Pharmacology & Therapeutics 129 (2011) 260–266

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Pharmacology & Therapeutics

j ourna l homepage: www.e lsev ie r.com/ locate /pharmthera

Local drug delivery for percutaneous coronary intervention

S. Sharma a, C. Christopoulos a, N. Kukreja a, D.A. Gorog a,b,⁎a East & North Herts NHS Trust, UKb Imperial College London, UK

Abbreviations: BMS, Bare Metal Stent; DEB, Drug EluStent; DDES, Dual Drug Eluting Stent; ISR, In-stent restenLate Stent Thrombosis; OR, Oral Rapamycin; PCI, PercutSES, Sirolimus Eluting Stent; TLR, Target Lesion Revascu⁎ Corresponding author. Department of Cardiology, E

Trust,Welwyn Garden City AL7 4HQ, UK. Tel.: +44 17073E-mail address: d.gorog@imperial.ac.uk (D.A. Gorog)

0163-7258/$ – see front matter © 2010 Elsevier Inc. Aldoi:10.1016/j.pharmthera.2010.11.003

a b s t r a c t

a r t i c l e i n f o

Available online 25 November 2010

Keywords:Local drug deliveryIn-stent restenosisDrug eluting stentsDrug eluting balloonBioabsorbable stentsPercutaneous coronary intervention

Since the first successful coronary angioplasty by Andreas Grüntzig in 1977, the field of percutaneouscoronary intervention (PCI) has expanded rapidly. Rapid technological refinement has seen equipment andcomplementary pharmacotherapy to improve the outcome of PCI evolve dramatically, driven by clinical needand enormous market forces. The ideal intervention should expand the vessel lumen without inflictingendothelial injury, and provide local drug delivery to prevent subsequent acute thrombosis and neointimalhyperplasia. Drug eluting stents, once regarded as the “gold standard” in PCI, and established as the treatmentof choice for nearly a decade, remain limited in their performance by important risks of in-stent restenosis andlate stent thrombosis. In this review, we discuss need for local drug therapy as an adjunct to angioplasty andpresent exciting new technological advances to deliver local pharmacotherapy to the coronary artery, whichwill hopefully overcome some of the limitations of DES and may represent the way forward in coronaryintervention.

ting Balloon; DES, Drug Elutingosis; LLL, Late Lumen Loss; LST,aneous Coronary Intervention;larization.ast & North Hertfordshire NHS65036; fax:+44 1707365968..

l rights reserved.

© 2010 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2602. Systemic vs. local drug delivery (LDD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2603. Local drug delivery: Drug eluting stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2614. Local drug delivery: Newer approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2615. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262

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1. Introduction

1.1. The need for drug delivery in patients undergoing PCI

Percutaneous balloon angioplasty is an established method oftreating severe coronary artery stenosis to improve downstreamblood flow. The immediate procedural success and early enthusiasmfor percutaneous balloon angioplasty was, however, tempered by

firstly post-procedural acute vessel closure due to coronary dissectionor suboptimal results, and secondly by early elastic recoil of theballooned segment and negative vessel re-modeling, both of whichalso contributed to luminal re-narrowing.

However, the mechanical injury caused to the vessel wall by thesemetal stents, with resulting localized inflammatory reaction aroundthe stent struts, frequently triggered a complex cascade of eventsinitiating neointimal proliferation. This process, which eventually ledto in-stent restenosis (ISR), involves expression of adhesion mole-cules, inflammatory cell infiltration, release of growth factors,macrophage recruitment, smooth muscle proliferation, proteoglycandeposition and extracellular matrix formation (Geary et al., 1996).Restenosis and ISR are histologically distinct process as highlighted inTable 1. Much of what is known about restenosis and neointimalproliferation comes from animal injury models and comparison withhuman tissue, which usually is derived from autopsy specimens(Schwartz et al., 2004).

Table 1Legend—Mechanisms contributing to angioplasty and stent device-induced restenosis(adapted from Tesfamariam, 2007).

