Over the past decade, drug-coated balloons (DCBs) have emerged as an exciting new therapeutic option to prevent restenosis in the treatment of peripheral vascular disease.^1-3 The DCB is an attractive device because it offers the promise of improved patency in comparison with percutaneous transluminal angioplasty (PTA) and a reduction in the need for stents. This is particularly important in the dynamic stress environment of the superficial femoral and popliteal arteries, in which mechanical fatigue results in stent fracture and in-stent restenosis.^4,5 These new balloons utilize paclitaxel as the therapeutic agent with different concentrations of the drug and different excipients to aid in drug delivery. In the U.S., two DCBs have been approved by the Food and Drug Administration (FDA) for the treatment of femoropopliteal artery disease. In Europe, several DCBs are already approved for clinical use.

In this year, three major pivotal trials have confirmed the safety and efficacy of paclitaxel-coated balloons in the endovascular treatment of femoropopliteal artery disease. These are the Drug-Coated Balloon Versus Standard Percutaneous Transluminal Angioplasty for the Treatment of Superficial Femoral and/or Popliteal Peripheral Artery Disease (IN.PACT SFA) trial,⁶ the Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis 2 (LEVANT 2) trial,⁷ and five-year follow-up of the Local Taxan With Short Time Contact for Reduction of Restenosis in Distal Arteries (THUNDER) trial.⁸

The pooled IN.PACT SFA I and II trials⁶ are multicenter, single-blind, randomized trials to assess the safety and efficacy of a DCB versus standard PTA balloons in patients with moderate-to-severe intermittent claudication or ischemic rest pain and stenosis of ≥70% of superficial femoral and popliteal artery. In both treatment groups, provisional stenting was allowed only in the case of PTA failure. The primary patency rate (defined as freedom from binary restenosis or from the need for target lesion revascularization [TLR]) at 12 months was 82.2% for the DCB, which was superior to control angioplasty (52.4%, P <0.001). Similarly, the clinically-driven TLR rates were significantly lower with the DCB as compared to those achieved with angioplasty (2.4% vs. 20.6%, P <0.001).

The LEVANT 2 pivotal study⁷ is a global, prospective, single-blind, randomized, study of 54 sites (in the United States and Europe); the study enrolled the patients similarly to the IN.PACT SFA trial comparing DCB with standard PTA. As noted, the patients with flow-limiting dissections or clinically significant residual stenosis (>70%) that was likely to require placement of a stent were excluded from randomization. At 12 months, the primary patency rate achieved with Lutonix DCB was 65.2%, while the primary patency rate achieved with angioplasty was 52.6%, P = 0.02), demonstrating superior efficacy. In contrast to the findings of IN.PACT SFA and several smaller trials of DCBs,^2,3,9 the LEVANT 2 trial did not find a significant difference between the two groups in the clinically important point of TLR 12.3% versus 16.8% (P = 0.21). The investigators mentioned several factors that may contribute to an explanation. First, LEVANT 2 followed a rigorous blinding protocol, by which the investigators and patients were unaware of both the index treatment and the duplex ultrasonographic findings during follow-up, which probably reduced potential bias in making the decision to perform a repeat revascularization. Second, the rate of TLR was substantially lower in the standard angioplasty group, which would reduce the power of this trial to show a difference.

For safety issues, there were no device- or procedure-related deaths, no major amputations, and a low rate of vessel thrombosis in both IN.PACT SFA and LEVANT 2 trials. Unlike the discouraging result of IN.PACT DEEP trials¹⁰ in infrapopliteal disease in patients with critical limb ischemia, which had a trend towards an increased major amputation. Significant drug/excipient "wipe off" from the balloon into the distal vasculature was believed to cause a non-healing wound.

In terms of efficacy compared between these two DCBs, the differences in performance regarding primary patency and freedom from clinically-driven TLR seem to attribute to the different coating technologies and possible adjunctive stent implantation. Baseline patient and lesion characteristic in these two large cohort trials (IN.PACT SFA and LEVANT 2) were quite comparable regarding diabetes (43.2% vs. 42.9%), current smoking (37.7% vs. 34.7%), mean lesion length (89 mm vs. 63 mm), and total occlusions (25.8% vs. 21%). However, the rates of provisional stents were less frequent in the Lutonix DCB group than in the standard angioplasty group (2.5% vs. 6.9%, P = 0.02), but there was no statistical difference in the IN.PACT DCB group (7.3% vs. 12.6%, P = 0.11). Blinding for the treatment, as it was part of the LEVANT 2 protocol but not of the IN.PACT SFA protocol, did not significantly impact the clinical outcome because the clinicians were to re-intervene following a blinded, noninvasive, diagnostic test on the basis of the patient's clinical symptoms.

