Abstract: Revascularization of infrainguinal peripheral artery disease has traditionally been accomplished via percutaneous transluminal angioplasty. However, long-term results have been hampered by high rates of restenosis. Along with the advent of stents, paclitaxel-coated balloons are an emerging therapeutic option for the invasive management of infrainguinal peripheral artery disease. Paclitaxel has been successful in inhibiting neointimal hyperplasia, the main mechanism for in-stent restenosis. Technological advances have facilitated the development of paclitaxel-coated balloons, which show promise in early trials for femoropopliteal stenosis relative to uncoated balloons. For infrapopliteal stenoses, the data remain scant and conflicted. Therefore, large-scale randomized clinical trials with long-term follow-up evaluating safety and effectiveness between various strategies need to be performed to determine the optimal invasive management strategy for infrainguinal peripheral artery disease.
J INVASIVE CARDIOL 2016;28(7):281-286
Key words: femoropopliteal stenosis, paclitaxel-coated balloon, restenosis
Since Dr Charles Dotter described the first percutaneous transluminal angioplasty (PTA) over 50 years ago, endovascular therapy has remained an important treatment option for infrainguinal peripheral artery disease (PAD).1 Despite numerous advances in technology over time, endovascular approaches to femoropopliteal and infrapopliteal PAD remain plagued by high rates of restenosis.2 Despite the effectiveness of PTA in establishing immediate revascularization, the vascular injury generated can lead to elastic recoil and plaque dissection which can lead to abrupt vessel closure.3
The introduction of stents in the 1990s appeared to have solved these issues by providing a metal scaffold.2 However, exaggerated neointimal hyperplasia frequently led to in-stent restenosis, with multiple randomized controlled trials failing to find a long-term benefit of using stents over angioplasty.4-7 Rates of restenosis for both PTA and stenting due to neointimal hyperplasia vary by arterial bed and lesion length, but can approach up to 50% at 2 years regardless of intervention type.5,8,9
The Need for Improved Technology
Neointimal hyperplasia is caused by vascular smooth muscle migration and proliferation following vascular injury. This problem occurs frequently whether arterial intervention included angioplasty or angioplasty plus stenting. The chemotherapeutic agent paclitaxel delivered locally reduces neointimal hyperplasia, thereby reducing restenosis and late lumen loss.10,11 Paclitaxel is a potent cytotoxic agent that arrests the cell cycle during the M phases of mitosis. Through this mechanism, the drug demonstrates a significant antiproliferative effect, arresting microtubule function by binding to the β subunit of tubulin. Animal studies have confirmed a dose dependent inhibition of neointimal hyperplasia with paclitaxel.12 Further studies have demonstrated sustained inhibition for up to 14 days with a single dose, making it an ideal agent for local delivery.3,12,13 In fact, the combination of lipophilic properties promoting cellular uptake, short absorption, and prolonged duration of effect make paclitaxel an ideal agent for preventing neointimal hyperplasia.12 Local drug delivery for paclitaxel and other chemotherapeutic agents is accomplished by utilizing drug-eluting stents (DESs) as their scaffold and drug delivery device. By combining the advantages of a metal scaffold with slow local drug delivery over time, DESs are the preferred therapeutic option in the coronary vasculature. However, the optimal approach in the treatment of infrainguinal peripheral arteries still remains a subject of debate. Although short-term and mid-term results have been promising for both femoropopliteal and infrapopliteal arteries, restenosis rates remain high.14,15
Given the limitations in current approved technology, drug-coated balloons (DCBs) may provide a viable treatment option for patients with infrainguinal PAD. Advantages of DCBs include decreased rates of restenosis compared with PTA due to local delivery of antirestenotic agents without the use of a permanent scaffold like a stent. DCBs can be used where stent placement is not ideal, such as tortuous areas, flexion points, or bifurcation lesions.2,3 Traditionally, in-stent restenosis was considered another situation where stent placement was not ideal. However, a study of 108 patients who underwent placement of paclitaxel-coated nitinol stents for in-stent restenosis in the femoropopliteal system demonstrated a primary patency rate of 96% at 6 months and 79% at 1 year. Target-lesion revascularization (TLR) was avoided in 96.2% of participants at 6 months and 81.0% at 1 year. In this study, the stent fracture rate was only 1.2% at 1 year compared with a pretreatment fracture rate of 8%.16 Although these results are promising and demonstrate clear improvements in stent technology, DCBs are another potential method to avoid even the remote possibility of stent fracture.