Angioplasty restenosis In-stent restenosis

Elastic recoil √ –

Vessel shrinkage √ –

Constriction √ –

Vessel remodeling Negative Positive↑Smooth muscle cell proliferation – √↑Extracellular matrix formation – √↑Neointimal formation – √

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New devices were developed in an attempt to overcome theseproblems, and include lasers and atherectomy catheters. Unfortunate-ly none of these have been able to demonstrate a significantimprovement compared to balloon angioplasty alone (Steg et al.,1994). Brachytherapy (intra-coronary radiation therapy) significantlyreduced re-vascularization but was limited by the need for multidis-ciplinary expertise, expensive equipment and radiation, and the long-term efficacy remained limited by stent edge restenosis and latethrombosis (Leon et al., 2001;Waksman et al., 2002; Costa et al., 1999).

Over the years there have been intensive research efforts to identifypossible pharmacotherapeutic regimens to prevent the neointimalrestenotic process. Initially numerous antiplatelet and anticoagulantdrugs were studied, with disappointing results (Kastrati et al., 1997).Subsequently, the role of calcium antagonists, omega 3 fatty acids, lipid-lowering drugs, anti-inflammatory drugs, steroids, growth factor antago-nists, angiotensin-converting enzyme inhibitors, and various antiproli-ferative agents were also studied. Although most experimental studiesand some small initial clinical studies showed promise, subsequent largerandomized trials have been disappointing (Faxon, 1995; Bertrand et al.,1997; Boccuzzi et al., 1998; Serruys et al., 2000; Faxon, 2002).

Many agents were found to be effective in preventing restenosis inanimal models of vascular injury following systemic administration(Hamon et al., 1998). However, the potency and narrow therapeuticwindow of many of the compounds limits their tolerance whenadministered systemically. Of the many potential explanations for thefailure of such agents to overcome restenosis, the inability to achieveadequate drug levels at the site of angioplasty has been the mostcommonly cited reason for the failure of systemic drug therapy(Faxon, 2002).

2. Systemic vs. local drug delivery (LDD)

As platelets and thrombi were attributed a primary role in theneointimal proliferation, initial efforts to reduce restenosis afterpercutaneous coronary intervention (PCI) focused on the use ofantiplatelet and anticoagulant agents. Although these therapiesreduced the risk of abrupt vessel closure due to acute or sub-acutethrombosis, they failed to reduce neo-intimal hyperplasia and rest-enosis. Since then, different pharmaceutical regimens have been triedfor systemic therapy with mixed clinical results.

A recent study assessed the efficacy of oral rapamycin (4 mgloading dose followed by 2 mg per day for 1 month) in reducingrestenosis after the implantation of bare metal stents (BMS). In thisprospective, single-blind study 108 patients were randomized torapamycin or placebo immediately after stent implantation. Oralrapamycin significantly reduced the incidence of angiographic ISR at6 months' follow-up {14% vs. 32%, relative risk (RR) of 0.45 (95% CI0.24–0.84, p=0.015)}. The rapamycin blood concentration at 15 daysinversely correlated with binary restenosis (p=0.044). The volume ofrestenosis as assessed by intravascular ultrasound was also signifi-cantly lower in the rapamycin arm (18±11% and 27±16%,p=0.002). This study emphasizes the need for further largerandomized studies of systemic therapy in preventing restenosis(Cernigliaro et al., 2010). In the OSIRIS trial involving 300 symptom-

atic patients with ISR, Hausleiter et al. showed significant reduction inangiographic restenosis and a reduced need for target vesselrevascularization (TVR) at 1-year follow-up with an intensifiedloading regimen of oral rapamycin. The rapamycin concentration inthe blood at the time of the procedure correlated significantly withlate lumen loss (LLL) at follow-up (with minimal LLL in the highrapamycin loading dose group), indicating that inhibition of theinitiating steps in neointima proliferation by rapamycin is critical forthe prevention of restenosis. A significant reduction in the leukocytecount was observed in the rapamycin-treated group, with nosignificant clinical consequences (Hausleiter et al., 2004).

