Drug eluting balloons for treatment of femoropopliteal disease

The VIVA Physicians conference for vascular medicine and intervention, held on November 4, 2014 in Las Vegas, Nevada, highlighted the results of a few late breaking clinical trials. Among the studies presented, quite a few were on drug coated balloon/drug eluting balloon devices for peripheral artery disease of the lower extremity femoropopliteal artery. Peripheral artery disease is a life-threatening condition that reduces blood flow to the lower limb. The American Heart Association estimates that peripheral artery disease affects eight million Americans. The aim of both invasive and noninvasive treatments is to improve the blood flow to the limb and maintain patency of the affected vessel for longer periods of time. Almost 700,000 patients in USA and Western Europe each year undergo an interventional procedure for peripheral artery disease, particularly superficial femoral artery [1]. Percutaneous transluminal angioplasty is the first line of treatment for peripheral artery disease according to the American College of Cardiology. Percutaneous transluminal angioplasty procedure may include balloon dilatation, with or without stent placement. Drug eluting stents and balloons, along with other different types of balloons are being studied to improve peripheral artery disease treatment outcomes, even in difficult lesions. This is a review of scientific evidence supporting percutaneous transluminal angioplasty for PAD with emphasis on drug eluting balloons. *Correspondence to: Aayla Jamil, Baylor University Medical Center, 3410 Worth Street, Suite 560, Dallas, USA, Tel: 1-214-960-032; E-mail: Aayla.Jamil@ BSWHealth.org Received: September 26, 2018; Accepted: October 12, 2018; Published: October 16, 2018 Introduction Ischemic injury can be caused in any part of the body where vascular supply is compromised. Limbs may be affected by acute limb ischemia due to thrombosis, embolism, dissection or trauma. Critical limb ischemia occurs when the condition becomes advanced and the survival of the limb is threatened due to lack of blood flow. Critical Limb Ischemia (CLI) is associated with rest pain, non-healing ulcers and gangrene. Ischemia is caused by Peripheral Artery Disease (PAD) in limbs due to plaque forming atherosclerosis. Atherosclerosis can lead to thrombosis and partial or complete occlusion of the arterial vessel [2]. According to the CDC, 8 million people in the US are suffering from PAD with almost 20 percent above the age of 60 years [3]. CLI is an extreme form of PAD and requires vascular intervention to prevent severe sequelae. PAD is more common in the legs than arms. Risk factors for PAD include diabetes, high cholesterol, hypertension, smoking, atherosclerosis and age older than 60 years [3]. PAD is classified according to Fontaine and Rutherford classification [4] (Appendix A). Pad and Critical Limb Ischemia Critical Limb Ischemia (CLI) is defined when the symptoms are chronic and present for more than two weeks. It is usually diagnosed by the Ankle Brachial Index (ABI) which a measure of the difference in the ankle and brachial blood pressure. Normal ABI ranges from 1.00 to 1.40 with an abnormal ABI measure of 0.90 and less. ABI of more than 1.40 indicates non-compressible vessel [4]. Claudication is a typical symptom of PAD causing CLI. Initially intermittent claudication may be present with aches, pains, cramping, or uncomfortable feeling in the legs on walking and is relieved with rest. It may be felt in any part of the leg like the thigh, hip, buttock, calf or foot. As the disease progresses the onset of claudication symptoms occurs sooner on walking till a time comes when pain is present even at rest. Rest pain indicates development of irreversible ischemia in the legs. According to the Merck Manual, 20 percent of the patients may be asymptomatic due to their sedentary lifestyle [5]. In moderate to severe PAD there may be diminished or absent peripheral pulses. The skin may be pale or dusky red with loss of hair and there may be muscle atrophy. As the condition worsens, non-healing ulcers and sores may develop especially upon trauma. Gangrene may also occur. Patients with peripheral neuropathy due to diabetes or alcoholism may not even feel any pain. Concomitant infection may lead to cellulitis. Signs and symptoms usually develop distal to the level of occlusion. PAD in the legs is diagnosed by ABI, ultrasound and angiography [5]. Risk factor modification, ACE inhibitors, antiplatelet medication, medication for claudication relief and smoking cessation are among the noninterventional treatment regimens for CLI. When CLI develops with