loss in lumen diameter over 2 years of follow-up [77,78]. At 2 years, one patient from the fast release group developed restenosis at the target lesion, one patient underwent CABG due to progression of disease, one patient sustained myocardial infarction presumably due to rupture plaque, one patient suffered a subacute occlusion due to an edge dissection and one patient had a fatal stroke. A series of angiograms at 2-year follow-up are presented in Fig. 6. Three-year follow-up continues to demonstrate durability of the results without evidence of late restenosis. 6.2. The Randomized Study with the Sirolimus-Eluting BX Velocity Balloon-Expandable Stent (RAVEL) The RAVEL trial is a multicenter, medium-scale trial designed to determine the safety and efficacy of the use of the sirolimus vs. bare stent in patients with Type A de novo lesions. The sirolimus stent was used in 120 patients, and

the bare stent in 118 patients. Overall, the mean lesion length was 9.6 mm, and the reference vessel diameter was 2.6 mm. The degree of neointimal proliferation, manifested as the mean late loss, was significantly lower in the sirolimus stent group (0.01F0.33 mm compared to 0.80F0.53 mm, P<.001). The binary restenosis rate in the sirolimus group was 0% vs. 26.6% of those in the standardstent group ( P<.001) [79,80]. There were no episodes of stent thrombosis and at 1-year follow-up, the overall rate of major cardiac events was 5.8% in the sirolimus-stent group and 28.8% for the bare stent driven by the revascularization of the target vessel. IVUS performed in a subset of 95 patients from the RAVEL demonstrated nearly complete abolition of the neointima in the sirolimus group. In addition, patients with sirolimuseluting stents revealed 21% (10/48) incomplete stent apposition vs. 4% (2/47) of patients with uncoated stents. This phenomenon of late stent malapposition was not associated with any clinical events [81]. 6.3. The SIRIUS trial The SIRIUS trial is a multicenter, large-scale, 1101 randomized, double-blind study of the SIRolImUS-coated BX Velocity stent for patients with de novo lesions. This pivotal study was designed to examine the efficacy and safety of the sirolimus-coated stent in a more difficult subset of patients; 24.6% had diabetes and longer lesions (15 – 30 mm) located in smaller vessels (2.5 – 3.5 mm). Eight-month follow-up performed on 85% of patients detected 10.5% diameter stenosis in the sirolimus and 40.1% in the control stent ( P<.001). The binary in-stent

Fig. 6. Results: 2-year follow-up with sirolimus-coated stent.

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restenosis rate in patients receiving the sirolimus-eluting stent was 3.2% vs. 35.4% in the control group ( P<.001) [82]. However, for the in-segment analysis including the stent margins, the binary restenosis in the sirolimus group was 8.9% compared to 36.3% in the controls ( P<.001). This edge effect was more prominent in the proximal edge of the sirolimus stents in smaller vessels. Clinical events at 9 months demonstrated target vessel failure (TVF) of 8.6% in the sirolimus group vs. 21.0% in the control group ( P<.001). The safety of the sirolimus-eluting stent was also demonstrated in the SIRIUS study with no evidence of late thrombosis and with similar rates of death (0.9%) and myocardial infarction (2.8%) in the sirolimus group, compared to 0.6% and 3.2% in the control group, respectively. Yet, stent malapposition was reported in 10% of patients who underwent IVUS evaluation. The SIRIUS study identified subsets of patients and lesions that continued to experience high rates of restenosis, despite the sirolimus-eluting stent. Specifically, insulindependent diabetic patients had 35% of restenosis and late loss of 0.59 mm that was not significantly different from the control stent in this subset of patients. Other subsets of patients with restenosis that varied from 16% to 18% were patients with long lesions and small vessels. Overall, however, the sirolimus stent was superior for every subset of patients and lesions in this study. 6.4. Other sirolimus studies Other registries using the sirolimus-eluting stents are being conducted to evaluate the efficacy and safety of this technology for other indications. The efficacy of the sirolimuseluting stents for bifurcated lesions revealed focal stenosis at the side arm in up to 29% of the lesions [83]. The efficacy of the sirolimus-eluting stent for the treatment of in-stent restenosis was examined in two small registries, with excellent results for focal in-stent restenotic lesions and high major adverse events in another registry with a complex subset of patients some who had total occlusion and failed prior radiation treatment [84,85]. A randomized study of the drug-eluting stent vs. vascular brachytherapy will determine the yield of this technology for this application. The utility of the sirolimus-eluting stent in acute coronary syndrome and the total occlusion vein grafts for patients who failed brachytherapy are under investigation, but the ‘‘real world’’ of sirolimus-eluting stents will be examined in the postmarketing surveillance registries after approval of the technology.