Drug eluting stents (DES) were launched when systemic drugtherapy for ISR was in its infancy and since the introduction of DESs,studies evaluating systemic therapy for the treatment of restenosishave reduced to a quarter (Faxon, 2002). Although DES has a numberof potential advantages, they also have significant limitations. The keyadvantage is the lack of systemic toxicity, with effective local drugdelivery. The drug can be delivered over a defined period of time withkinetics appropriate to the vascular healing process. However, thereare limitations to the amount of drug that can be placed on the stentand the duration of time the drug delivery can be achieved. Cost isanother major limitation of DES technology. The use of oral agents incombination with standard metal stents may offer a potentiallycheaper and more effective means of dealing with restenosis.

Recently the results of the Oral Rapamycin in Argentina study(ORAR III) were presented (Pereira et al., 2009). This randomizedstudy compared DES with bare metal stents plus oral rapamycin (OR)(10 mg loading one day before PCI followed by daily doses of 3 mgplus 180 mg of diltiazem for 13 days), for the treatment of de novocoronary lesions in 200 patients. Diltiazem was added to achievehigher rapamycin blood concentrations. At 2.7-year follow-up, theprimary end point of cumulative costs revealed that a strategy of ORplus BMS resulted in cost saving when compared to DES (p=0.001).Initial cost saving advantage wasmaintained at follow up. The efficacyof OR+BMS was comparable to DES for the secondary endpoints ofmajor adverse cardiovascular event (MACE), target vessel revascu-larization (TVR) and target lesion revascularization (TLR).

Failure to achieve significant reduction in ISR with systemic drugtherapy led to the exploration of the concept of local drug delivery.Local drug delivery, in theory, should achieve greater local drugconcentration with lower overall dose compared to systemic therapy,to help achieve maximal tissue effects while minimizing undesiredsystemic toxicity. It also has the advantage of being able to utilizedrugs with low systemic bio-availability or short half-life.

Many devices have been developed to administer drugs or geneticmaterial locally to the site of injury. Studies have shown that localadministration of pharmacologic agents directly into the site ofcoronary intervention is an effective means of delivering sufficientamount of drugs into the injured arterial tissue site to cause anantirestenotic therapeutic effect (Schwartz et al., 2004).

Major limitations that have been encountered in intra-coronarydrug delivery, apart from finding the best drug, include: (1) the designof devices which enable delivery of adequate quantities of drug withminimal injury to the vessel wall and without limitation of the distalflow, (2) the development of delivery vehicles that allow localretention of the administered drug for sufficient time to ensure atherapeutic effect, (3) the optimization of strategies enabling thetransfer of genetic material into cells within the vessel wall, and (4)the development of sustained delivery polymeric coatings for stentsthat do not produce thrombosis or an inflammatory tissue response(Brieger & Topol, 1997).

3. Local drug delivery: Drug eluting stents

The efficacy of intracoronary stenting was compared with balloonangioplasty in two landmark clinical trials. The North American Stent

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Restenosis Study (STRESS) showed a lower angiographic restenosis rate(32% vs. 42%, p=0.046) in the stent group (Fischman et al., 1994). TheEuropean Benestent Study Group demonstrated a similar, but moreimpressive reduction in the rate of restenosis (22%vs. 32%,p=0.02) andTVR rate (13% vs. 23%, p=0.005) in the stent group (Serruys et al.,1994). Although the problems of elastic recoil and negative vesselremodeling were eliminated by the bare metal stent, stenting broughtwith it its own new problems, namely that of sub-acute stentthrombosis and neointimal proliferation, the major pathomechanismbehind ISR (Virmani & Farb, 1999). The problem of subacute stentthrombosis was addressed with the concurrent use of systemicantiplatelet drugs but neointimal hyperplasia remained a major hurdlein coronary intervention. As this process occurs locally due toendothelial injury caused by the metallic stent, it seems logical to usethe stent itself to deliver a drug locally in order to overcome thisproblem. A DES has 3 components—the metallic platform, the drug toprevent neointimal proliferation and the carrier matrix that stores andtransfers the drug to the local environment. All three of theseparameters must be optimal to achieve a reduction in ISR. Even8 years after the commercialization of the first DES in Europe the searchfor perfection is still on. Table 2 gives a list of stent-based platformsusedin experimental andclinical studies. In theongoing search for theperfectdevice for local drug delivery (LDD), the stent based platform has so farbeen the most successful. DES are now the accepted modality for theprevention and treatment of restenosis. DES have shown dramaticresults in lowering the restenosis rates post angioplasty (Grube et al.,2001; Gershlick et al., 2004; Park et al., 2003). In a large meta-analysis,Stettler et al. (2007) reported a 70% reduction in TLRwith sirolimus (a.k.a. rapamycin)-eluting stents (SES) (pb0.0001) and 58% (pb0.001)withpaclitaxel-eluting stents (PES) compared to BMS.

