Local Drug Delivery to Prevent Restenosis

Abstract

Introduction

Despite significant advances in vascular biology, bioengineering and pharmacology, restenosis remains a limitation to the overall efficacy of vascular reconstructions, both percutaneous and open. Although the pathophysiology of intimal hyperplasia is complex, a number of drugs and/or molecular tools have been identified that can prevent restenosis. Moreover, the focal nature of this process lends itself to treatment with local drug administration. In this article we provide a broad overview of current and future techniques for local drug delivery that have been developed to prevent restenosis following vascular intervention.

Methods

A systematic electronic literature search using PubMed was performed for all accessible published articles through September 2012. In an effort to remain current, additional searches were performed for abstracts presented at relevant societal meetings, filed patents, clinical trials and funded NIH awards.

Results

The efficacy of local drug delivery has been demonstrated in the coronary circulation with the current clinical use of drug-eluting stents (DES). Until recently, however, DES were not found to be efficacious in the peripheral circulation. Further pursuit of intraluminal devices has led to the development of balloon-based technologies with a recent surge in trials involving drug-eluting balloons. Early data appears encouraging, particularly for treatment of lesions in the superficial femoral artery, with several devices having recently received the CE mark in Europe. Investigators have also explored periadventitial application of biomaterials containing anti-restenotic drugs, an approach that could be particularly useful for surgical bypass or endarterectomy. In the past systemic drug delivery has been unsuccessful, however, there has been recent exploration of intravenous delivery of drugs designed specifically to target injured or reconstructed arteries. Our review revealed a multitude of additional interesting strategies including more than 65 new patents issued over the past two years for approaches to local drug delivery focused on preventing restenosis.

Conclusion

Restenosis following intraluminal or open vascular reconstruction remains an important clinical problem. Success in the coronary circulation has not translated into solutions for the peripheral arteries. However, our review of the literature reveals a number of promising approaches including drug-eluting balloons, periadventitial drug delivery as well as targeted systemic therapies. These innovations as well as others suggest that the future is bright and a solution for preventing restenosis in peripheral vessels will soon be at hand.

INTRODUCTION

Without exception, all interventions designed to treat atherosclerotic occlusive disease are complicated by restenosis. The development of recurrent restenotic disease affects not only vessels treated with angioplasty or stent, but also surgical bypasses or endarterectomy for coronary as well as peripheral arterial disease (PAD). Restenosis severely limits the overall efficacy of these interventions and can occur in up to 80% of patients.¹ The process involves a complex cascade of reactions that result in luminal narrowing through a combination of neointimal hyperplasia and constrictive remodeling. Despite many advances in the fields of vascular biology, pharmacology and bioengineering, restenosis remains a significant problem.^2,3

The use of systemic drug therapy to prevent restenosis was first seriously investigated in the late 1970s. Despite years of study, many of the compounds that have been evaluated are poorly tolerated, have narrow therapeutic ranges, and diminished efficacy when administered systemically.^4,5 These outcomes have led to the concept of local drug delivery (LDD) where high doses of a therapeutic agent are administered directly to a treated artery or vein without engendering adverse systemic effects. LDD can result in drug concentrations in vascular tissues that are 400-1000 higher than that achieved following systemic administration of the same compound.^6-9 The concept of applying pharmacologic agents directly to vessel wall is an attractive strategy that is likely to be effective if several conditions can be met: 1) there is steady delivery of the drug over time 2) effective drug concentrations can be maintained, 3) there is absence of local or systemic toxicity and importantly 4) the mechanism of delivery does not insight restenosis.¹⁰ Fortunately, restenosis lends itself to treatment by local drug delivery because it is often a focal process.

Consequently, over the past two decades, there has been an explosion of interest by clinicians, scientists and medical device manufacturers to develop devices and/or biomaterials that locally release drugs that can prevent restenosis. We have focused on technologies that prevent restenosis in the peripheral circulation. However, mention of the coronary vasculature is relevant in many sections because of the historical significance, (eg drug-eluting stents). Moreover, some technology to date has only been evaluated in the coronary circulation with the presumption that at some point, it will be translated to the periphery. We have attempted to provide a comprehensive overview of the available options to prevent restenosis, incuding innovations that have been tested only in animals as well as those that have been recently approved for clinical use.

Intraluminal Drug Delivery Devices

The Drug-Eluting Stent

Drug-eluting stents (DES) are routinely used to treat coronary artery disease with the first generation of these devices approved by the U.S. Food and Drug Administration (FDA) in 2003. DES over the short term produce a significant reduction in intimal hyperplasia or restenosis when compared to bare metal stents (BMS).¹¹ In a meta-analysis, Settler et al., found a noticeable reduction in target lesion revascularization (TLR) rates (defined as a repeat percutaneous intervention or by-pass surgery of the target lesion because of restenosis or other complications). Both sirolimus and paclitaxel DES produced significant reductions in TLR (30 and 42%, respectively) when individually compared to BMS.¹² Further analysis revealed that the sirolimus-DES had a more robust reduction in TLR compared to paclitaxel.¹² Currently, Abbott, Boston Scientific and Medtronic all market FDA approved DES.