Drug Coating Process
Local drug delivery using a stent-based platform typically occurs over a period of months. In contrast, DCBs provide a localized bolus of drug without a permanent indwelling implant.17 To accomplish this task, the DCB platform includes three key components: the angioplasty balloon, the antirestenotic agent, and a carrier molecule or excipient that facilitates binding and transfer of the drug to the tissue during balloon inflation (Figure 1). The challenge is to deliver a therapeutic dose of the drug for an adequate period of time in order to achieve meaningful inhibition of neointimal hyperplasia. Prior to DCBs, the use of infusion balloons, direct injection into the arterial wall, or mixing of drug with contrast media did not lead to improved clinical outcomes.18-22
Paclitaxel is an antineoplastic drug that inhibits smooth muscle proliferation as well as extracellular matrix secretion and migration.3,17 It disrupts the cell cycle in the M phase of the mitosis. Certain drug properties of paclitaxel allow it to be used in a DCB strategy. Given its lipophilicity, crystalline paclitaxel can be combined with contrast media, the excipient, to coat the angioplasty balloon. Furthermore, paclitaxel remains bound to the excipient and balloon during arterial transit to the target vessel. Lastly, short inflations of the balloon allow local delivery of therapeutic doses of paclitaxel, which can last for months. Experiments in animals show that only 10%-20% of the drug is finally taken up by the vessel wall.17 Given the experience with DESs, if therapeutic doses can be sustained for months, neointimal hyperplasia should be adequately inhibited. Furthermore, toxicity can be limited due to small dosages and local application.
The femoropopliteal arterial bed contains the longest arterial conduit in the body, not counting the aorta. It is subject to bending, torsion, and shear stress due to hip/knee flexion and extension. Despite the marginal superiority of stent implantation compared with PTA alone, 1-year patency rates range from 60%-80%.8,9,23-25
The first randomized control trial examining the efficacy of paclitaxel-coated balloons (PCBs) in the femoropopliteal system was the THUNDER (Local Taxane with Short Exposure for Reduction of Restenosis in Distal Arteries) trial, which randomized 154 symptomatic patients with at least 70% stenosis of at least 2 cm in length in the femoral or popliteal arterial bed into three groups (PCB, uncoated balloon with paclitaxel in contrast media, and uncoated balloons [control group]) (Table 1).25 The primary outcome was late lumen loss at 6 months. Angiographic follow-up was completed in about 83% of patients. The PCB group had less late lumen loss (0.4 mm vs 1.7 mm; P<.001) compared with the control group (uncoated balloons) as well as less TLR at 6 months (4% vs 37%; P<.001). The 5-year follow-up data were available on only a minority of the initially enrolled patients since only the PCB and control arm groups were followed.26 TLR occurred in 30 of 54 patients (56%) in the control group compared with 10 of 48 patients (21%) in the PCB group (P<.001). The primary outcome of late lumen loss also maintained the initial statistical difference seen (0.7 ± 1.5 mm for PCB vs 1.9 ± 1.9 mm for control; P=.01).
The FemPac trial randomized 87 patients with clinically significant femoropopliteal stenosis or restenosis to angioplasty with uncoated vs PCB therapy.27 The primary endpoint was late lumen loss at 6 months, with about 75% of the patients completing 6-month follow-up. Despite the small sample size, the PCB group had significantly less late lumen loss (0.5 mm vs 1.0 mm; P=.03) compared with the uncoated balloon group. Similarly, they found a decrease in TLR in the PCB group (6.7% vs 33.3%; P=.01).
A meta-analysis of pooled data including the initial studies with two additional trials to include 381 patients had a median follow-up of 10 months.28 DCBs compared with angioplasty alone significantly reduced TLR (12.2% vs 27.7%; odds ratio, 0.22; P<.001), angiographic restenosis (19% vs 46%; odds ratio, 0.26; P<.001), and late lumen loss (range, -0.05 to 0.50 mm vs 0.61-1.7 mm; P<.001).