Due to the small surface area of the stent, only a limited amount ofdrug can be loaded on to it, necessitating a drug carrier vehicle toenable sufficient drug loading and release. The drug carrier matrixallows the release of the drug in a diffusion-controlledmanner over anextended time period following stent implant. It should also providestructural integrity and should not be affected by themechanical stressduring stent expansion. It should have a consistent time and dosecontrolled drug release (controlled release kinetics) and should be bioand hemocompatible to minimize adverse effects (Tesfamariam,2007) The commonly used drug carrier vehicles are polymer coatingswhich are long chain molecules consisting of small repeating units.Polymers can be subdivided into bioerodable and nonbioerodablecategories. The bioerodable polymers can be further subdivided intoeither bulk or surface erosion. The biodegradable polymers releasedrug as it degrades and is eventually eliminated from the body.Examples of such coating include polyglycolic acid, poly lactic acid etc.The non-bioerodable polymer stays on the metal surface even aftercomplete elution of the drug.

There have been reports that the polymer coating that remainsafter elution of the drug can lead to late stent thrombosis (Virmaniet al., 2004). It has also been reported that the polymeric coating

Table 2Legend—List of stent-based platform used in experimental and clinical studies.

Stent based devices

Bare metal stents in combination with balloon based devices as adjunctsInert substance coated stents e.g. Heparin, Gold, silverNatural substance coated stents e.g. Fibrin coatedAutologous vein or arterial graft covered stents.Endothelial cell seeded stentsRadioactive stentsPolymer coated stentsDrug eluting stentsBiodegradable polymer coated stentsBioabsorbable stentsDouble drug eluting stents

materials of DES may cause hypersensitivity reactions (Nebeker et al.,2006). Thus, there is a need to develop newer stent coatings that canbe used to deliver drugs without the risk of late thrombosis andhypersensitivity reaction. More novel biodegradable polymers releasedrug as they degrade and the polymer is eventually eliminatedfrom the body. Examples of such coatings include poly glycolic acid,poly-L-lactic acid, polycaprolactone, polyethyleneoxide/polybutyleneterephtalate, polyorthoester, and polyhydroxybutyrate/valerate. Theprinciple approaches (Kavanagh et al., 2004) which are employed tobind a drug to the surface of the stent are: absorption—this refers toincorporation of the drug into a polymer/matrix which is then coatedto the stent surface, (b) adsorption—refers to surface layering of thestent with a drug and (c) on strut approach—refers to dip coating thestent with a drug solution and then allowing it to dry. In absorptionand adsorption, the drug is held through either covalent or non-covalent bonds (Whelan et al., 1998). The amount of drug that can beattached to or released from a stent is determined by the drug, stentconfiguration, coating/binding agent biocompatibility and the releasekinetics (pore size, coating degradation rate, hydro phobicity of thedrug) (Raman & Edelman, 1998).