ulcers, claudication at rest, or gangrene then surgical intervention (minimally invasive or invasive) is needed to relieve the arterial blood flow occlusion and to salvage the limb and toes to avoid amputation and premature death. Khan UJM (2018) Drug eluting balloons for treatment of femoropopliteal disease Volume 1(1): 2-7 J Cardio Case Rep , 2018 doi: 10.15761/JCCR.1000102 PAD in the lower limb due to atherosclerosis may cause aortoiliac disease (inflow disease), common femoral artery lesions (CFA), Superficial Femoral Artery (SFA) and popliteal artery disease, or tibial and peroneal artery disease [6]. It can be treated using minimally invasive endovascular procedures by interventional radiologists. These treatments include Percutaneous Transluminal Angioplasty (PTA) with balloon inflation, PTA with stent placement, laser angioplasty, atherectomy and Catheter Directed Thrombolysis (CDT). Severe and non-responsive cases may need to be surgically treated. The vascular surgeons either remove the blockage or perform bypass surgery for the affected artery by grafting a vein from the patient or by using a synthetic graft. An algorithm by Kenneth Oriel, MD, at The Cleveland Clinic in Ohio, demonstrates the management of patients with severe lower extremity PAD [7] (Figure 1). Types of endovascular interventions Stents are metallic cylindrical tubes placed inside the artery with the help of a catheter during a PTA procedure. It is used for long lesions and tortuous vessels. A stent holds the artery open after it has been cleared of the obstruction and then expanded by a balloon catheter. Stent is placed when there is failure of PTA procedure. PTA may be done with balloon expansion of the artery alone, without requiring the placement of a stent. PTA is useful to treat short concentric segments of stenosis. Upto 10 cm of lesions can also be treated by balloon dilatation [5]. PTA cannot be used to treat small arteries or long occlusions. Following PTA antiplatelet medication is taken for life to maintain patency of the artery. In laser angioplasty, pulsed bursts of ultraviolet energy are transmitted via a catheter to dissolve the occluding clot [8]. Atherectomy or thromboendarterectomy is a procedure during which plaque is shaved from the inside of the artery using a small catheter. It is done for short lesions in the aortoiliac, common femoral and deep femoral arteries [5]. For catheter directed thrombolysis (CDT), thrombolytic drugs like urokinase, alteplase, and reteplase are injected into the thrombotic clot via a catheter to dissolve the clot [7]. CDT is done to treat cases of Acute Limb Ischemia (ALI) which present within 2 weeks of the obstruction. ALI may develop due to trauma, embolism, thrombosis, graft thrombosis, and peripheral aneurysm with an embolus or thrombosis [4]. ALI due to graft failure with thrombosis may also be treated with PTA, stent placement and surgical revision. Mechanical thrombectomy is another method where the clot is sucked out with a catheter [9]. The TransAtlantic Inter Society Consensus (TASC I) document established recommendations for diagnosis and management of PAD in the lower extremity, which later had an updated consensus document in 2007 (TASC II). TASC classifies femoropopliteal disease according to four types of lesions [4] (Appendix B). For TASC A lesions treatment is endovascular therapy which encompasses PTA. For TASC B endovascular therapy is preferred method of treatment but depends on comorbidities. In case of TASC C and TASC D, surgical intervention like bypass and endarterectomy are the recommended treatments [10]. Generally asymptomatic stenosis is not treated with PTA. PTA should be considered in cases with critical limb ischemia, intermittent claudication limiting ability to work, lifestyle limitations, or as an adjunct for cardiac rehabilitation. PTA Using Balloon Technologies Percutaneous transluminal angioplasty was developed in the 1960’s by the innovative works of Thomas Fogarty and Charles Dotter. In 1961 the balloon embolectomy catheter was introduced by Thomas Fogarty to remove an embolus. In 1964 Charles Dotter used this catheter technique to treat atherosclerotic stenosis. He passed an 8 French (F) tetrafluoroethylene (Teflon) catheter into a stenotic vessel and then passed a 12 F Teflon catheter over it to dilate the vessel. In 1965 Dotter used the first balloon catheter made by Fogarty to treat a case of iliac stenosis. This catheter had two balloons one over the other for extra thickness. Thus, Fogarty was the inventor of the first minimally invasive surgical device while Dotter is known as the father of interventional radiology. These two created a whole new revolutionary chapter in the field of vascular interventional therapy. In 1974 Andreas Grüntzig used polyvinyl chloride in place of latex as the balloon material which made the catheter more flexible than the stiff Teflon catheters and allowed more force to act on the plaque [11]. Ingemar Henry Lundquist developed the over the wire balloon used for angioplasty procedures [12]. Various types of balloons are being made now a days. Most balloons used these days are made of polyethylene terephthalate and other strong plastic polymers. Balloons made of stiff materials like woven nylon are used for tight calcified stenotic sites. Cryoballoons stop the in


