After the "mechanical era" in interventional cardiology, represented by balloon angioplasty and bare-metal stent (BMS) implantation, we have now arrived at the "local dispensing" era with the delivery of antithrombotic or anti-restenotic drugs to coronary and peripheral arteries using drug-eluting stents (DES) and drug-coated balloons (DCB), which are the focus of this review.

In the treatment of coronary artery disease (CAD), the advent of DES technology has significantly reduced the secondary problem of in-stent restenosis due to intimal hyperplasia. Some of the limitations of DES include treatment of small vessel disease, issues related to the duration of dual antiplatelet therapy (DAPT), and treatment failure leading to restenosis and late stent thrombosis. In this light, DCB represents an innovation with a high potential impact on the treatment of patients with CAD. The proposed advantages of DCB over DES include patients with contraindications for prolonged DAPT, reduced restenosis rates in indications for which DES show limited efficacy, and the option of leaving no foreign object behind, resulting in vascular restoration with potential plaque regression instead of neo-atherosclerosis. Lastly, the treatment of DES restenosis remains challenging because when a second stent is deployed to treat in-stent restenosis, the second strut layer results in excessive stiffening of the vessel wall and injury to the ostium of collateral vessels.¹

Historically, in-stent restenosis represents the first clinical application of DCB in coronary arteries and is where its most robust scientific evidence is found. In 2006, the first human trial involving DCB demonstrated the superiority of DCB over plain balloon angioplasty in terms of in-segment late lumen loss for the treatment of BMS restenosis. The superiority of DCB in terms of target vessel revascularization persisted at 5-year follow-up (38.9 vs. 9.3%, p = 0.004).² Positive results were obtained in the PEPCAD II (The Paclitaxel-Eluting PTCA-Balloon Catheter in Coronary Artery Disease to Treat In-Stent Restenoses) trial as well. This study compared the SeQuent Please (B. Braun, Melsungen, Germany) DCB with the Taxus Liberte (Boston Scientific, Natick, MA) paclitaxel-eluting stent, showing DCB superiority in terms of in-segment late lumen loss (0.17 +/- 0.42 vs. 0.38 +/- 0.61 mm, p = 0.03) with a trend toward lower target vessel revascularization (6.3 vs. 15.4%, p = 0.15).³ Finally, favorable results for treating DES in-stent restenosis were found in the ISAR-DESIRE 3 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis: 3 Treatment Approaches) trial that demonstrated the non-inferiority of DCB compared with paclitaxel-eluting stent in terms of diameter stenosis at 6–8 months follow-up.⁴

The recent clinical data for DCB use in acute myocardial infarction have been disappointing. In the DEB-AMI (Drug Eluting Balloon in Acute Myocardial Infarction) pilot trial, despite adequate lesion preparation with thrombectomy and pre-dilation followed by SeQuent Please (B. Braun, Melsungen, Germany) DCB and BMS, restenosis was unacceptably high, leading to a target lesion revascularization (TLR) rate of 17% at 1 year.⁵ This, followed by the negative results of the DEB-AMI trial in which DES showed significantly superior angiographic and clinical outcomes compared with DCB and BMS, suggests that the DCB and BMS combination has no role in acute myocardial infarction.⁶

The treatment of atherosclerotic disease involving small coronary vessels is a very promising scope for DCB. The first study investigating DCB use in small vessels was the PEPCAD I (The Paclitaxel-Eluting PTCA-Balloon Catheter to Treat Small Vessel Coronary Artery Disease) study, a single arm trial investigating SeQuent Please (B. Braun, Melsungen, Germany) DCB in vessels with a mean diameter of 2.36 mm.⁷ The DCB-only group had superior angiographic and clinical results at 6 months (binary restenosis: 5.5%; TLR: 4.9%). In contrast, 28% of patients who had BMS had an eight-times higher restenosis rate and five-times higher TLR. Other randomized trials of DCB for use in small vessels have been completed (PICCOLETTO [Paclitaxel-Coated Balloon Versus Drug-Eluting Stent During PCI of Small Coronary Vessels] and BELLO [Balloon Elution and Late Loss Optimization]), and it appears that a DCB-only strategy with provisional BMS might be a reasonable approach in this population.^7–9