Despite their ready adoption into clinical use, DES have a number of limitations as detailed in Table I. Prime amongst these is the potential for DES to produce late in-stent thrombosis resulting in the need for dual anti-platelet therapy. In January 2007, the FDA advised that DES are associated with a small but significant increase in early stent thrombosis compared with BMS; the clinical consequence of stent thrombosis can be devastating. There is a lack of reendothelialization related to inhibition of endothelial cell proliferation and migration since drug is delivered to the luminal surface. Another limitation of DES is that drug delivery to the vessel wall is not uniform, with the majority of the drug concentrated at the struts of the stent. Moreover, stents have also been shown to incite intimal hyperplasia because of increased trauma to the vessel wall. Although metallic stents prevent the elastic recoil that can develop following balloon angioplasty, the trauma they produce can incite an intense inflammatory reaction leading to in-stent restenosis; the degree of restenosis is greater than that produced by conventional balloon angioplasty.⁵ Lastly and importantly, DES are costly, a factor that is becoming more relevant in an era of constrained health care resources.

Table I.

Intraluminal Drug Delivery Devices

Intra Luminal Devices	Advantages	Disadvantages	Current status	Representative Publications (Author, Date)
Drug-eluting stent	Reduced incidence of restenosis Effectively prevents restenosis in coronary vessels Safe Lack of systemic toxicity Prevents sub-acute recoil	Poor results in peripheral arteries Hypersensistivity reactions Costly Incomplete reendothelialization Late stent thrombosis Lifelong antiplatelet therapy Localized aneurysms Drug delivery not uniform Limited drug delivery due to small surface area of stent	Currently in clinical use in the coronary circulation	Bosiers et al (2008)
				Herdeg et al (2008)
				Tepe et al (2008)
				Sharma et al (2011)
				Gertz et al (2010)
Dual drug-eluting stent	Can release both anti-proliferative and anti-thrombotic drugs (at different rates) Reduction in restenosis Antirestenotic efficacy seen at long-term follow-up at 2 years	Same as single-drug stents	Currently in clinical trials	Krucoff et al (2008)
				Kerheye et al (2009)
Drug-eluting balloon	Homogenous drug delivery to vessel wall Limited need for antiplatelet therapy No stent thrombosis No stent scaffolding to disrupt patterns of flow Can be used in very small vessels Immediate drug release Simultaneous plaque compression and drug delivery No residual foreign body	Not as effective as DES in coronary vessels Elastic recoil Negative remodeling Cost One-time use	Currently in clinical trials	Brieger (1997)
				Werk et al (2008)
				Teper et al (2008)
				Boisers (2008)
				De Labriolle et al (2009)
Porous balloon	More effective drug delivery through a balloon	Vascular barotrauma due to jetting Holes can become obstructed leading to nonhomogeneous drug delivery Systemic release of drug	Currently in clinical trials	Lambert et al (1993)
				Brieger et al (1997)

Despite the initial success of DES in the coronaries, the effectiveness of this technology in the peripheral circulation has only recently become evident. The SIROCCO trials (Cordis Corporation; Hialeah, FL) were randomized, double-blinded studies designed to assess the efficacy of a sirolimus-DES for the treatment of superficial femoral artery (SFA) lesions.¹³ The STRIDES trial (Abbott Vascular; Abbott Park, IL) utilized a novel everolimus-DES designed with a high drug load and longer elution profile was evaluated for the treatment of SFA and popliteal lesions.¹⁴ In both of these trials, however there was no significant difference in the outcomes of drug eluting versus bare metal stents.

Recently, Cook Medical (Bloomington, IN) reported more favorable outcomes in a randomized, controlled, multinational trial comparing its Zilver PTX polymer-free paclitaxel-eluting nitinol DES to standard angioplasty for femoropopliteal lesions. Four hundred seventy-nine patients were enrolled from three countries – the U.S., Japan and Germany. At twelve months, the primary patency for patients receiving DES compared to standard angioplasty was 83.1% vs 32.8%.¹⁵ Patients receiving the primary DES also exhibited superior 12-month event-free survival (90.4% vs 82.6%). As an evolution of this trial, DES was compared to bare metal stent after angioplasty failure. In this secondary evaluation, the Zilver DES also exhibited superior primary patency (89.9% vs 73.0%) and clinical benefit (90.5% vs 72.3%) compared to BMS.¹⁵ As a result of these findings, the FDA has very recently approved the Zilver PTX device for use in treating femoropopliteal lesions.

The DESTINY trial was a randomized, multicenter study comparing the efficacy of Abbott’s Xience® Prime everolimus-DES (Abbott Vascular; Abbott Park, IL) to BMS in patients with infra-popliteal lesions. Results at twelve months demonstrated significantly improved patency rates with use of the everolimus-DES compared to BMS (85.2% vs 54.4%). The YUKON-BTK is a randomized, double-blinded study of a polymer-free sirolimus-DES (Yukon, Translumina, Munich, Germany) versus BMS. The primary patency rate at one-year was 80.6% in patients receiving the sirolimus-DES compared to 55.6% in patients receiving the BMS. Although the TLR rate was lower in the sirolimus-DES group (9.7%) compared to the BMS group (17.5%), this finding did not achieve statistical significance. In trials involving infrapopliteal disease, patients treated were almost exclusively those with limb threatening ischemia.

