ILLUMENATE European RCT Demonstrates Durability of Low-Dose DCB in Humans For the First Time Sustainable Antirestenosis Effect With a Low-Dose Drug-Coated Balloon: The ILLUMENATE European Randomized Clinical Trial 2-Year Results

The two-year results of the ILLUMENATE European randomized clinical trial conducted by Brodmann and her colleagues have displayed a sustained treatment effect with a low-dose drug-coated balloon (DCB) with an optimized coating formulation. This trial, published in JACC Cardiovascular Interventions, has demonstrated, for the first time, a statistically significantly higher primary patency rate for a low-dose DCB versus PTA at 2 years.

The aim of this study was to assess the safety and effectiveness of a next-generation low-dose drug-coated balloon (DCB) designed to optimize the amount of drug transferred into the vessel wall and to maximize the amount of time the drug resides in the vessel wall. Devices that deliver antiproliferative drugs to the vessel wall have proved their efficacy for the treatment of peripheral artery disease in the femoropopliteal arteries. Drug-eluting stents have proved to be an effective treatment, as demonstrated by the long-term outcomes of the Zilver PTX randomized clinical studies. These results showed that drug-eluting stents support sustained safety and effectiveness, including the long-term superiority of drug-eluting stents to uncoated percutaneous transluminal angioplasty (PTA) balloons. Several randomized controlled studies evaluating various DCBs had also demonstrated a significantly higher patency rate compared with noncoated percutaneous transluminal angioplasty balloons at 1 year. However, the data were limited and varied by DCB at longer follow-up time points. An earlier generation low-dose DCB failed to demonstrate significant treatment effect at 2 years, raising questions regarding the durability of low-dose DCBs.

In this prospective, multicenter trial, 294 patients were randomized (3:1) to treatment with a DCB or an uncoated percutaneous transluminal angioplasty balloon. Assessments at 2 years included primary patency with duplex ultrasonography, clinically driven target lesion revascularization, and functional outcomes. The investigators reported that primary patency at 2 years was significantly higher in the DCB cohort (75.9% vs. 61.0%; p ¼ 0.025), and the rate of clinically driven target lesion revascularization was significantly lower (12.1% vs. 30.5%; p < 0.001). There were no major limb amputations in either group. The rates of all-cause (6.5% vs. 5.1%; p ¼ 1.00) and cardiovascular-related (1.6% vs. 1.7%; p ¼ 1.00) mortality were similar between groups. Additionally, functional improvements over baseline were sustained in both groups, with 60% fewer reinterventions in the DCB group. Therefore, the ILLUMENATE EU RCT demonstrated a durable treatment effect of the Stellarex DCB, with no indication of deterioration in superior patency and clinical benefit through 2 years. These outcomes validated the first-in-human results and for the first time demonstrated a low-dose DCB with sustained outcomes on the basis of objective, blinded, core laboratory assessment of patency. The investigators acknowledged that DCB performance is driven by the total dose of drug effectively transferred and retained in the tissue. Moreover, coating configuration is critical for DCB performance, and it varies on a spectrum from pure crystalline to pure amorphous. These components continue to be modified as DCBs evolve.

The ILLUMENATE EU RCT is the first study to demonstrate a significantly higher primary patency rate through 2 years with a low-dose DCB compared with an uncoated balloon. The ILLUMENATE EU RCT Investigators stated that previously, the sustainability of the biological effect was not supported beyond 12 months on the basis of randomized data. Therefore, the implications of these findings were important as they supported the use of this technology in vascular territories never explored before and could help expand the therapeutic options for current generation DCB technologies. Speaking of the next steps, Dr. Marianne Brodmann, from Medical University Graz, Auenbruggerplatz, Austria,  professed that additional studies of the use of DCBs for more complex lesions, such as in-stent restenosis and lesions that cannot be adequately pre-dilated, are needed. Additional research is necessary on the use of DCBs in conjunction with atherectomy devices.

Emphasizing on the importance of future research, Dr. Andrew J. P.Klein, Piedmont Heart Institute,Atlanta, Georgia, stated, “Although the optimal treatment for FP arterial disease remains elusive, clearly DCBs provide an important “leave nothing behind” treatment option with superb short- and mid-term outcomes over plain “old” angioplasty. DCBs will continue to evolve in their drug formulation and dose, coating, deliverability, efficacy, and cost. Longer (>3 to 5 years) follow-up studies are needed to confirm the durability of reported outcomes with low-dose DCBs.Randomized comparisons of different DCBs are necessary given each DCB’s distinctive characteristics in terms of excipient, drug dose, and delivery, balloon material, and manufacturing process, which may produce different outcomes. Further studies are needed to better understand the contribution of each of these factors and their role in DCB effectiveness.”