Introduction
Ischemic injury can be caused in any part of the body where vascular supply is compromised. Limbs may be affected by acute limb ischemia due to thrombosis, embolism, dissection or trauma. Critical limb ischemia occurs when the condition becomes advanced and the survival of the limb is threatened due to lack of blood flow. Critical Limb Ischemia (CLI) is associated with rest pain, non-healing ulcers and gangrene. Ischemia is caused by Peripheral Artery Disease (PAD) in limbs due to plaque forming atherosclerosis. Atherosclerosis can lead to thrombosis and partial or complete occlusion of the arterial vessel [2]. According to the CDC, 8 million people in the US are suffering from PAD with almost 20 percent above the age of 60 years [3]. CLI is an extreme form of PAD and requires vascular intervention to prevent severe sequelae. PAD is more common in the legs than arms. Risk factors for PAD include diabetes, high cholesterol, hypertension, smoking, atherosclerosis and age older than 60 years [3]. PAD is classified according to Fontaine and Rutherford classification [4] (Appendix A).

Pad and Critical Limb Ischemia
Critical Limb Ischemia (CLI) is defined when the symptoms are chronic and present for more than two weeks. It is usually diagnosed by the Ankle Brachial Index (ABI) which a measure of the difference in the ankle and brachial blood pressure. Normal ABI ranges from 1.00 to 1.40 with an abnormal ABI measure of 0.90 and less. ABI of more than 1.40 indicates non-compressible vessel [4].
Claudication is a typical symptom of PAD causing CLI. Initially intermittent claudication may be present with aches, pains, cramping, or uncomfortable feeling in the legs on walking and is relieved with rest. It may be felt in any part of the leg like the thigh, hip, buttock, calf or foot. As the disease progresses the onset of claudication symptoms occurs sooner on walking till a time comes when pain is present even at rest. Rest pain indicates development of irreversible ischemia in the legs. According to the Merck Manual, 20 percent of the patients may be asymptomatic due to their sedentary lifestyle [5]. In moderate to severe PAD there may be diminished or absent peripheral pulses. The skin may be pale or dusky red with loss of hair and there may be muscle atrophy. As the condition worsens, non-healing ulcers and sores may develop especially upon trauma. Gangrene may also occur. Patients with peripheral neuropathy due to diabetes or alcoholism may not even feel any pain. Concomitant infection may lead to cellulitis. Signs and symptoms usually develop distal to the level of occlusion. PAD in the legs is diagnosed by ABI, ultrasound and angiography [5]. Risk factor modification, ACE inhibitors, antiplatelet medication, medication for claudication relief and smoking cessation are among the noninterventional treatment regimens for CLI. When CLI develops with ulcers, claudication at rest, or gangrene then surgical intervention (minimally invasive or invasive) is needed to relieve the arterial blood flow occlusion and to salvage the limb and toes to avoid amputation and premature death. PAD in the lower limb due to atherosclerosis may cause aortoiliac disease (inflow disease), common femoral artery lesions (CFA), Superficial Femoral Artery (SFA) and popliteal artery disease, or tibial and peroneal artery disease [6]. It can be treated using minimally invasive endovascular procedures by interventional radiologists. These treatments include Percutaneous Transluminal Angioplasty (PTA) with balloon inflation, PTA with stent placement, laser angioplasty, atherectomy and Catheter Directed Thrombolysis (CDT). Severe and non-responsive cases may need to be surgically treated. The vascular surgeons either remove the blockage or perform bypass surgery for the affected artery by grafting a vein from the patient or by using a synthetic graft. An algorithm by Kenneth Oriel, MD, at The Cleveland Clinic in Ohio, demonstrates the management of patients with severe lower extremity PAD [7] (Figure 1).