There are many clinical trials currently underway to determine the efficacy of DES for the treatment of infrainguinal disease. Ongoing trials include, PADI a randomized, controlled trial comparing a paclitaxel-DES to standard angioplasty; ACHILLES a randomized, controlled trial comparing a sirolimus-DES to standard angioplasty, as well as others. Thus, encouraging data has emerged regarding the use of drug eluting stents for the peripheral circulation (Table II). The trials thus far have been small and restrictive with regard to TASC lesion. Further evaluation will be necessary to determine the role of DES in the full spectrum of infrainguinal pathology. A variation of the conventional single-DES is the dual drug-eluting stent (DDES). The rationale for the development of the DDES is to allow a combination of drugs, the effect of which may be additive or synergistic, to be delivered from the same stent. Although preclinical studies with this technology have been encouraging, clinical studies with DDES not demonstrated benefit. Another innovation has been the development of the covered stent. Although these stents are not drug-eluting, they were developed with the goal of providing a physical barrier to ingrowth of intimal hyperplasia into the treated artery. Unfortunately, covered stents have not provided a significant advance beyond outcomes of BMS.

Table II.

Trials evaluating drug eluting stents.

Trial Name/Author	Vascular Territory (SFA/POP /BTK)	Status	Study Period	Drug; Stent	Study Type	Pts (N)	Primary Patency Rate (timeframe)	Rate of Binary Restenosis (time frame)	Target Lesion Revascularization, TLR (timeframe)
SIROCCO	SFA	published	Feb 2001-June 2003	Sirolimus; Cordis SMART	Prospective, Multicenter, Double Blind, Randomized	93	NR	DES:23%(24M)	DES:6% (24M)
								BMS:21%(24M)	BMS:13% (24M)
STRIDES	SFA/POP	published	May 2007 - July 2008	Everolimus; Dynalink-E	Prospective, Multicenter, Non-randomized, Single Arm, Open Label	104	DES:68%(12M)	NR	DES:0%(12M)
Zilver PTX	SFA/POP	published	Mar 2005 – Oct 2009	Paclitaxel; Zilver PTX	Prospective, Multicenter, Randomized, Open Label	474	DES:83%(12M)	NR	DES:10%(12M)
							PTA:33%(12M)		BMS:18% (12M)
DESTINY	infrapopliteal	published	Mar 2008 – Nov 2010	Everolimus; Xience V	Prospective, Multicenter, Single Blind, Randomized	140	DES:85%(12M)	DES:17%(12M)	DES:8%(12M)
							BMS:54%(12M)	BMS:36%(12M)	BMS:35%(12M)
Yukon BTK	infrapopliteal	published	Apr 2006-Mar 2010	Sirolimus; YUKON-BTX	Prospective, Multicenter, Double Blind, Randomized	161	DES:81%(12M)	DES:19%(12M)	DES:10%(12M)
							BMS 56%(12M)	BMS:44%(12M)	BMS:18%(12M)
ACHILLES	BTK	presented at LINC 2011	Mar 2008 – Jan 2011	Sirolimus; Cypher Select	Prospective, Multicenter, Randomized, Open Label	200	NR	DES:21%(12M)	DES:10%(12M)
								PTA:45%(12M)	PTA:17%(12M)
SiroBTK	infrapopliteal	published	June 2002-Sept 2005	Sirolimus; Cypher	Prospective, Non-randomized, Single arm, Open label	30	DES:97%(8M)	NR	NR
PADI trial	infrapopliteal	ongoing	Aug 2007-Dec 2012	Paclitaxel; Taxus	Prospective, Multicenter, Randomized, Open Label	140	primary outcome at 6M	N/A	N/A
DESTINY 2	BTK	ongoing	July 2011 - July 2013	Everolimus; Xience Prime	Prospective, Multicenter, Single arm, Open Label	60	primary outcome at 12M	N/A	N/A
Promus BTK	BTK	not yet enrolling	Aug 2012-Aug 2014	Everolimus; Promus Element	Prospective, Multicenter, Single arm, Open Label	70	primary outcome at 12M	N/A	N/A
PES-BTK-70	BTK	ongoing	Jan 2012 – Oct 2012	Paclitaxel; nitinol self-expanding stent	Prospective, Multicenter, Single arm, Open Label	70	primary outcome at 6M, 12M	N/A	N/A

Abbreviations:

N/A - not available

NR - not reported

SIROCCO - Sirolimus-Coated Cordis Self-expandable Stent

STRIDES - Superficial Femoral Artery Treatment with Drug-Eluting Stents

DESTINY - Drug-eluting stents in the critically ischemic lower leg

PADI - Percutaneous transluminal Angioplasty and Drug eluting stents for Infrapopliteal lesions in critical limb ischemia

PES-BTK-70 - Paclitaxel-Eluting Stent to Treat Below The Knee Arteries

Bioresorbable stents

Bioresorbable stents are devices designed to provide temporary architectural support for the vessel wall but are fully biodegradable. They may or may not elute drugs. The hypothetical advantages of biodegradable stents are several. The absence of a permanent foreign body might diminish the inflammatory response of the arterial wall to stent implantation and diminish restenosis. Moreover, the absence of a permanent rigid metal object fixed in the arterial wall might allow the vessel to maintain its normal physiological vasomotor tone.¹⁶ Also, in the absence of a permanent metal implant, the potential for reinterventions might be enhanced. Reintervention in a conventionally stented artery is difficult because of the inability to dilate the artery beyond the original size of the stent. Moreover, if a surgical bypass is subsequently required, vessels treated with metal stents cannot be clamped or used for anastomosis; these issues are resolved by bioresorbable stents. Lastly, bioresorbable stents can be used in pediatric patients where vessels need to grow or in patients with metal allergies.^16,17