Although the initial findings are encouraging, long-term follow-up will be useful in determining whether the benefit of these new devices is sustained, increased, or attenuated over time. In the LEVANT 2 trial, the primary patency endpoint from the Kaplan-Meier curves seem to drop distinctly in the Lutonix arm after 12 months, while the control arm remained unchanged.⁷

So far, the longest follow-up time of the DCB is five years reported from the THUNDER trial,⁸ which was the first-study to investigate the treatment of femoropopliteal arteries with a paclitaxel-coated balloon. There was significantly lower TLR in the DCB group than in the control group (21% vs. 56%, P = 0.0005). As noted, the TLR rate was lower in men than in women at five-year follow-up. In the small group of patients with angiographic and duplex ultrasonographic follow-up, DCB was associated with a lower rate of binary restenosis (17% vs. 54%, P = 0.04). Importantly, there were no signs of drug-related local vessel abnormalities in the long-term, such as aneurysm formation or constrictive fibrosis.

In conclusion, although DCBs are generally safe and superior to standard balloon angioplasty, there are many unanswered questions about DCB technology. The results of these trials cannot be generalized to patients not included in these trials. Future studies should be performed in longer lesions, densely calcified lesions, or in-stent restenosis, and consider comparison with bare metal stents and drug-eluting stents. Trials combining DCBs with atherectomy (Atherectomy Followed by a Drug Coated Balloon to Treat Peripheral Arterial Disease [DEFINITIVE AR] trial) are being conducted to clarify if there is an additive effect. Another inconclusive issue is the appropriateness use of these devices. Which patient should be a good candidate for using these DCBs as the first-line therapy instead of standard balloon? In order to justify their broad use, the DCBs must show reduction in repeat revascularization, cost benefit, and improving quality of life. Another concern is the learning curve of how to use the DCBs to ensure proper uptake of the drug and minimize downstream drug loss. This is important to maximize the results of treatment. Post-approval study is also suitable for longer-term follow-up, which is certainly needed to confirm the durability of the benefit.

References

1. Scheinert D, Duda S, Zeller T, et al. The LEVANT I (Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv 2014;7:10-9.
2. Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med 2008;358:689-99.
3. Werk M, Albrecht T, Meyer DR, et al. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv 2012;5:831-40.
4. Scheinert D, Scheinert S, Sax J, et al. Prevalence and clinical impact of stent fractures after femoropopliteal stenting. J Am Coll Cardiol 2005;45:312-5.
5. Iida O, Nanto S, Uematsu M, Ikeoka K, Okamoto S, Nagata S. Influence of stent fracture on the long-term patency in the femoro-popliteal artery: experience of 4 years. JACC Cardiovasc Interv 2009;2:665-71.
6. Tepe G, Laird J, Schneider P, et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation 2015;131:495-502.
7. Rosenfield K, Jaff MR, White CJ, et al. Trial of a paclitaxel-coated balloon for femoropopliteal artery disease. N Engl J Med 2015;373:145-53.
8. Tepe G, Schnorr B, Albrecht T, et al. Angioplasty of femoral-popliteal arteries with drug-coated balloons: 5-year follow-up of the THUNDER trial. JACC Cardiovasc Interv 2015;8:102-8.
9. Werk M, Langner S, Reinkensmeier B, et al. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation 2008;118:1358-65.
10. Zeller T, Baumgartner I, Scheinert D, et al. Drug-eluting balloon versus standard balloon angioplasty for infrapopliteal arterial revascularization in critical limb ischemia: 12-month results from the IN.PACT DEEP randomized trial. J Am Coll Cardiol 2014;64:1568-76.

Keywords: Amputation, Aneurysm, Angioplasty, Angioplasty, Balloon, Angioplasty, Balloon, Coronary, Atherectomy, Constriction, Pathologic, Control Groups, Cost-Benefit Analysis, Diabetes Mellitus, Diagnostic Tests, Routine, Drug-Eluting Stents, Excipients, Follow-Up Studies, Intermittent Claudication, Learning Curve, Paclitaxel, Pain, Peripheral Arterial Disease, Popliteal Artery, Prospective Studies, Quality of Life, Random Allocation, Research Personnel, Single-Blind Method, Smoking, Thrombosis, United States Food and Drug Administration

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