Lastly, the opportunity to shorten the duration of DAPT compared to the prolonged duration necessary when a DES is implanted represents a potential advantage of DCB. Current manufacturers advise for 3 months of DAPT following DCB treatment. However, because several of the DCB studies have been a mix utilizing provisional BMS, and because of the lack of studies specifically testing this aspect, definitive conclusions on DAPT and DCB cannot be made.

The role of DCB in CAD is still being defined. The DCB data on the treatment for in-stent restenosis and small coronary vessels are the most encouraging, but until further refinements in DCB technology are made and larger randomized clinical trials are performed, the role of this technology remains to be completely understood.

Peripheral Drug-Coated Balloons

In many ways, the maturation of device-based treatment of the peripheral vasculature has paralleled the coronary vascular bed but at a slower pace, often repeating lessons learned. The coronary and peripheral vascular beds do differ, with the external forces much higher in the infrainguinal area. Historically, the endovascular therapies for the femoropopliteal region included percutaneous transluminal angioplasty (PTA), atherectomy, self-expanding BMS, and stent grafts. These technologies continued to improve outcomes, though patency clearly was not optimized.¹⁰ When the Food and Drug Administration first approved the use of DES in 2012 followed by DCB in 2014, they allowed for a paradigm shift in the treatment of disease in the femoropopliteal arterial bed. The ability to reduce repeat interventions by delivering paclitaxel directly to the arterial wall without leaving a metal scaffold is particularly attractive in the femoropopliteal region with its associated mechanical stressors. Regardless of the mode of delivery, it appears that this new era of drug-elution technology has become the standard barer for symptomatic treatment of lower extremity peripheral arterial disease, thus making PTA alone obsolete.

Paclitaxel was first approved on a self-expanding stent platform, Zilver PTX (Cook Medical, Bloomington IL), in late 2012. A level 1 randomized, controlled trial demonstrated a greater than 45% improvement in patency and TLR compared with both PTA and BMS at 12-months and found stable to 5 years.¹¹ Though use of a stent-based platform has been readily accepted in the epicardial coronaries protected by the thorax, use of a stent in the lower extremity, regardless of the presence of an anti-proliferative agent, remains somewhat controversial due to early platforms being associated with stent fractures. Fortunately, later generations of stents have seen dramatic reductions, though not elimination, of fractures.

Following positive European data, two large US-based pivotal trials have demonstrated superiority of DCB over PTA in claudicants. The IN.PACT SFA (Drug-Coated Balloon Versus Standard Percutaneous Transluminal Angioplasty for the Treatment of Superficial Femoral and/or Popliteal Peripheral Artery Disease) trial, a randomized, controlled trial, evaluated the IN.PACT™ Admiral™ DCB (Medtronic, Inc. Minneapolis, MN) verses PTA. Recently, 2-year data demonstrated significant efficacy with stable primary patency of 78.9% in the DCB group verses 50.1% for the PTA group (p < 0.001) and a TLR rate of 9.1 vs. 28.3% for the PTA group (p < .001).¹² Interim data from a large registry completed outside the United States have also demonstrated low clinically driven TLR in longer lesions and in-stent restenosis. The randomized LEVANT I (The Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis) trial evaluated a second DCB verses PTA in femoropopliteal lesions. This DCB incorporates different excipients: sorbitol and polysorbate. At 12 months, the primary patency for DCB versus PTA was (65.2 vs. 52.6%, p = 0.02).¹³ The Lutonix Global Real-World Registry 24-month data demonstrated small but superior patency rate of 58.6 verses 53%, respectively (p = 0.05), and TLR rate of 18%. Recently presented data appear to demonstrate that this platform is associated with low TLR rates in longer lesions and in-stent restenosis. A third DCB platform has completed a registry reporting excellent and stable TLR rates of 10.3% at 2 years with the pivotal US trial currently in the follow-up stage.¹⁴