Bioresorbable stents have been constructed from both polymer and metallic alloys. The initial polymer-based bioresorbable stents were tested in animals and produced marked inflammation resulting in enhanced intimal hyperplasia and thrombosis.¹⁶ Lincoff et. al., however, demonstrated in a porcine model that stents composed of poly-L-lactide (PLLA) produced minimal inflammation and durable results.¹⁸ Yamawaki et. al. combined a tyrosine kinase inhibitor that blocked proliferation, with a biodegradable stent made of PLLA and found a diminution in restenosis.¹⁹ PLLA degrades over a two year period following implantation. There is a decrease in radial support at approximately 6 months, loss of mass starting at 12 months and complete resorption by 24 months.¹⁹

The ABSORB trial (Abbott Vascular; Abbott Park, IL) was a prospective but uncontrolled, multicenter study to assess the efficacy of an everolimus-eluting bioresorbable stent with a polylactic acid backbone.²⁰ Thirty patients with single de novo coronary lesions were treated and at 2 years post-implantation, the stents had completely resorbed and the rate of restenosis was 0%.²⁰ At 4-year follow-up, there was no stent thrombosis or closure. In 2011, Abbott initiated the ABSORB II trial, which is a randomized, controlled, multicenter study comparing the Absorb® bioresorbable vascular scaffolding with its Xience Prime® everolimus-DES for treatment of coronary lesions. The study is underway and the investigators aim to recruit approximately 500 patients at forty different sites. The Absorb® bioresorbable scaffold has received CE mark and is currently available at select European centers.

Bioresorbable alloy stents, most commonly composed of magnesium, have been used both in animals and clinically. Magnesium has been the chosen alloy because it is an essential mineral well tolerated by the body and it absorbs over four months. Metallic bioresorbable stents have specific advantages over polymer-based analogs including: increased strength, more rapid degradation, complete radioopacity and importantly, metal alloys produce only a minimal inflammatory response. The PROGRESS-AMS trial was a prospective multicenter controlled but nonrandomized study intended to evaluate the treatment of a single de novo coronary lesion using a magnesium bioresorbable stent containing a calcium antagonist. Intravascular ultrasound revealed that stents were completely absorbed by the vessel wall at 4 months. However rates of restenosis at 4 months were identical for the magnesium alloy and the BMS (approximately 38% for both).¹⁷ Although this stent failed to show superiority over BMS in this limited trial, biocompatibility of the alloy in humans was demonstrated.

Thus, clinical evaluation of bioresorbable stent technology is ongoing. However, larger randomized control trials are necessary to truly assess efficacy. Further investigation is needed to verify that this technology is indeed an advance over drug-eluting stents or balloons. At this point in time, these stents have not been evaluated in the peripheral circulation although an evaluation of a PLLA stent (Remedy®, Kyoto Medical; Japan) in the superficial femoral artery is currently underway.

Drug-eluting balloon

Initially developed in the 1980s, drug-eluting balloons (DEBs) have recently had a resurgence as investigators search for ways to overcome the limitations of drug-eluting stents. A limitation of drug-eluting stents is the inconsistentency of drug delivery; specifically a stent contacts only 15% of the vessel wall and this small area is where drug elution occurs.²¹ Using a balloon to deliver drug to the arterial wall allows for uniform delivery with near-complete and homogenous coating of the surface of the lesion. Further limitations of DES include the need for long lengths to cover the entire surface of a diseased vessel. Moreover, stents are associated with excessive intimal hyperplasia and don’t allow for adaptive remodeling. Restenotic or thrombosed stents are difficult to reopen. Lastly, stents are costly compared to conventional balloon angioplasty. Although the initial cost of DEBs will be high, this is likely to diminish over time relative to stents.

The quest for non-stent based pharmacologic platforms has steered both clinical investigators and device manufacturers toward the development of DEBs. These devices, which are comprised of an angioplasty balloon coated with a polymer that elutes an antiproliferative agent, are designed to compress and disrupt plaque as well as simultaneously deliver a drug to prevent restenosis. Interestingly, the overwhelming majority of DEB trials have used paclitaxel; a drug that inhibits microtubule assembly and selectively inhibits smooth muscle proliferation, migration and extracellular matrix deposition.²² Paclitaxel is well suited for delivery by a DEB because it is highly lipophilic, allowing rapid intracellular uptake after a brief administration. To date, there appears to have been minimal success with DEBs and rapamycin.

Older methods of balloon eluting drug delivery failed to achieve clinical success because of poor retention of drug at the site of injury. However, in recent years, newer technologies have been developed, with balloons composed of polymers that allow enhanced drug loading and improved controlled release into the vessel wall. Many of the currently available balloons employ an organic substrate, or an excipient such as urea or iopromide, which helps attach paclitaxel to the balloon and also allows for a more uniform distribution of the drug into the arterial wall.