3.1. Drugs for DES

DES remains the mainstay for treatment of coronary artery diseaseand restenosis until further definitive technology or pharmacotherapybecomes available. The first attempts at local drug delivery involvedagents that either worked outside the cell or that could easily cross thecell membrane, such as traditional pharmaceuticals and small mole-cules. Sirolimus (also known as rapamycin) is an immunosuppressantthat inhibits cyclin-dependent kinases to cause cell cycle arrest.Sirolimus is amacrolide antibioticwith antifungal, immunosuppressive,antimitotic properties and is produced by cultured Streptomyceshyroscopicus (Marx & Marks, 2001). Sirolimus has been shown in vitroto block smooth muscle cell proliferation—a major component ofrestenosis. The mechanism of action of sirolimus is distinct from otherimmunosuppressive agents that act solely by inhibiting DNA synthesis.Upregulation of FK506-binding protein 12 (FKBP12) has been observedin human neointimal smooth muscle cells. Within cells, sirolimusinactivates mammalian target of rapamycin (mTOR) by forming acomplex with FKBP12. As a result, the down-regulation of kinase p27 isprohibited, inhibiting passage of the cell cycle from G1 to S phase, andpreventing cell proliferation and smooth muscle growth.

Paclitaxel (Taxol; Bristol-Myers Squibb), another small molecule is amicrotubule-stabilizing agent with potent antitumor activity. Paclitaxelbinds to beta-tubulin, resulting in inhibition of microtubule depoly-merization in a dose-dependent fashion. At high concentrations, thisinhibits smooth muscle cell (SMC) proliferation and migration bydisturbing the cell's M phase (Rowinsky & Donehower, 1995).

Several trials have shown that rapamycin (e.g. CYPHER, RAVEL,SIRIUS) and paclitaxel (ASPECT, ELUTES, TAXUS) delivered on apolymer coated stent surface exhibit superior performance inpreventing restenosis compared to BMS. Other small molecules thathave been used or screened for DES include zotarolimus (ABT-578),everolimus, tacrolimus, pimecrolimus, novolimus, actinomycin D,cytochalasin D, dexamethasone, 17-beta-estradiol, mycophenolicacid, angiopeptin, cyclic RGD containing peptide.

4. Local drug delivery: Newer approaches

4.1. Early balloon-based systems

Although now arriving on the angioplasty scene as an exciting newtechnology (vide infra), as far back as the late 1980s, early balloon-based drug delivery was explored using a double balloon catheter.This device is delivered over a guide wire akin to a conventionalangioplasty balloon, the dual balloons are inflated proximal and distal

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to the stenosis site, and drug is infused into the isolated vesselsegment between the two balloons (Goldman et al., 1987; Jørgensenet al., 1989). The technique was limited by distal ischemia due to therequirement for prolonged inflation time to allow time for drugdelivery, potential loss of drug in side branches in coronaryvasculature and the requirement for high-pressure inflation makingit impractical for use in the human coronary system. Some of theballoon based devices invented for LDD are shown in Fig. 1. To try andovercome the shortfalls of the double balloon, Wolinsky and Thung(1990) used a perforated balloon but it was limited by the potentialfor non-homogenous delivery due to blockage of the pores andvascular injury caused by the fluid jet. The microporous balloon(Cordis Corp) was a modification of the porous balloon to try andreduce the potential of vascular barotrauma (Lambert et al., 1993).Other balloon-catheter delivery systems (Fig. 1) that have been used

Fig. 1. (Adapted from Brieger & Topol, 1997). a. A, B Photograph ofWolinsky double balloon.showing jet streaming during balloon inflation. (Reprinted with permission from Wolinskyballoon at 5 atm pressure. (Reprinted with permission from Lincoff et al., 1994). d. Photograand circumferential drug infusion channels. (Reprinted with permission from Hong et al., 1with a central perfusion channel. (Reprinted with permission from Lincoff et al., 1994).

either in animal models or clinical studies for LDD delivery are listedin Table 3.

The main reason why balloon based devices failed to achieveclinically significant results was because balloon systems did notovercome the problems of elastic recoil and negative vascularremodeling, and furthermore, the retention of drug, to achieveeffective doses at the local site, has been poor with these devices(Brieger & Topol, 1997; Gershlick, 2002).

4.2. Newer balloon-based technology

4.2.1. Occlusive balloonTheGENIE™ catheter technology (Acrostak,Winterthur, Switzerland)

(Fig. 2) is a relatively new system consisting of a distal and proximalocclusive segment and a central segment. The distal ramp has holes,

(Reprinted with permission Nabel et al., 1989). b. Photograph of porous balloon catheter& Thung, 1990). c. Photograph of microporous balloon with drug ‘weeping’ from theph of cross section of a ‘channel catheter’ with central high-pressure inflation chamber993). e. Illustration of Dispatch catheter showing the coil shaped drug infusion balloon

Table 3Legend—Balloon-catheter based delivery systems for local drug delivery.