7. Paclitaxel Three formulations using paclitaxel or taxane with and without polymers were tested clinically. The status of these studies is summarized in Table 2.

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7.1. The Study to Compare Restenosis Rate Between QueST and QuaDS-QP2 (SCORE) trial The SCORE trial examined stent-based delivery of the taxane derivative 7-hexanoyltaxol (QP2). In this trial, 127 patients were treated with the QuaDS-QP2 drug-eluting stent, a Quanam stainless-steel stent wrapped with polymer sleeves designed to elute QP2 in a controlled fashion; 139 patients were treated with QUEST (bare) stent. A significant reduction in restenosis was observed at 5-month follow-up, with 0% restenosis in the treatment group and 52% in the control group [86,87]. However, late thrombotic events occurred in 8% of those treated with the QP2-eluting stent vs. 0% in those who received the bare stent. The late thrombosis continued beyond 6 months and the study was halted. 7.2. The Taxus trials The Taxus trials are utilizing a nonerodible polymercoated stent to control local delivery of paclitaxel. The Taxus I trial examined the safety and efficacy of the paclitaxel-eluting stent. Fifty-eight patients were randomized to receive either paclitaxel-eluting or bare stent. At 6 months angiographic follow-up of the paclitaxel stent was 0% vs. 11% in those treated with the bare stent, with overall diameter stenosis of 13.2% in the vessel treated with paclitaxel-eluting stent vs. 27.5% in those treated with the bare stent [88]. The results of the study continued to demonstrate efficacy at 12 and 24 months. In Taxus II, two different types of release (moderate and slow) of paclitaxel were compared to the bare stent. In Taxus II, 537 patients with short lesions (<12 mm) in large vessels (3.0 – 3.5 mm) were enrolled. A total of 269 patients were enrolled in the moderate release arm and 267 patients in the slow release arm of the study. The primary end point was percent of in-stent net volume obstruction as assessed by IVUS at 6 months. In the moderate release arm of the study, the in-stent volume obstruction was 7.8% in the eluting stent group vs. 20.5% in the bare stent group ( P < .001). The in-segment restenosis was 5.5% and 20.1%, respectively [88]. The overall target vessel revascularization (TVR) was 6.2% in the paclitaxel arm vs. 17.7% in the bare stent ( P=.007). Similar results were observed in the slow release arm, with in-stent volume obstruction of 7.8% in the paclitaxel group and 23.2% in the bare stent group ( P<.001), while the TVR was 7.7% vs. 14.3% ( P=NS) [89]. In both the slow and moderate release arms, there was no evidence of late thrombosis to edge effect, and the benefit of the paclitaxel-eluting stent was even beyond the stent margins. The Taxus III study was a small registry using the paclitaxel-eluting stent for 30 patients with in-stent restenosis, less than 30 mm in length, using the slow release formulation [90]. At 12 months, there was no stent thrombosis, but overall MACE was 28.6% at 6 months, with

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Fig. 7. Geographic miss between two TAXUS stents.

target lesion revascularization of 21.4%. In part, the restenosis in this study was attributed to geographic miss, as shown in Fig. 7. Taxus IV is the pivotal study using the slow formulation of the paclitaxel-eluting stent on the Express stent. The objectives of this study are to demonstrate safety and superior performance of the paclitaxel stent for treatment of de novo lesions. In the study there were 1326 patients with de novo lesions up to 32 mm in length with 2.5 –3.5 mm vessel diameter. At 30 days, the overall MACE was 30% in both treatment groups. The complete follow-up is due in the autumn of 2003. 7.3. Asian Paclitaxel-Eluting Stent Clinical Trial (ASPECT) and European Evaluation of Paclitaxel-Eluting Stent (ELUTES) ASPECT and ELUTES were designed as dose-finding studies to evaluate a nonpolymeric paclitaxel-eluting stent bound directly to the outer surface of the metal struts. These studies were designed and sponsored by Cook (Bloomington, IN). In ASPECT, 176 patients were randomized to the Supra G stent coated with HD (3.1 Ag/mm2) paclitaxel, low-dose (LD; 1.3 Ag/mm2) paclitaxel or to an uncoated stent. The primary end point of mean angiographic percent diameter stenosis at 4 – 6 months was 39% in the control group, 23% in the LD group and 14% in the HD group (LD vs. control P<.001; HD vs. control P<.03; LD vs. HD, P=NS). The corresponding binary restenosis rates were 27%, 12% and 4%, respectively, ( P<.001) [91]. Similar findings were observed by quantification of the mean intimal volume at