There has been a surge in clinical trials investigating the use of DEB technologies for treatment of infrainguinal disease. One of the earliest was the THUNDER, a multicenter, randomized, controlled trial for the treatment of femoropopliteal disease comparing a paclitaxel-eluting (Bavaria Medizin Technologie GmbH, Germany; 3μg of paclitaxel/mm² of balloon surface) to an uncoated balloon.²³ Lesions treated with the paclitaxel-eluting balloon had reduced late lumen loss (LLL) compared to control and also a reduced target lesion revascularization (TLR) rate at 6 and 24 months follow-up. FemPac was another multicenter, randomized, controlled trial investigating the safety and efficacy of DEB for the treatment of femoropopliteal disease. This trial compared the use of a paclitaxel-eluting balloon (Bavaria Medizin Technologie GmbH, Germany; 3 μg of paclitaxel/mm² of balloon surface) to an uncoated balloon. Investigators reported a statistically significant lower LLL and TLR rate at 6 months in the eluting balloon group as well as clinical improvement as evidenced by an improved Rutherford class.²⁴

LEVANT I was a randomized trial designed to evaluate the use of a paclitaxel-eluting balloon (Moxy, New Hope, MN; 2 μg/mm² paclitaxel/mm² of balloon surface)to an uncoated balloon with and without stenting for the treatment of femoropopliteal disease. The DEB used in this study has a proprietary hydrophilic, non-polymeric carrier molecule that facilitates rapid drug transfer upon inflation. Investigators enrolled 101 patients to receive either DEB (n=37 patients), uncoated balloon (n=38) or stenting (n=26). In the stent group, patients were treated with either DEB (n=12) or uncoated (n=14) balloon before stenting. Patients receiving the DEB had a lower LLL at six months although the TLR rate was not significantly diminished. In sub-group analysis, a similar LLL was found for patients receiving DEB and DEB plus stent. Based on the success of this trial, the sponsors have initiated the LEVANT II trial to assess primary patency at twelve months. Recently presented was PACIFIER, a 91 patient randomized, controlled trial evaluating the use of a paclitaxel-eluting balloon for treatment of femoropopliteal disease. Investigators in this trial reported an extraordinarily low LLL and TLR at 6 months for DEBs.

A number of studies are ongoing. Preliminary data from a multi-center Italian registry, revealed high patency rates for the DEB IN.PACT® Amphirion (Medtronic; Minneapolis, MN) and improved clinical outcomes at one year compared to historical controls of primary angioplasty. Medtronic has invested heavily in its IN.PACT DEB and has initiated several single and multicenter trials worldwide. The IMPACT SFA I & II will evaluate the efficacy of the IN.PACT® Admiral DEB for femoropopliteal lesions. DEBATE-BTK, INPACT DEEP and PICCOLO are all comparing the IN.PACT® Amphirion paclitaxel-eluting balloon to an uneluting balloon for below-the-knee vascular lesions. These trials will be important to determine the efficiency of DEBs for distal lesions. The DEBELLUM trial which is also currently underway will evaluate the same DEB, IN.PACT® Amphirion for treatment of all infrainguinal disease. A comprehensive list of completed and ongoing trials is included in Table III.

Table III.

Trials evaluating drug-eluting balloons.

Trial Name/ Author	Vascular Territory (SFA/POP/BTK)	Status	Study Period	Drug; Balloon	Excipient/ Carrier	Randomization	Pts (N)	Late Lumen Loss (time)	Target Lesion Revascularization (time)	Rate of Binary Restenosis (timeframe)
Montevergine Registry	SFA	presented at LINC 2012	unknown	Paclitaxel; unknown	unknown	Single arm, Observational registry	39	NR	DEB: 7.9%(12M)	NR
Micari et al.	SFA/POP	published	May 2008-Sept 2010	Paclitaxel; In.Pact Admiral	Freepac (urea)	Single arm, Observational registry	105	NR	DEB: 7.6%(12M)	NR
PACIFIER	SFA/POP	presented, ongoing	Mar 2010 – Dec 2012	Paclitaxel; In.Pact Pacific	Freepac (urea)	Prospective, Multicenter, Single Blind, Randomized	91	DEB: -0.01mm (6M)	DEB: 7.1%(6M)	DEB: 8.6%(6M)
								PTA: 0.65mm (6M)	PTA: 21.4%(6M)	PTA: 32.4%(6M)
THUNDER	SFA/POP	published	July 2004 – Oct 2007	Paclitaxel; unknown	unknown	Prospective, Multicenter, Double Blind, Randomized	154	DEB: 0.4 +/- 1.2mm (6M)	DEB: 15%(24M)	DEB: 17%(6M)
								PTA: 1.7 +/- 1.8mm (6M)	PTA: 52%(24M)	PTA: 44%(6M)
FEMPAC	SFA/POP	published	April 2004 - July 2007	Paclitaxel; unknown	unknown	Prospective, Multicenter, Single Blind, Randomized	87	DEB: 0.5 +/- 1.1mm (6M)	DEB: 13%(24M)	DEB: 19%(6M)
								PTA: 1. 0+/- 1.1mm (6M)	PTA: 50%(24M)	PTA: 47%(6M)
LEVANT I	SFA/POP	presented	Jun 2009 – Dec 2011	Paclitaxel; Moxy	Lutonix proprietary hydrophilic non-polymeric carrier	Prospective, Multicenter, Single Blind, Randomized	101	DEB: 0.36mm (6M)	DEB: 6% (6M)	NR
								PTA: 1.08mm (6M)	PTA: 21%(6M)
LEVANT II (clincal trial)	SFA/POP	ongoing	July 2011 – Dec 2016	Paclitaxel; Moxy	Lutonix proprietary hydrophilic non-polymeric carrier	Prospective, Multicenter, Single Blind, Randomized	~700	N/A	N/A	N/A
Inpact SFA I	SFA/POP	ongoing	Sept 2010 - July 2016	Paclitaxel; In.Pact Admiral	Freepac (urea)	Open Label, Randomized	~150	N/A	N/A	N/A
Inpact SFA II	SFA/POP	ongoing	Mar 2012 – Mar 2018	Paclitaxel; In.Pact Admiral	Freepac (urea)	Single Blind, Randomized	~450	N/A	N/A	N/A
Advance 18 PTX	SFA/POP	unpublished	Oct 2008 - Dec 2013	Paclitaxel; Advance 18PTX	none	Open Label, Randomized	~150	N/A	N/A	N/A
DEBELLUM	SFA/POP/BTK	presented at LINC 2012	unknown	Paclitaxel; In.Pact Admiral &Amphirion	Freepac (urea)	Single Center, Randomized, Blinding unknown	50 (92 SFA/POP lesions, 30 BTK lesions)	DEB: 0.5 +/- 1.4mm (6M)	DEB: 8% (6M)	NR
								PTA: 1.6 +/- 1.7mm (6M)	PTA: 36% (6M)
Leipzig Registry, Schmidt et al.	BTK	published	Jan 2009	Paclitaxel; In.Pact Amphirion	Freepac (urea)	Single Arm, Observational Registry	104	NR	DEB: 17.3%(12M)	DEB: 27.4%(3M)
			Feb 2010
DEBATE-BTK	BTK	presented at LINC 2012	Nov 2010	Paclitaxel; In.Pact Amphirion	Freepac (urea)	Single Center, Double Blind Randomized	111	NR	NR	DEB: 29%(12M)
			Nov 2012							PTA: 72%(12M)
Inpact DEEP	BTK	ongoing	Sep 2009	Paclitaxel; In.Pact Amphirion	Freepac (urea)	Multicenter, Double Blind, Randomized	unknown	N/A	N/A	N/A
			Dec 2015
PICCOLO	BTK	unpublished	Apr 2008-Apr2011	Paclitaxel; Invatec Ampherion	unknown	Multicenter, Double Blind, Randomized	114	N/A	N/A	N/A