Types of endovascular interventions
Stents are metallic cylindrical tubes placed inside the artery with the help of a catheter during a PTA procedure. It is used for long lesions and tortuous vessels. A stent holds the artery open after it has been cleared of the obstruction and then expanded by a balloon catheter. Stent is placed when there is failure of PTA procedure. PTA may be done with balloon expansion of the artery alone, without requiring the placement of a stent. PTA is useful to treat short concentric segments of stenosis. Upto 10 cm of lesions can also be treated by balloon dilatation [5]. PTA cannot be used to treat small arteries or long occlusions. Following PTA antiplatelet medication is taken for life to maintain patency of the artery. In laser angioplasty, pulsed bursts of ultraviolet energy are transmitted via a catheter to dissolve the occluding clot [8]. Atherectomy or thromboendarterectomy is a procedure during which plaque is shaved from the inside of the artery using a small catheter. It is done for short lesions in the aortoiliac, common femoral and deep femoral arteries [5]. For catheter directed thrombolysis (CDT), thrombolytic drugs like urokinase, alteplase, and reteplase are injected into the thrombotic clot via a catheter to dissolve the clot [7]. CDT is done to treat cases of Acute Limb Ischemia (ALI) which present within 2 weeks of the obstruction. ALI may develop due to trauma, embolism, thrombosis, graft thrombosis, and peripheral aneurysm with an embolus or thrombosis [4]. ALI due to graft failure with thrombosis may also be treated with PTA, stent placement and surgical revision. Mechanical thrombectomy is another method where the clot is sucked out with a catheter [9].
The TransAtlantic Inter Society Consensus (TASC I) document established recommendations for diagnosis and management of PAD in the lower extremity, which later had an updated consensus document in 2007 (TASC II). TASC classifies femoropopliteal disease according to four types of lesions [4] (Appendix B). For TASC A lesions treatment is endovascular therapy which encompasses PTA. For TASC B endovascular therapy is preferred method of treatment but depends on comorbidities. In case of TASC C and TASC D, surgical intervention like bypass and endarterectomy are the recommended treatments [10]. Generally asymptomatic stenosis is not treated with PTA. PTA should be considered in cases with critical limb ischemia, intermittent claudication limiting ability to work, lifestyle limitations, or as an adjunct for cardiac rehabilitation.

PTA Using Balloon Technologies
Percutaneous transluminal angioplasty was developed in the 1960's by the innovative works of Thomas Fogarty and Charles Dotter. In 1961 the balloon embolectomy catheter was introduced by Thomas Fogarty to remove an embolus. In 1964 Charles Dotter used this catheter technique to treat atherosclerotic stenosis. He passed an 8 French (F) tetrafluoroethylene (Teflon) catheter into a stenotic vessel and then passed a 12 F Teflon catheter over it to dilate the vessel. In 1965 Dotter used the first balloon catheter made by Fogarty to treat a case of iliac stenosis. This catheter had two balloons one over the other for extra thickness. Thus, Fogarty was the inventor of the first minimally invasive surgical device while Dotter is known as the father of interventional radiology. These two created a whole new revolutionary chapter in the field of vascular interventional therapy. In 1974 Andreas Grüntzig used polyvinyl chloride in place of latex as the balloon material which made the catheter more flexible than the stiff Teflon catheters and allowed more force to act on the plaque [11]. Ingemar Henry Lundquist developed the over the wire balloon used for angioplasty procedures [12].