IVUS—31 mm3 in the control group, 18 mm3 in the LD group and 12 mm3 in the HD group (LD vs. control P<.001; HD vs. control P<.017; LD vs. HD, P=NS). No subacute stent thrombosis was observed in this study among patients undergoing antiplatelet therapy with aspirin and clopidogrel or ticlopidine. Conversely, among patients undergoing antiplatelet therapy with aspirin and cilostazol (N=37), four (all of whom receive coated stents) suffered subacute stent thrombosis (15% of the patients who received cilostazolcoated stents) [91 –93]. The ELUTES dose-finding study involved 190 patients randomized to 0 (control), 0.2, 0.7, 1.4 or 2.7 mg/nm2 paclitaxel loaded in a polymer-free fashion to a V-FlexPlus stent (Cook). At 6 months, the percent diameter stenosis was 34% in the control group and 33%, 26%, 23% and 14% in the coated stent groups (between control and highest paclitaxel dose, P<.001) [94]. The corresponding binary restenosis rate was 21% in controls and 20%, 12%, 14% and 3%, respectively (between control and highest paclitaxel dose, P=.055). No stent thrombosis was reported. The paclitaxel in-stent pilot study addressed the use of one 16-mm paclitaxel-coated stent in 21 patients with instent restenosis. One in-hospital thrombosis was observed (5%), one patient previously treated with brachytherapy had late thrombosis (5%) and three patients had restenosis (14%). However, none of them had complete stent coverage of the injured lesion. The incidence of MACE on follow-up was 24% [94,95]. The ELUTES in-stent restenosis trial is now randomizing up to 600 patients, with satisfactory results after conventional treatment (i.e., balloon angioplasty or cutting balloon;

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no brachytherapy) for in-stent restenosis to LD or HD paclitaxel-coated stent or to no additional treatment. 7.4. The DELIVER trial The DELIVER study has been investigating the use of the ACHIEVE Drug-Eluting Coronary Stent System (paclitaxel 3 Ag/mm2 loaded on a MULTI-LINK PENTA Coronary Stent System; Guidant) compared to the bare stent in 1043 patients. The study was designed to demonstrate a 40% reduction in the primary end point of the 270-day TVF for the ACHIEVE Drug-Eluting Coronary Stent System as compared to the PENTA Coronary Stent System. The preliminary analysis indicates that although there was a trend toward improvement in TVF, the primary end points were not met. Additionally, while there appears to be a trend toward a reduced angiographic binary restenosis rate (ABRR), the planned 50% reduction in angiographic binary restenosis also was not obtained. The percent reduction in both TVF and ABRR was less than expected (9-month TVF of 14 – 15% and in-segment ABRR of 21 – 22% in the control). There was a higher-than-expected 11– 12% TVF and 16 – 17% in-segment ABRR in the ACHIEVE arm of the study [96]. The DELIVER II trial was designed to examine the performance of the ACHIEVE stent in a more difficult subset of patients. The results are pending. 7.5. The ACTION trial A prospective feasibility study (ACTION) that was intended to examine the safety and efficacy of actinomycin D loaded on a polymer for de novo lesions was prematurely stopped. In the ACTION trial, 360 patients were randomized to the bare MULTI-LINK TETRA-D Drug-Eluting Stent System (Guidant), a 2.5 Ag/mm2 actinomycin Dloaded stent or a 10 Ag/mm2 loaded stent. Six-month angiographic follow-up on 302 patients demonstrated no benefit in terms of percent diameter stenosis (33%, 37% and 34%, respectively) or binary restenosis (11%, 25% and 17%), and an increased stenosis at the stent ends (edge effect) (5%, 7% and 16%, respectively) [97].