Abbreviations:

N/A - not available

NR – not reported

PACIFIER - Paclitaxel-coated Balloons in Femoral Indication to Defeat Restenosis

THUNDER - Local Taxane with Short Exposure for Reduction of Restenosis in Distal Arteries

PICCOLO - Drug Coated Balloons for Prevention of Restenosis

DEBELLUM - Drug Eluting Balloon Evaluation for Lower Limb mUltilevel treatMent

Currently, all aforementioned DEBs have received the CE mark and the data for this technology is highly encouraging. Thus far, these trials have proven the safety and efficacy of DEB but larger, better controlled trials are necessary with longer-term follow-up. Nevertheless, many of the large medical device manufactures have sensed significant potential and have embraced DEBs. There is little doubt that this technology will play a significant role in vascular treatments in the future.

Porous and Microporous balloon

As balloon technology has evolved, investigators continue to search for a more efficient means to locally deliver drug using the balloon as a platform. A variant of the drug-eluting balloon is the porous balloon. Rather than coating the balloon with drug, the agent to be applied is contained within the balloon and released through pores at the time of balloon inflation. Like more conventional drug eluting balloons, these devices have the ability to conform to the shape of a vessel allowing complete and circumferential drug delivery. Two approaches have been reported. The first involves initial angioplasty with a conventional balloon followed by drug infusion through a low-pressure porous balloon. The alternative method involves concurrent drug infusion and angioplasty using the same balloon. One of the concerns regarding this technology is that barotrauma from the fluid jet produced by the porous balloon might stimulate intimal hyperplasia.²⁵ Also, there is the potential for non-homogenous drug delivery if the pores occlude. Lastly, the drug may escape into the systemic circulation if there is not good apposition of the balloon to the arterial wall.²⁵ To address the concern of barotrauma related to fluid release from the balloon, a microporous balloon has been developed. This consists of an inner porous balloon, surrounded by an outer membrane with narrower fenestrations which reduce the force of the solution as it is released.²⁶

Porous balloons have been used clinically but only in a few patients and not as part of large prospective trials. Latif & Hennebry, reported the use of a porous balloon to treat in stent restenosis in two patients with extensive peripheral vascular disease. Paclitaxel was administered following angioplasty using a Vascular Clearway irrigation balloon, a porous balloon made by Atrium Medical (Hudson, NH) which is FDA approved device for the delivery of thrombolytic agents.²⁷ Drug delivery was successful in both patients with no evidence of restenosis by angiography four months following intervention.²⁷ Atrium has recently sponsored the IRRITAX trial, a randomized, single-center pilot study to evaluate this balloon in combination with paclitaxel for the treatment SFA stenosis. Large and randomized trials will be needed to fully validate long-term outcomes with this technology.²⁷

Extraluminal Drug Delivery Devices

Perivascular Biomaterials

Although intraluminal therapies for coronary and peripheral vascular disease have become increasingly prevalent, there are still thousands of open surgical revascularizations performed around the world each year and no available techniques to limit restenosis or intimal hyperplasia in these patients. Interestingly, the opportunity exists at the time of surgery to extraluminally apply a therapy that can prevent the development of recurrent disease (Table IV). Extraluminal application of a restenotic drug has distinct advantages over intraluminal therapy. Drugs applied extraluminally will saturate the arterial adventitia and it is well recognized that the adventitia contributes substantially to intimal hyperplasia, through activation and migration of myofibroblasts into the neointima.²⁸ Drugs applied extraluminally will also diffuse into the media as well as the subintima and can prevent the production of subintimal plaque. Lastly, the concentrations of drug that reach the intima or the endothelial layer are markedly diminished, lessening that chance that drug application will inhibit re-endothelialization of the vessel lumen.