Various types of balloons are being made now a days. Most balloons used these days are made of polyethylene terephthalate and other strong plastic polymers. Balloons made of stiff materials like woven nylon are used for tight calcified stenotic sites. Cryoballoons stop the inflammatory response of smooth muscle cells by generating cold temperature and thus reducing the rate of restenosis. Cutting balloons form controlled fault lines in the plaque by 3-4 small cutting blades that create longitudinal cuts into the fibrotic material and allows the vessel to be dilated with lesser force, thereby decreasing the inflammatory response and risk of restenosis [11]. Drug delivering balloons, derived from the principles of drug coated stents, are a new development in the field of balloon angioplasty. Basic principle of drug eluting balloons is local release of drug to resist smooth muscle proliferation after dilatation of the artery. Porous or double balloons may be used. Porous balloons deliver drug locally to the lesion via pores, while with double balloons two balloons block the proximal and distal end of the lesion to bathe the area in between the balloons with the drug.

Drug Eluting Stents (DES)
Drug eluting stents (DES) have been under research since the 1990's.  property. Paclitaxel (Antiproliferative Agent) Eluting Stent (PES) Taxus by Boston Scientific, Natick, was introduced in 2004 [13]. Zotarolimus (Sirolimus analogue) eluting stent (ZES) Endeavor by Medtronic, and Everolimus eluting stent (EES) Xience V by Guidant, Abbot Vascular are also approved for use in the US [14]. Despite all the above coronary drug eluting stents, Zilver PTX by Cook Medical is the only paclitaxel eluting stent approved for use in femoropopliteal disease [15]. The need for prolonged dual antiplatelet therapy, late stent thrombosis, stent fracture, and stent restenosis brought about the need for improved treatment modalities. Drug eluting balloon has been considered as an alternative to Drug Eluting Stent (DES). DEB can be useful in cases where DES cannot be used, like long calcified plaques, tortuous vessels, bifurcations, and small vessels. The drug release can be done without the use of a polymer, which is needed by some DES which can cause chronic inflammation and late thrombosis. DES has a slower rate of drug release than DEB.

Paclitaxel for Drug Eluting Balloons (DEB)
Paclitaxel has been identified as an ideal drug for DEB due to its lipophilic property causing rapid uptake and absorption by the arterial luminal surface, and prolonged retention of up to one week [16]. Some of the inactive agents for paclitaxel transfer are the contrast agent iopromide, urea, polysorbate and sorbitol. Paclitaxel has less impact on long term inflammatory response and the balloon transfers drug homogeneously to the vessel wall. Without the presence of the stent polymer, there is a reduction in chronic inflammation and thrombosis. Need for aggressive antiplatelet therapy is decreased with local drug availability. There are different ways to deliver drugs via balloon. These include using nanoparticles loaded with the drug, spraying, dipping and imprinting drug onto the rough surface of the balloon. Drug release kinetics with various doses, the percentage of drug release at varying balloon inflation timings and frequencies are important for the safety and efficacy of the procedure. Ensuring drug delivery to the lesion site and not losing it before the balloon reaches the lesion site is also crucial [14].

Trials for Drug Eluting/Coated Balloons (DEB / DCB)
In 1999 Ulrich Speck from Charite Hospital, Berlin, Germany, and Bruno Sheller from Saarland University Hospital, Homburg, Germany, added an antiproliferative drug to a contrast agent that served as a carrier for the drug to the vessel. In 2001 experimentation with drug coated balloons for drug delivery to lesion specific sites rather than the whole vessel began, with animal trials starting in 2002 [17]. The Paccocath ® technology was developed by Speck and Sheller and is owned by Bayer Schering Pharma AG, developed and marketed by Medrad International as Cotavance™ [18]. In December 2003 the first patient was enrolled in the coronary Paccocath ® ISR (In Stent Restenosis) I / II trial. In this technology paclitaxel is embedded in hydrophilic iopromide contrast agent Ultravist 370 to increase the solubility and ease of transfer to the vessel wall [16]. Initial dose of 10 to 15 percent of the drug is delivered to the vessel wall on 60 second inflation.
