**Drug Eluting Balloon**

S. Sharma1, N. Kukreja2 and D. A. Gorog2,3 *1Frimley Park Hospital NHS Trust,* 

*2East and North Hertfordshire NHS Trust, 3Imperial College, London UK* 

#### **1. Introduction**

126 Coronary Interventions

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Since the first percutaneous transluminal coronary angioplasty (PTCA) performed by Andreas Gruntzig in 1977 the technology has evolved significantly. Progress of PTCA has seen the development of many devices, some of which are still in use and many others that have fallen in disuse. The main limitation of the plain old balloon angioplasty (POBA) was the problem of elastic vascular recoil causing abrupt vessel closure and restenosis. The patho-mechanism of restenosis that occurs following balloon angioplasty involves negative vascular remodeling, elastic recoil and thrombosis at the site of injury {Moreno, 1999}. While the thrombus formation can be reduced by use of antiplatelet drugs, the restenosis threat remains. Early restenosis occurred in as many as 30% of angioplasty cases. This led to the development of the metal stent to exert radial force on the vessel wall and thus prevent elastic recoil. Although stents reduced restenosis, their use led to the realisation of a different and new challenge of in stent restenois (ISR). This occurs mainly due to neointima formation {Mach, 2000,Mudra et al, 1997, Hoffman et al, 1996, Kearney et al, 1997} that is principally composed of proliferating smooth muscle cells (SMC) and extra cellular matrix {Geary et al, 2003, Grewe et al, 1999}. By the late 1990s, it was acknowledged that although the incidence of ISR was lower than that of restenosis following balloon angioplasty {Serruys et al, 1991}, it occurred in 15–30% of patients, and possibly more frequently in certain subgroups {Holmes et al, 2002}.

#### **2. Treatment of restenosis**

Over the years there have been intensive research efforts to identify possible pharmacotherapeutic regimens to prevent the neointimal restenotic process. Although most experimental studies and some small initial clinical studies showed promise, subsequent large randomized trials have been disappointing {Faxon, 1995, Bertrand et al, 1997, Boccuzzi et al, 1998, Serruys et al, 2000, Faxon, 2002}. Failure to achieve significant reduction in ISR with systemic drug therapy led to the exploration of the concept of local drug delivery. Local drug delivery (LDD), in theory, should achieve greater local drug concentration with lower overall dose compared to systemic therapy, to help achieve maximal tissue effects while minimizing undesired systemic toxicity. It also has the advantage of being able to utilize drugs with low systemic bioavailability or short half-life. Many devices have been

Drug Eluting Balloon 129

folded balloon, which is homogenously coated with paclitaxel embedded in contrast medium coating. Paclitaxel (3 μg/ 373mm2 balloon surface) is the pharmacologically active substance whereas the contrast medium has a matrix builder function to facilitate

Fig. 1. Photograph of SeQuent (top) and the paclitaxel coated SeQuent® Please balloon

The ideal drugs for local delivery should be lipophilic in nature, rapidly adsorbed and have a high retention rate by the vessel intima, in order to exert maximal beneficial effects {Baumbach et al, 1999}. Paclitaxel is a lipophilic drug and bind tightly to various cell constituents {Rowinsky et al, 1995}, resulting in effective local retention at the site of delivery { Creel et al , 2000} and it exerts a long-lasting effect in the cell due to structural alteration of the cytoskeleton. Thus, paclitaxel, with its lipophilic nature, combined with the fact that adding a small amount of hydrophilic contrast medium {Scheller et al, 2003} enhances its solubility, makes it well suited for delivery on a drug-delivery balloon. Various other drugs like, sirolimus, zotarolimus, rapalog and others are being studied currently as a possible alternative to paclitaxel for coating the PTCA balloon {Schnorr et

The first preclinical study was conducted by Scheller et al {Scheller et al, 2004}. In this study stainless steel stents (n = 40; diameter: 3.0–3.5 mm; length: 18 mm) were implanted in the left anterior descending and circumflex coronary arteries of pigs. Both conventional uncoated and three different types of paclitaxel-coated coronary angioplasty balloons were used, and contact with vessel wall was maintained for 1 min. The results were assessed by quantitative angiography and histomorphometric studies of the stented arteries. There was a marked reduction (up to 63%) of parameters characterizing ISR in the paclitaxel-coated balloon group, without evidence of increased inflammation in proximity to the stent struts or any effect on re-endothelialisation of the struts. They also showed that paclitaxel-coated balloons lose only 6% of the drug when introduced into the coronary circulation and retracted without inflation. Approximately 80% of the drug is released during inflation, suggesting

catheter (bottom).

al, 2010}.

**3.1 Pre- clinical data** 

immediate release of drug during balloon inflation {Scheller & Speck, 2009}.

developed to administer drugs or genetic material locally to the site of injury {Sharma et al, 2011}. Studies have shown that local administration of pharmacologic agents directly at the site of coronary intervention is an effective means of delivering sufficient amount of drug into the injured arterial tissue site to cause an anti-restenotic therapeutic effect { Schwartz et al, 2004}.

Various approaches for local drug delivery have been tried including nanoparticles, contrast media and drug delivery balloons, such as porous {Herdeg et al, 2000} and double balloons {Oberhoff et al, 2001}. Other options for treating ISR included POBA using either conventional or cutting balloons, implanting a stent inside the stent, rotablation or brachytherapy. However, most of these techniques were not adopted into widespread clinical use due to their various shortcomings and limitations. Until recently, stent-based local drug delivery using drug-eluting stents (DES) is still considered the percutaneous treatment of choice for coronary restenosis. As the process of neo intimal hyperplasia occurs locally due to endothelial injury caused by the metallic stent, it seems logical to use the stent itself to deliver a drug locally in order to overcome this problem.

Thus DES have become the mainstay of intervention for coronary atherosclerotic disease {Kirtane et al, 2009}. However, DES use is limited by small but unpredictable risk of late stent thrombosis due to withdrawal of antiplatelet therapy { McFadden et al, 2004}, delayed mal-apposition {Kozuma et al, 1999}, delayed vascular healing as a result of initial antiproliferative effect {Jakabcin et al, 2008}, or a hypersensitivity reaction to the drug, polymer coating or both { Finn et al, 2007}.

ISR continues to occur with DES, although at a lower rate compared to BMS. However, the relative massive increase in number of DES implantations in recent years means the problem of ISR although less in relative terms compared to BMS, still causes a problem in absolute terms requiring a significant number of repeat procedures every year globally and remains a treatment challenge {Maisel, 2007}. Treatment of restenosed DES with a second DES is associated with risk of subsequent restenosis of up to 43% {Lemos et al, 2008}. The ideal treatment of a coronary stenosis would eliminate both the stent and the polymer related late problems, while at the same time deliver an antiproliferative agent to reduce the risk of restenosis.