However, not all patient subsets may experience the same benefit. There has been a significant degree of bailout stenting in long lesions and some early evidence that severe calcification may significantly decrease the efficacy of DCB platforms.^15,16

The promising results of paclitaxel delivery via a DCB seen in the above-the-knee region at first appeared to be transferable to the tibial arterial bed in single center registry and a small randomized trial.^17,18 However, improved patency and limb salvage were not demonstrated in a large, multinational randomized trial (INPACT DEEP [Study of IN.PACT Amphirion™ Drug Eluting Balloon vs. Standard PTA for the Treatment of Below the Knee Critical Limb Ischemia]) performed outside the United States.¹⁹ The trial was completed with a similar drug excipient combination but different coating method. In fact, there was a non-statistically significant trend in major amputations seen in the DCB group. At 12 months, the rate of clinically driven TLR was 9.2% in the DCB arm versus 13.1% for PTA (p = 0.291). Late lumen loss was not different: 0.61 ± 0.78 mm versus 0.62 ± 0.78 mm (p = 0.950). Major amputations through 12 months trended higher in the DCB arm (8.8 vs. 3.6%; p = 0.080). The Lutonix DCB Versus Standard Balloon Angioplasty for Treatment of Below-The-Knee (BTK) Arteries multicenter randomized trial for critical limb ischemia is currently enrolling.

In summary, the use of DCB in the femoropopliteal region evaluated in two separate clinical trials demonstrates durability and safety as well as continued superiority of this technology. The results appear to demonstrate greater efficacy in the IN.PACT platform; however, differences in trial design make comparisons difficult. Both real-world registries appear to demonstrate good efficacy. The infrapopliteal use of DCB has not confirmed safety or efficacy to date and awaits further study.

References

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3. Unverdorben M, Vallbracht C, Cremers B, et al. Paclitaxel-coated balloon catheter versus paclitaxel-coated stent for the treatment of coronary in-stent restenosis. Circulation 2009;119:2986–94.
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9. Serra A. Results of the Paclitaxel Eluting Balloon (DIOR) for the Treatment of in-Stent Restenosis and Small Vessel at 1-year follow-up: Insights from the Spanish Registry (EuroPCR website). 2011. Available at http://www.eurocor.de/kunden/eurocor/content/e3/e735/e1585/e1989/Serra_20110517_1355_room352AB.pdf. Accessed 02/03/2016.
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14. Schroeder H, Meyer DR, Lux B, Ruecker F, Martorana M, Duda S. Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: outcomes from the ILLUMENATE first-in-human study. Catheter Cardiovasc Interv 2015;86:278–86.
15. Cortese B, Granada JF, Scheller B, et al. Drug-coated balloon treatment for lower extremity vascular disease intervention: an international positioning document. Eur Heart J 2016;37:1096-103.
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17. Schmidt A, Piorkowski M, Werner M, et al. First experience with drug-eluting balloons in infrapopliteal arteries: restenosis rate and clinical outcome. J Am Coll Cardiol 2011;58:1105–9.
18. Liistro F, Porto I, Angioli P, et al. Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia. Circulation 2013;128:615–21.
19. 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, Angioplasty, Balloon, Coronary, Atherectomy, Constriction, Pathologic, Coronary Artery Disease, Drug-Eluting Stents, Excipients, Hyperplasia, Lower Extremity, Myocardial Infarction, Paclitaxel, Peripheral Arterial Disease, Polysorbates, Registries, Sorbitol, Stents, Taxus, Thrombectomy, Thrombosis, Angiography

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