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graphic follow-up that has led to an increase in TVR in the bare stent groups and an artificial increase in the delta efficacy. The real world of restenosis is not as high as presented in those studies. A recent report on 6186 patients and 6219 lesions documented repeat revascularization of the original target lesions for clinical indication in only 12.2% by 1 year [98]. Also, registries of new bare metal stents report TVR ranges from 6% to 11%. Thus, the question is not only whether drug-eluting stents are effective, but whether it is really necessary to toxify 87% of the vessels and expose the patients to an unnecessary risk of thrombosis, drug leaching, nonabsorbable polymers, late stent malapposition and edge effect, when only 13% can potentially benefit from drugeluting stents. In addition, of this 13%, some will continue to experience restenosis, even with drug-eluting stents. Therefore, one should ask if it is necessary to treat every patient and every lesion with drug-eluting stents? By now, we should have learned the lessons from the introduction of other devices into the field of interventional cardiology; and by all means, we should not introduce a new technology that will substitute one disease with a new one. Before expanding the technology for every patient and every lesion, some of the following questions need to be addressed. Case reports on subacute thrombosis with drugeluting stents [99] raise the concern of an increased risk of this complication in patients with acute MI or acute coronary syndrome cases. What are the risks of local inflammation? What would be the consequences of treatment vessels that were previously irradiated? Is there a higher risk for late aneurysm formation? Stent malapposition (separation of the stent from the vessel wall, as seen in Fig. 8, was reported in at least 10% of the patients who received the sirolimus drug-eluting stent without accompanied clinical events [100]. However, the small number of patients studied by IVUS could not be predictive for a larger population that will be exposed to this complication. The question for broad utilization depends on the comfort level of interventional cardiologists exposing their patients to these potential complications.

9. Cost-effectiveness and alternatives 8. Clinical perspective and a word of caution Although sirolimus and paclitaxel demonstrate promising initial results, there are many losers in the search for the ideal drug-eluting stent. We have learned that only largescale clinical trials can support the use of drug-eluting stents. Among the compounds to be tested in such trials are everolimus, dexamethasone, h-estradiol, tacrolimus and others. Drug-eluting stents are now advocated for every patient and for every lesion. Even with the best results presented in RAVEL, SIRIUS and Taxus II, the degree of effectiveness should be challenged, because it was influenced by the mandatory angio-

The estimated price tag of drug-eluting stents without adequate reimbursement could be a burden on the health care system. Indeed, in Europe, 6 months after approval, the penetration of drug-eluting stents ranged between 5% and 10%, primarily for economic considerations. In the US with the suggested reimbursement of US$1800 for a single stent per patient and a rate of nearly two stents per patient during PCI, high-volume hospitals will be subjected to a loss of millions of dollars if broad conversion from bare metal stents to drug-eluting stents occurs. This cost burden should alert investigators to search for other alternatives. First, targeted efforts should be directed

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Fig. 8. SIRIUS study: incomplete stent apposition of a sirolimus coated stent.

to enhance the detection of correlates for restenosis. Prior work using large databases helped to identify clinical, angiographic by QCA and IVUS indices to detect predictors for restenosis. Further work utilizing gene discovery methods may help to identify the real benefactors of drug-eluting stents. If this technology continues to be expensive, other alternatives that have the potential to mimic its success will be explored. Among them are the use of oral rapamycin or its analogs, which have shown to be effective in preclinical trials.

use of drug-eluting stents can be expanded for the treatment of the vulnerable plaque or nonobstructive disease. The experience with drug-eluting stents taught us that stents can be used as a vehicle for therapy of vascular disease and the technology of local elution of drugs via a stent platform may be used for applications beyond restenosis prevention. Among those could be treatment of vulnerable plaque, angiogenesis, atherosclerosis, acute myocardial infarction and so on. Thus, drug-eluting stents today are only on the tip of breakthrough in treating vascular disease.

10. Future directions The goal of drug-eluting stents is only to reduce the restenosis rate. As of now, the technology should provide further improvement to reach this goal. Biodegradable polymers, stent design and an increase in dose at the edges of the stent are only some of the improvements tested now in preclinical trials. A continued search for potent nontoxic drugs or a combination of drugs such as antiproliferative and antithrombogenic on one stent is being perused. It is possible that different drugs will be used for different subsets of patients or lesions (diabetic, calcified, fibrotic, etc.). With drug-eluting stents, the target of single digit restenosis never seems to be too close. Nevertheless, continued improvement of the bare stents can close the gap with less potential complications. The challenge of interventional cardiologists to address all lesions with percutaneous technology and to avoid bypass surgery will continue to motivate further improvements. If it continues to be successful, some propose that the

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