The THUNDER trial (Local Taxane with Short Exposure for Reduction of Restenosis in Distal Arteries) started in 2004 by Gunar Tepe at the University Hospital of Tuebingen, Germany, gave the first data on DEB angioplasty of the leg using Paclitaxel (Taxane) [17]. One hundred and fifty-four (154) patients with stenosis or occlusion of the superficial femoral or popliteal artery were enrolled and evaluated for restenosis following treatment with either DCB or conventional PTA at 6, 12, and 24 month follow up. The results of the THUNDER trial were published in 2008 in The New England Journal of Medicine. It was a double-blind study using either paclitaxel coated balloons, paclitaxel delivered through contrast medium, or controls with uncoated catheters. The paclitaxel balloon treated restenosis at six months was 17 percent while that in the control group was 44 percent (p = 0.01) [19]. At 12 months TLR in the DCB group was 10 percent compared to 48 percent in the control group, and revascularization remained significantly low even at 24 months (15 percent versus 52 percent) with the difference being statistically significant at a P value of less than 0.001 [20].
The FemPac (Femoral Paclitaxel) trial by Micheal Werk at Charite, Universitätsmedizin Berlin, enrolled 87 patients from 2004 to 2006 with stenosis or occlusion of SFA or popliteal artery [21]. They were randomized to receive either the standard balloon angioplasty or the propriety Paccocath ® paclitaxel balloon [17]. At 6 months follow up those treated with DEB showed lower restenosis of 19 percent compared to the control group with 47 percent (p = 0.035) [19]. The trial had an 18 and 24 month follow up period.
Both Thunder and FemPac trials were initiated at almost the same time at different hospitals. and demonstrated that short term exposure to paclitaxel reduces restenosis. These trials were limited in design with small sample size, heterogeneous population sample, and short-term endpoints.
The DEBELLUM (Drug-Eluting Balloon Evaluation for Lower Limb Multilevel Treatment) study enrolled 50 patients collectively presenting with 122 lesions, either femoropopliteal (75.4 percent) or below the knee (24.6 percent), randomized to receive either DEB or conventional angioplasty balloon therapy. At six months, endpoint TLR in DEB group was 6.1 percent compared to 23.6 percent for control group. This trial was conducted from 2010 to 2011 by Fabrizio Fanelli, University of Rome, Italy. Binary restenosis was 9.1 percent in DEB group versus 28.9 percent in the control group [22].
The Advance 18 PTX (paclitaxel) trial compared Advance 18 PTX paclitaxel balloon by Cook Medical (Bloomington, IN) to the uncoated Advance 18LP balloon catheter. The trial was to initially enroll 100 patients but then increased the number by 50 patients to improve the statistical power of the study [23]. It is not approved for use in the US.
The  [25]. There was also an increased rate of amputation in the patients who had received DEB treatment (8.8 percent) than the ones who had angioplasty (3.6 percent) with p = 0.08 [26]. Medtronic [28].
The PACIFIER (Paclitaxel-coated Balloons in Femoral Indication to Defeat Restenosis) study results were presented in the 2012 EuroPCR congress. The study used Medtronic's IN.PACT Pacific TM drug eluting balloon versus conventional non-coated balloons with an enrollment of 91 patients from three hospitals in Germany . At 12 months the result showed that the target lesion revascularization (TLR) for IN.PACT Pacific TM was 7.1 percent versus 34.9 percent for the control (p = 0.003) [29].