Balloon catheter based devices

Guiding catheter itself to deliver drugsDouble balloonLeaky or porous balloonMicro-porous balloonChannel and transport balloonsHydrogel balloonIontophoretic balloonInfusion sleeve catheterDispatch catheterNeedle row balloonsOcclusive GENIE™ catheterRetractable-needle catheterDrug eluting balloons Fig. 3. Photograph of ClearWay™ Infusion balloon catheter.

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which allow drug transfer to the vessel wall by means of coaxiallydirected jets. In LOCAL TAX, a single blinded, randomized study (Herdeget al., 2009) 204 patientswith native coronary stenosiswere randomizedtooneof threegroups: implantationof aBMS followedby local deliveryofliquid paclitaxel (Group I); implantation of a BMS only (Group II); orimplantation of a paclitaxel eluting stent (TAXUS) (Group III). Theprimary end point was in-stent LLL, and secondary end points includedbinary restenosis rate N50% and a composite clinical end point (majoradverse cardiovascular events and revascularization of the target lesion).At 6 months, in-stent LLL was 0.61 mm in-group I, 0.99 mm in-group IIand0.44 mmin-group III.Major cardiac events occurred in13.4%of groupI, 26.8% of group II and 14.9% of group III. TLR rates were 13.4% (group I),22.1% (group II), and 13.4% (group III). This showed that althoughsuperior to BMS alone, the additional use of local paclitaxel was notsuperior and perhaps inferior to DES.

The potential advantages of this system include homogenous localdrug delivery and avoidance of polymer related problems encounteredwithDES, but the trial failed to showsuperiority ofGroup1overGroup3.

4.2.2. Microporous balloonThe ClearWay™ RX system (Atrium Medical Corporation, New

Hampshire, USA) is a novel microporous balloon perfusion catheter. Itis produced using expandable polytetrafluoroethylene (ePTFE) ma-terial. ClearWay provides a less traumatic approach to deliver the drugdue to the use of a low-pressure system (1–4 atm) and tortuouschannels of ePTFE, which prevents the “jetting” affect (Fig. 3). Itconforms to the shape of the native coronary vessel, stents or anysynthetic grafts, thus allowing complete circumferential drug deliveryat the site (Moodie et al., 2005). This balloon catheter uses theocclusion, containment and infusion (OCI) therapeutics, as follows.During inflation, drug is infused through the balloon pores whileblood flow is occluded, maximizing drug availability withoutsubstantial loss in systemic circulation. Containment and controlledinfusion of the drug increases the exposure time and enhancesbioavailability at the desired local site.

In a recent retrospective analysis of 30 acute coronary syndromepatients undergoing PCI, intra-coronary drug-therapy (nitroprussideor nicardipine) using the ClearWay RX catheter, significantlyimproved flow and myocardial blush grade, compared to pre-LDD.In this very small single center observational report, this technologyappeared to be safe and could help to improvemyocardial perfusion ina selected patients presenting with acute coronary syndrome (ACS)who developed no-reflow during PCI (Maluenda et al., 2010).

Fig. 2. Photograph of an inflated GENIE™ balloon catheter showing proximal and distalocclusive segments and a central segment.