The IN.PACT Admiral Drug-Eluting Balloon versus Standard Percutaneous Transluminal Angioplasty for the Treatment of Atherosclerotic Lesions in the Superficial Femoral Artery and/or Proximal Popliteal Artery (IN.PACT SFA) trial randomized 331 patients with intermittent claudication or ischemic rest pain in a 2:1 ratio to DCB vs PTA.29 The primary outcome of primary patency at 12 months was higher in the DCB group (82% vs 52%; P<.001). TLR was lower in the DCB arm (2.4% vs 20.6%; P<.001).
The most recent and largest study to compare DCB with PTA in the femoropopliteal segment randomized 476 patients with intermittent claudication or ischemic pain at rest in a 2:1 ratio across 54 sites.30 Using a primary efficacy endpoint of target-lesion patency at 12 months, the Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis (LEVANT) 2 trial found superior results with the DCB group (65% primary patency) vs the PTA group (53% primary patency) (P=.02).
Comparing the patient populations across these studies, the patient and lesion characteristics were remarkably similar. Most patients were suffering from severe claudication (Rutherford class 3). The shortest lesion length was in the FemPac study (4-5 cm), while IN.PACT SFA had the longest lesion at almost 9 cm. However, only 8% of lesions were calcified, whereas in THUNDER, FemPac, and IN.PACT SFA, >50% of the lesions were calcified. Therefore, DCBs appear effective relative to PTA in patients with claudication and lesion lengths <9 cm regardless of calcification.
All of the studies to date have demonstrated a consistent advantage for DCBs relative to conventional angioplasty. However, several additional multicenter randomized control trials are ongoing to investigate this question further, including the FREERIDE (Freeway Paclitaxel Coated Balloon Catheter to Treat Peripheral Artery Disease) trial; the ADVANCE 18PTX (Treatment of Lesions in Superficial Femoral Artery/Popliteal Artery With a Paclitaxel-coated Balloon) trial; and the ILLUMENATE Pivotal (Prospective, Randomized, Single-Blind, US Multicenter Study to Evaluate Treatment of Obstructive Superficial Femoral Artery or Popliteal Lesions With a Novel Paclitaxel-Coated Percutaneous Angioplasty Balloon).31-33
While the above studies investigated the comparison between DCBs and PTA, the DEBATE-SFA (Drug Eluting Balloon in Peripheral Intervention for the Superficial Femoral Artery) trial evaluated 104 patients randomly assigned to predilation with DCB vs conventional balloon angioplasty prior to stenting.34 Twelve-month follow-up revealed a statistically significant reduction in binary stenosis with DCB (17% vs 47%; P=.01) and a trend toward higher freedom from TLR (83% vs 67%; P=.07) that did not meet statistical significance.
The first study to examine DCB vs stenting was an indirect meta-analysis including 1464 patients, 441 of whom were in studies that randomized to DCB or uncoated balloon angioplasty, whereas 1023 were in trials that randomized bare nitinol stenting vs uncoated balloon angioplasty.35 Using uncoated balloon angioplasty as the comparator, there was no difference between DCB and stenting in regard to TLR, restenosis, death, or amputation. The ongoing REAL PTX (Randomized Evaluation of the Zilver PTX Stent vs Paclitaxel-Eluting Balloons for Treatment of Symptomatic Peripheral Artery Disease of the Femoropopliteal Artery) trial is the first randomized control trial investigating a head-to-head comparison of DCB with DES for the femoropopliteal segment.36
Given the encouraging results in the femoropopliteal arterial bed, research with DCBs has also been ongoing with regard to infrapopliteal PAD. Restenosis of lesions in this territory is high, ranging from 42%-69% in the first 12 months after angioplasty alone.37,38
In the multicenter ACHILLES trial, a total of 200 patients were randomized to DES (with sirolimus) or PTA with a primary endpoint of 1 year in segment binary restenosis.38 All patients received quantitative angiography at baseline and at 12 months. Binary restenosis was significantly reduced in the DES arm vs the PTA arm (22% vs 42%, respectively; P=.02). This translated into greater vessel patency in the DES group vs the PTA group (75% vs 57%, respectively; P=.02) at 1 year. Rates of other major clinical endpoints including death and TLR were similar. There was only 1 stent fracture in the trial.