The DEBATE SFA study (Drug Eluting Balloon in peripheral intervention) evaluated DEB angioplasty followed by nitinol stent placement versus non-drug coated PTA followed by nitinol stent placement. The study enrolled 104 patients with 110 femoropopliteal lesions. Fifty one (51) [17]. Patency with Lutonix DCB was 71.8 percent while those treated with conventional balloon angioplasty was 48.6 percent [32].  = 0.001). There was an a sustained improvement in the Rutherford scores and low rate of reintervention for restenosis. The LEVANT 2 along with LEVANT I, LEVANT 2 Continued Access (started in 2012, N = 657), and LEVANT 2 Safety Registry [33] in summation added up to 1000 patients and was the basis of submitting Lutonix ® DCB for approval by the FDA [34]. FDA recently approved Lutonix ® DCB for use in the US.
The DANCE (dexamethasone infusion to the adventitia to enhance clinical efficacy after femoropopliteal revascularization) study under supervision of Christopher D Owens, M.D., University of California, San Francisco, is investigating the new balloon angioplasty procedure using the Bullfrog drug-delivery catheter by Mercator MedSystems, US, to infuse the anti-inflammatory drug, dexamethasone, by a microneedle into the adventitia of the vessel. The drug is diffused through the vessel from the outside towards the inside, creating a drug eluting vessel reservoir. Enrollment started in February of 2011. By September 2012 twenty patients had been enrolled and results were presented at the MEET (Multidisciplinary European Endovascular Therapy) Congress in Rome, Italy, in June 2013. Results showed improvement in the ABI's on discharge, and at 6-and 12-month follow-up. There was an improvement on the Rutherford scores and six-month patency was comparable to DEB for longer lesions [19].

Recently Presented Breakthrough Trials on Drug Eluting Balloons:
In 2014 quite, a few DEB related study results and trials were presented at various medical conferences. Some of these are highlighted below.

Viva 14 conference
IN.PACT SFA II principal investigators are John Laird, M.,at the University of California Davis and Peter Schneider MD, Kaiser Foundation Hospital in Honolulu, Hawaii. The study showed higher primary patency (89.8% vs 66.8%; p < 0.001) and lower Target Lesion Revascularization (TLR) rate (2.4% vs 20.6%; p < 0.001) at 12 months for drug-coated balloon (DCB) versus PTA for femoropopliteal lesions. Diabetic patients in the trial were studied as a subgroup analysis. In the diabetic group 12-month analysis gave a higher primary patency (82.7% vs 62.3%; p = 0.0015) and lower TLR (3.7% vs 23.1%; p < 0.001) for the DCB versus PTA treated diabetic group [35].
The DEFINITIVE AR (Atherectomy Followed by a Drug Coated Balloon to Treat Peripheral Arterial Disease) was designed to compare the benefits of plaque removal via atherectomy followed by DEB or DAART (directional atherectomy and anti-restenosis therapy) with drug coated balloons versus only Drug Coated Balloon (DCB) to treat complex PAD. Thomas Zeller of the Universitaets-Herzzentrum, Bad Krozingen, Germany presented the 12-month results at the Vascular Interventional Advances (VIVA) 2014 conference in Las Vegas. The study enrolled 121 patients from 2011 to May 2014. This trial compared Covidien's TurboHawk™ or SilverHawk ® plaque excision systems followed by the Medrad Bayer Healthcare 's Cotavance™ drug-eluting balloon catheter having Paccocath ® technology versus the Cotavance balloon catheter alone [36]. This study utilized 10 sites in Europe. The patency rates for the long lesions of 10 cm or more for the DAART group was 96.8 percent at 12 months, while it was 85.9 percent for the DCB group. For severely calcified lesions, the 12-month patency rate was 70.4 percent in the DAART group and 62.5 percent for the DCB group. Thus, DAART was better than DCB in long and calcified complex lesions [37]. Patients will be followed up for a total of 24 months. This is a pilot study to be followed by larger trials to confirm the promising results of the DAART treatment strategy. Cotavance™ paclitaxel drug-eluting balloon catheter having Paccocath™ technology is approved for use in Europe. Cotavance™ production was suspended in US in 2012 due to regulatory requirements by the FDA, citing problems with drug adhesion to the balloon.