4.2.3. Drug eluting balloons (DEB)Drug eluting balloons achieve LDD by means of an angioplasty

balloon coated with drugs such as paclitaxel, which are wellestablished in DES technology. One of the commercially approveddevices, the SeQuent® Please (Braun, Germany) balloon catheter(Fig. 4) has a folded balloon, which is homogenously coated withpaclitaxel embedded in contrast medium coating. Paclitaxel (3 μg/mm2 balloon surface) is the pharmacologically active substancewhereas the contrast medium has a matrix builder function tofacilitate immediate release of drug during balloon inflation (Scheller& Speck, 2009). The PEPCAD ΙΙ-ISR Trial was a prospective,randomized study directly comparing the DEB catheter (SeQuentPlease, B.Braun, Melsuungen, Germany) to the paclitaxel-elutingTaxus stent (Boston Scientific, Natick, MA) in 131 patients with ISR.In 6.2% of the Taxus stent group, the stent was undeliverable and aballoon catheter had to be used instead. At 6 months' follow up, ISRwas observed in 7% of patients treated with the DEB compared to 20%in the DES group. Adverse cardiac events occurred in 9% of the coatedballoon group and in 22% of the stent group (p=0.08), drivenpredominantly by reduced need for TLR (6% vs. 15%) (Unverdorbenet al., 2009). These findings suggest that DEB is at least as effective asDES in treating ISR (Hamm, 2009). By comparison, the Piccoleto Trialfailed to show the “non-inferiority” of a different competitorpaclitaxel-eluting balloon (DIOR, Eurocor, Bonn, Germany) comparedto a paclitaxel eluting stent (Taxus Liberte, Boston Scientific, USA) inthe treatment of de novo lesions in small coronary arteries (≤2.75 mmdiameter). This was a small, single center trial in patients with stableor unstable angina undergoing PCI, randomized to either receive DES(Taxus Liberte, Boston Scientific, US) or DEB (DIOR, Eurocor, Bonn,Germany). At 6 months' angiographic follow up, the rate of binaryrestenosis was 32% in the balloon group and 10% in the stent group(p value=0.043) (Cortese, 2009).

4.3. Dual drug-eluting stent (DDES)

Recently Venkatraman reported a DDES that has an anti-proliferative and an anti-thrombotic drug in a biodegradable polymer,coated onto a cobalt-chromium stent. The DDES was prepared byspray coating the BMS with a biodegradable polymer loaded withsirolimus and triflusal, for restenosis and thrombosis, respectively.The in vitro study showed that DDES can sustain release bothsirolimus and triflusal and the delivery of the two drugs wascontrolled at different rates (sirolimus over 30 days, triflusal over5 days) with the aim that, in vivo, this would effectively reducethrombosis and proliferation at the same time (Huang et al., 2010). Invivo porcine studies performed by the same group, for acutethrombosis, inflammation, and restenosis at 30 days showed asignificant reduction in restenosis with DDES compared with controls(a BMS, a sirolimus-coated, and a pure polymer-coated stent). Thereduction in restenosis with DDES is associated with an inhibition of

Fig. 4. Photograph of SeQuent (top) and the paclitaxel coated SeQuent® Please ballooncatheter (bottom).

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inflammation and thrombus formation, suggesting that such DDESmay have a role to play for the treatment of coronary artery disease(Huang et al., 2009).

Byrne et al. (2010) published the 2-year clinical and angiographicoutcomes of ISAR-TEST-2 trial. In this trial, 1007 patients wererandomized for treatment of ≥50% de-novo lesions of native coronaryarteries with SES, n=335, zotarolimus eluting stent (ZES, n=333) ora new generation polymer free sirolimus and probucol-eluting stent(DDES, n=339). The DDES technology showed promising resultswith 2-year TLR rates of 10.7%, 7.7% and 14.3% in the SES, DDES, andZES groups respectively, and without evidence of a differential safetyprofile between the three-stent designs with respect to the rates ofdeath, myocardial infarction and stent thrombosis in the 3 groups.

4.4. Second generation DES and bioabsorbable stents

Despite significant advances in DES technology there are stillconcerns regarding the possibility of very late stent thrombosis (LST)(Onuma, 2009) due to impaired endothelialization, hypersensitivityreaction, inflammation and vascular dysfunction. Once the drug iseluted completely from the surface of a DES there is no utilitydemonstrated for stents and their presence serves as a nidus forpotential LST and chronic inflammation.

This has led to extensive changes in DES design involving bothpolymers and stent platforms.