Table IV.

Extraluminal Drug Delivery Devices.

Extra-Luminal Devices	Advantages	Disadvantages	Current status	Representative Publications (Author, Date)
Injection catheter	Periadventitial drug release through a percutaneous approach High concentration of drug can be delivered	Uneven distribution of drug (highest concentration of drug at injection site)	Currently in pre-clinical animal studies	Tian et al (2006)
				Gasper et al (2011)
Perivascular Biomaterials	Drug delivery applicable to open surgical repair or bypass	Material may produce perivascular inflammation Need for materials that provide long term drug delivery	Currently in pre-clinical animal studies	Moon et al (2004)
				Kelly et al (2006)
				Siow et al (2007)
				Yau et al (2008)

In multiple animal studies of restenosis, hydrogels have been used to suspend drugs for adventitial delivery. Hydrogels are a composed of network of hydrophilic polymer chains that have a high content of water. They are biocompatible and their permeability makes them ideal for drug-delivery. There are innumerable studies where hydrogels have been used in animals to deliver drugs and or molecular tools to prevent intimal hyperplasia.^29,30 In fact, hydrogels have become a common research tool for the delivery of agents under investigation as inhibitors of restenosis. Although results in animals have been encouraging, one of the disadvantages of traditional hydrogels is their rapid release of drug. Early generation hydrogels elute drugs in less than 3 days. It has become increasingly clear that prolonged drug release may be necessary to prevent recurrent disease associated with most vascular reconstructions. This clinical and pharmacological limitation has led to the development of newer hydrogels with modifications (pH or temperature) that allow controlled and sustained release of drug.

Another approach to periadventitial drug delivery is the perivascular wrap. Kelly et. al. tested ethylene vinyl acetate perivascular wraps loaded with paclitaxel in a porcine model of arteriovenous graft stenosis.³¹ These investigators found anastomoses treated at the time of surgery with the paclitaxel-loaded polymer wraps developed less luminal stenosis when compared to untreated graft-vein anastomoses (0.17% in the paclitaxel group vs. 37.90% stenosis in the control group). Poly(ε-caprolactone) (PCL) is a biocompatible and biodegradable polymer which has also been used to deliver paclitaxel and rapamycin to the vessel wall. PCL has been studied extensively in vitro and in vivo resulting in FDA approval of many medical drug delivery devices composed of PCL. In a mouse femoral artery injury model, investigators placed PCL cuffs loaded with paclitaxel or rapamycin or control cuffs around injured femoral arteries. At 3 weeks, paclitaxel and rapamycin-eluting PCL reduced intimal thickening by 76% and 75%, respectively. Furthermore, investigators found that delivery was indeed local with no adverse systemic effects.

Despite significant success in animal models, this technology has been slow to enter human clinical trials. We have found only one company that is close to human trials. VesselTek Biomedical (Chicago, IL) is currently developing a drug-eluting perivascular wrap (VTek-RA wrap) constructed from poly(diol citrate). Their wrap is designed for local drug delivery and is biodegradable. This product is currently in the FDA pre-market approval stage.

Injection catheters

Injection catheters are intraluminal devices that contain microneedles that are capable of delivering drugs to the periadventitial space. Upon insufflation, the microneedles pierce the vessel wall and release drug into and around the vessel’s adventitia. An obvious advantage of this device is that a drug can be delivered to the outer vascular wall via a percutaneous intervention. Therefore, drug is not delivered directly to the vessel lumen consequently diminishing its effect on reendothelializatoin. Tian et al, investigated the effect of adventitial paclitaxel delivery to the porcine femoral artery using a 3-prong needle injection catheter.³² The investigators concluded that the injection catheter was an effective method of drug delivery since neointimal area was reduced from 2.8 to 0.41 mm², and restenosis was reduced from 47 to 13%.³² Using the same animal model, Gasper et al., evaluated the delivery of nab-rapamycin using a modified version of the foregoing injection catheter containing a single microneedle and found decreased intimal hyperplasia and negative remodeling.³³ A disadvantage of injection catheters is the potential for uneven distribution of the drug.³⁴ Another concern is the possibility of a toxic effect if a drug is administered in excessive doses to a localized area with the potential of aneurysm formation or rupture related to extensive necrosis.

Mercator MedSystems (San Leandro, CA) recently introduced a micro-infusion catheter with a single injection needle. This is comprised of a balloon-sheathed microneedle that can be deployed by a low-pressure balloon. When the desired injection site is reached, the balloon is expanded, securing the system and allowing the sliding microneedle to penetrate the vessel wall. The FDA has given the Micro-Infusion Catheter 510(k) clearance. We were unable to find any published literature, using this Micro-Infusion Catheter, although data recently presented at the Society for Vascular Surgery Annual Conference suggests this device is ready for clinical safety trials. More recently, two injection catheters developed by Bavaria Medizin Technologie GmbH (Ger­many)and Binlab, Inc. (Webster, TX) have been patented but there is no published data describing their efficacy.

Systemic Drug Administration

Intravenous Drug Delivery

The FDA first approved Paclitaxel in December 1992 for marketing under the trade name Taxol (Bristol-Myers Squibb; Princeton, NJ). This form of paclitaxel is given to patients intravenously and contains ethanol and Cremophor® EL to increase its solubility (BASF Aktiengesellschaft; Germany). Unfortunately, these additives cause severe hypersensitivity reactions requiring patients be premedicated with corticosteroids and antihistamines prior to treatment.