A study on lithotripsy technology to disrupt calcification in the SFA and popliteal artery, DISRUPT PAD, was also presented on the second day of the VIVA 14 conference by Marianne Brodmann, M.D., from the Medical University of Graz, Austria [38]. This trial used Lithoplasty balloon by Shockwave Medical in 35 patients with calcified stenosis. Device success was at 87 percent with residual stenosis of only 23 percent. Follow up was targeted at 30 days and 6 months. 30-day patency was 100 percent. Unlike other devices that target superficial calcification, Lithotripsy may prove to have an effect on deep calcium deposition in vessel wall as well [39]. The ILLUMENATE Global trial aims to enroll 500 patients from 65 centers worldwide [42].

FDA approval for Lutonix ® Dcb
In October 2014 the FDA (U.S. Food and Drug Administration) approved Lutonix ® 035 drug coated balloon (Lutonix DCB) by Lutonix, Inc. of New Hope, Minnesota (which was acquired by C. R. Bard Inc. in 2011), as the first DEB angioplasty catheter to be used in the US for femoropopliteal PAD disease. It has been in use in Europe since 2012. The obstructed vessel is first mechanically dilated with a noncoated balloon followed by paclitaxel coated Lutonix balloon catheter to dispense the drug [32]. It is used to treat the superficial femoral or popliteal artery a stenotic or restenotic lesion of upto 150 mm with the vessel having a 4 -6 mm diameter [43]. FDA has instructed on conducting further two follow up studies, one to monitor the safety and effectiveness of Lutonix ® in 657 patients post PTA procedure, and one targeted specifically at female patients to observe any differences in this population group [44].
Medtronic has submitted its data to the FDA of its IN.PACT Admiral TM drug coated balloon for approval by June 2015 [45].
A list of DEB with their FDA approval status is given in table 1 [46].

Future of DEB
The field of endovascular treatments using percutaneous methods for peripheral vascular disease especially in the lower limbs has come a long way, widely replacing open surgery, and will continue to grow and expand. Current research and data in this area is still lagging behind compared to that for coronary interventions. About 50 million people in the US and Europe are suffering from PAD [27]. Improvement in long-term efficacy, safety, and patency is continuing with new innovational technologies in balloon angioplasty technologies, particularly drug eluting balloon angioplasty. For now, paclitaxel is the only drug being used in DEB, but some trials are looking at other drugs like dexamethasone as well. Different doses, excipients and release kinetics for paclitaxel are also being tested. Though DEB alone is showing promising results, studies comparing Drug Eluting Balloons (DEB) to Drug Eluting Stents (DES) have mixed results. DEB is also shown to be more safe and effective in femoropopliteal disease than uncoated balloon angioplasty. Calcified and bulky lesions may still require stenting and atherectomy but the use of DEB with stenting and DEB following atherectomy needs to be further evaluated. Improved designs need to be examined to treat longer SFA lesions and for belowthe-knee lesions.
DEB's generally have a higher price tag than non-coated standard balloons. However, many companies are investing in DEB's growing market which will eventually lead to lower sale prices. According to iData Research Inc. the global market for DEB is predicted to by a Compound Annual Growth Rate (CAGR) of 25 percent [47]. Global Data forecasts the US to have the largest share in the ever-expanding DEB market among 10 countries covered by a report, with the US market amounting to almost 26 percent by 2019 [48]. The global market growth may, however, be affected by lack of sufficient clinical data and reimbursement issues in countries like India, France and Brazil. Once the cost of drug-coated balloons is reduced, the procedure can be cost effective and the long-term health benefits of DEB can be experienced by patients. This growing market needs to be met with reliable medical evidence of the safety and credibility of these DEB's. Patients' safely and health need to be of foremost importance with strict regulations and reporting protocols. Comparing DEB to other treatments for CLI is needed to provide comparative data on longterm outcomes. Interventional cardiologists, radiologists, researchers, government regulatory bodies, and the healthcare industry need to be vigilant in collecting information on long-term outcomes to support decision making and pave way for improved DEB device technologies.