The second generation of DES, apart from using newer metallicplatforms (CoCr or nitinol unlike 316L stainless steel in earlier stents),utilize either biocompatible or fully biodegradable polymer coatings.For example, the latest FDA-approved DES, Endeavour (MedtronicLtd., CA, USA) uses cobalt chrome with a biocompatible phosphor-ylcholine coating that includes zotarolimus. Another relative new-comer, Xience V (Guidant, Abbott, Illinois, USA) uses L605 cobaltchrome with 2 polymer coatings; one acrylic polymer and anotherfluropolymer with drug everolimus (Sheiban et al., 2008).

Recently, the biodegradable polymer coated biolimus A-9 elutingstent (Nobori™, Terumo, Tokyo, Japan) has shown non-inferiority tothe paclitaxel eluting Taxus Liberté stent for the treatment of de novonative vessel disease in some 250 patients at 9 months' follow up inthe phase 2 randomized NOBORI1 trial (Chevalier et al., 2009).

The latest concept is of a bioabsorbable stent that once dissolvedwould leave behind only the healed natural vessel, allowing forrestoration of vasoreactivity with enhanced potential for vesselremodeling. Such therapy has been termed “vascular restorationtherapy” by Wykrzykowska et al. (2009)) to signify the return ofnormal vascular structure. The risk of LST and the need for prolongedantiplatelet therapy would thus be minimized (Colombo & Karvouni,2000). Apart from delivering the drug, another potential advantagewould be the presence of a mechanical scaffold initially, followed bycomplete dissolution of the scaffold, leaving no residual foreign bodybehind in the vessel. Although this concept was first studied in

humans a decade ago (Tamai et al., 2000), only two products haveentered clinical trials (Ormiston et al., 2008).

The first vascular restoration therapy trial involving a bioabsorb-able stent is the ongoing ABSORB trial (ClinicalTrials.gov numberNCT00300131). This trial is a feasibility trial using the bioabsorbableeverolimus-eluting stent (BVS) system (Abbott Vascular, Santa Clara,CA, USA). The stent is balloon expandable and consists of a backboneof PLLA coated with poly-D, L-lactide (PDLLA) that contains andcontrols the release of the antiproliferative drug, everolimus. BothPLLA and PDLLA are fully bioabsorbable. They are eventually reduceddown to lactic acid, which is metabolized via the Krebs cycle(Ormiston et al., 2008). In 30 patients with simple coronary lesions,the stent had dissolved completely by 2 years. Data regardingvasomotion, restenosis, and freedom from late thrombosis arepreliminary but promising. There was good clinical safety with onlyone major adverse cardiac event (Serruys et al., 2009). Although thiswas only a pilot study and patients had very simple coronary lesions,which are not an exact comparison to the routine indications for DESin clinical practice, it nonetheless provides encouraging earlyvalidation of the bioabsorbable stent technology and provides aplatform for further evaluation. The use of such bio-absorbabledevices has been dubbed as the fourth revolution in the interventionalcardiology (Wykrzykowska et al., 2009).

5. Conclusion

Ever since the first successful coronary angioplasty by AndreasGrüntzig in 1977, the field of percutaneous coronary intervention(PCI) has evolved rapidly. With each new technology, there have beenlimitations and newly emergent problems necessitating furtherresearch and technological refinement. The ideal technology wouldrestore the vessel lumen without inflicting endothelial injury, andprovide local drug delivery to prevent subsequent acute thrombosisand neointimal hyperplasia. Percutaneous coronary revascularizationwithout early or late complications may not be achievable, but thesearch for a technique or device providing near-perfection continues.

Balloon angioplasty achieved revascularization but was limited byacute vessel closure and elastic recoil. Bare metal stents provided themechanical scaffold to prevent vessel recoil but were limited by ISRand acute stent thrombosis. Administration of anti-platelet drugsreduced acute thrombotic events. Until recently, DESwere regarded asthe best available treatment to overcome ISR, but continuouslyhaunted by late stent thrombosis and hypersensitivity reactions tothe polymer matrix. Newer devices, including DEBs and stents withbioabsorbable matrix or platform appear very promising and haveshownencouraging preliminary results. Theperfect solutionmight notbe achieved by a single device but by a combination of different toolsalong with development of complementary local pharmacotherapy.

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