In January 2005, a novel albumin-bound nanoparticle version of paclitaxel (nab-paclitaxel, ABI 007, Abraxane®; Abraxis BioScience; Los Angeles, CA) was approved for the treatment of metastatic breast cancer. This modification significantly improved the efficacy and safety profile of paclitaxel. The absence of solvents abolished the need for premedication. There have been several clinical trials (SNAPIST-I, II, and III) to assess the efficacy of nab-paclitaxel (Coroxane®) in preventing restenosis after bare metal stenting of de novo coronary lesions. The complexity of this treatment is that it produces neutropenia, leucopenia and alopecia, particularly in high doses as detailed in Table V. The second version of this trial, SNAPIST-II was a randomized comparison in 76 patients of a single dose (35mg/m²) and a single dose plus a repeat dose at 2 months (35mg/m²) of nab-paclitaxel. At 6 months there was no statistically significant difference in rates of restenosis between the two groups by angiography or ultrasound. SNAPIST-III a randomized clinical trial enrolling 122 patients has been recently completed. This study randomized patients to four groups using lower doses of the nab-paclitaxel than in the previous two trials, specifically 10, 22, 35 and 45 mg/m². Results of this trial are currently being analyzed.Several other systemically administered pharmacotherapeutic regimens have been effective in preventing restenosis in animal models but their success is yet to be translated to human trials related to poor tolerance and a narrow therapeutic range for these drugs.^4,5

Table V.

Systemic Administration.

Systemic Administration	Advantages	Disadvantages	Current status	Representative Publications (Author, Date)
Intravenous	Cost No need for antiplatelet therapy No need for invasive intervention	Neutropenia, leukopenia, and alopecia	Currently in clinical trials (100-300 patiients)	Margolis et al (2006)
				Chan et al (2011)
				Deglau et al (2011)

Targeted Intravenous Drug Delivery

Another promising method of local drug delivery involves using tissue-specific targeted systemic treatments. These agents are systemically administered but because of tissue specific tags find their way to the injured vessel following vascular intervention. Deglau et al. investigated a site-specific delivery system using microspheres (capable of carrying therapeutic drugs) composed of a reactive polyethylene glycol tagged with avidin and a balloon that coats the injured artery with biotin.³⁵ The Remedy microporous balloon was used to deliver biotin molecules to the surface of rabbit femoral arteries after injury.³⁵ Avidin (which has a high affinity for biotin) -coated microspheres were then administered intravenously and these microspheres attached to the biotin on the arterial wall locally releasing the drug. This approach, using microspheres containing a drug that inhibits restenosis, has the potential to locally deliver a systemically injected anti-restenotic agent.

Another method of targeted drug delivery through systemic injection is by using microspheres that target proteins that are specifically expressed or upregulated after vascular injury. For example, investigators have created microspheres or particles that directly target surface markers that are exposed following vascular injury including E- and P-selectin, ICAM-1 and VCAM-1. Nanoparticles can also be modified to target and bind to specific proteins within the injured arterial wall. Chan et. al designed a nanoparticle with a lipid core-shell interface between polylactideco-glycolic acid and polyethylene glycol polymers and peptides directed against collagen IV. This nanoparticle loaded with paclitaxel was designed to bind to collagen IV in the basal lamina of the vessel wall, which is exposed after endothelial denudation from mechanical injury.⁴³ Safety studies have shown that rats receiving targeted nanoparticles had no signs of toxicity. In a rat carotid injury model, targeted nanoparticle delivery of paclitaxel given as a two-dose infusion on days 0 and 5 after injury prevented arterial stenosis, as evidenced by a 50% reduction in intima/media ratio when compared to control. The site-specific delivery of this nanoparticle could provide a safe and effective treatment of restenosis that does not require a direct intra or extraluminal intervention. However, clinical trials are needed to test the safety and efficacy of these innovative techniques.

CONCLUSION

The forgoing reveals an explosion of interest in the development of preventative treatments for restenosis. The spectrum ranges from drug eluting stents, which are used in routine clinical practice to drug eluting balloons that are now entering the clinical arena to targeted nanoparticles which are just being evaluated in animals.

A search of current NIH-funded projects using the keywords: “drug delivery” and “restenosis,” reveals a multitude of interesting endeavors. The majority of proposals that we identified were focused on systemic delivery of locally targeted drug carriers, such as liposomes, microshperes or nanoparticles with the goal of altering their biochemical properties to maximize efficiency of drug delivery to the arterial wall. Similarly, over the past two years, more than 65 new patents have been issued for approaches to local drug delivery that are focused on preventing restenosis.

With this incredible amount of innovation, it seems likely that in the near future, great strides will be made in the prevention of restenosis. The central theme that will likely produce this success is targeted or local and sustained delivery of high concentrations of an inhibiting compound or compounds. In this review we have attempted to comprehensively describe the approaches to local drug delivery that are currently in use or under investigations. This is a rapidly moving field and likely by the time of publication of this review, new trials will have come to completion and new innovations will have been developed.

Although there are many promising venues for drug delivery, drug eluting stents as well as drug eluting balloons currently have the full attention of industry; these are the technologies that will likely be assimilated into practice over the next few months to years. Nevertheless, there are many potentially less expensive and more effective technologies under development. There is little doubt that over the next decade, the methods used to prevent restenosis will continue to evolve. Restenosis is a devastating process that affects millions of individuals each year. Our review of this field suggests that the future is bright and a solution will soon be at hand.