The first study to examine DCBs in the infrapopliteal vessels enrolled 104 non-randomized consecutive patients, of which the majority had critical limb ischemia (CLI).39 In those who underwent angiographic follow-up at 3 months, restenosis occurred in 27% of patients, considerably less than historical cohorts.
The DEBATE-BTK (Drug-Eluting Balloon in peripheral intervention for Below-the-Knee Angioplasty Evaluation) trial randomized 132 patients with diabetes and CLI to DCB vs conventional angioplasty (Table 2).40 At 1 year, the DCB group had a lower rate of restenosis (27% vs 74%, respectively; P<.001) and TLR (18% vs 43%, respectively; P=.01).
The INPACT-DEEP (Randomized Study of IN.PACT Amphirion Drug-Eluting Balloon vs Standard PTA for the Treatment of Below-the-Knee Critical Limb Ischemia) trial (n = 358) compared DCB with standard angioplasty in CLI patients with infrapopliteal disease.41 In contrast to DEBATE-BTK, no significant differences in late lumen loss (0.61 mm vs 0.62 mm) or TLR (9.2% vs 13.1%) were observed. There was even a trend toward higher amputation rates for the DCB group (8.8% vs 3.6%; P=.08). The precise reason for these disparate results is unclear. One possible reason is that the DEBATE-BTK trial was performed at a high-volume center with a meticulous wound surveillance program and multidisciplinary team offering rigorous follow-up with office visits, along with a low threshold for reintervention. On the other hand, as a multicenter trial, wound management was not standardized across the centers in INPACT-DEEP. In fact, wound management was administered according to the individual sites’ standards of care. Furthermore, long-term outcomes in the angioplasty group were better than historically seen in previous studies. Additionally, questions regarding the ability to adequately coat this particular balloon type with paclitaxel may have led to suboptimal amounts of drug being delivered locally. Given these concerns and the negative results, this product was withdrawn from the market.
The IDEAS (Paclitaxel-Coated Balloon Angioplasty versus Drug-Eluting Stenting for the Treatment of Infrapopliteal Long-Segment Arterial Occlusive Disease) trial compared DCB to DES for infrapopliteal lesions >70 mm in length in 50 patients.42 The DES used was zotarolimus-eluting, sirolimus-eluting, or everolimus-eluting depending on the availability. The DES group had significantly reduced rates of binary restenosis (28% vs 58%; P=.046) and numerically lower TLR (7.7% vs 13.6%; P=.65).
The ongoing LUTONIX BTK (Lutonix Drug-Coated Balloon Versus Standard Balloon Angioplasty for Treatment of Below-the-Knee Arteries) trial will enroll 480 patients with CLI to examine the role of DCB therapy in infrapopliteal disease.43
Similarly the ongoing ADCAT (Atherectomy and Drug-Coated Balloon Angioplasty in Treatment of Long Infrapopliteal Lesions) study will investigate the role of atherectomy in conjunction with DCB in infrapopliteal stenosis.44
Despite high initial success rates, PTA has poor long-term patency rates. Largely due to neointimal hyperplasia, newer technologies such as DCBs have emerged as plausible solutions to this problem. In particular, DCBs have shown significantly improved results in the femoropopliteal arterial bed relative to uncoated balloons. However, these trials remain small and several larger ongoing studies will dictate whether these initial results are confirmed. In the infrapopliteal arterial bed, initial randomized data have produced conflicting results. Large randomized trials are needed to compare various invasive strategies to provide the optimal long-term clinical outcomes.
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From the Division of Cardiology, University of California, Los Angeles Medical Center, Los Angeles, California.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lee reports speaker’s bureau fees from CSI. Dr Sethi reports no conflicts of interest regarding the content herein.
Manuscript submitted July 27, 2015, provisional acceptance given September 18, 2015, final version accepted April 4, 2016.
Address for correspondence: Michael S. Lee, MD, Division of Cardiology, UCLA Medical Center, 100 Medical Plaza Suite 630, Los Angeles, CA 90095. Email: firstname.lastname@example.org