Sirolimus-coated balloons for peripheral arterial disease: walking free into the future of endovascular treatment

Peripheral arterial disease (PAD) has been a field ripe for innovation. A prime example is Andreas Grüntzig, who applied the technique of percutaneous balloon angioplasty (PTA) on peripheral arteries and, for the first time in humans, to coronary arteries (1).

While the use of PTA grew exponentially in the years that followed, it took some time before advancements in the management of PAD translated into a progressive reduction in major amputations (2). Of note, no published trial to date has shown that endovascular treatment or device is superior to medical therapy or by-pass surgery to improve hard clinical outcomes (3-5). In contrast, phase III trials showed that medical therapies such as low-dose rivaroxaban anticoagulation reduced the risk of amputation and other clinical endpoints (6).

The introduction of stents represented a key factor in the technical progress concerning endovascular treatment of PAD. Initially developed as a bailout strategy to manage recoil and flow-limiting dissections that could occur after PTA, stents came with their own challenges, including in-stent thrombosis, restenosis due to intimal hyperplasia, and stent fractures. These complications spurred further innovations, such as the development of drug-coated balloons (DCBs). Introduced about 20 years ago, DCBs were designed to offer a “metal-free” or “nothing left behind” approach to endovascular revascularization (7), aiming to reduce the complications associated with permanent implants.

Paclitaxel was the first and most studied drug. However, concerns arose after a 2018 meta-analysis (8) suggested a dose-dependent increased mortality associated with it, as well as possible issues with distal embolization of the drug. Further studies showed contrasting results and reassured about the safety of paclitaxel-coated products. This debate sparked interest in alternative drugs for DCB, such as sirolimus. Unlike paclitaxel, which acts as a cytotoxic agent, sirolimus exerts a cytostatic effect by blocking the activation of the critical signal transduction protein mTOR (9), thus inhibiting the proliferation of arterial smooth muscle cells.

Despite its commercial success, only a few studies to date have addressed the application of sirolimus-coated devices for peripheral arteries (10-12). This makes the results of the SELUTION SFA Japan trial (13), published in JACC: Cardiovascular Interventions, a needed additional evidence on this topic. In this prospective, observational, multicentric trial, Iida et al. investigated the safety and efficacy of the SELUTION SLR sirolimus-coated balloon (MedAlliance) in 134 symptomatic Japanese patients with femoropopliteal lesions (or occlusions) shorter than 20 cm. Unlike previous studies, the authors employed efficacy outcomes at 12 months, including primary patency of the target lesion (defined as the absence of restenosis on duplex ultrasound), reaching 87.9% [95% confidence interval (CI): 81.0–92.4%], and freedom from clinically driven target lesion revascularization (CD-TLR), at 97.0% (95% CI: 92.2–98.9%). The safety outcome, defined as a composite of CD-TLR, amputation of the target limb, and all-cause death, showed an incidence of 6.7% at 12 months. All outcomes were independently adjudicated by a clinical event committee and an imaging core laboratory.

Several observations are noteworthy. First and most importantly, the rate of target lesion revascularization at 12 months was low: only 3% of patients required a revascularization, despite a low rate of bailout stenting (1.5%) and nearly 20% of patients presenting with chronic total occlusions. In the XTOSI study (10), the only other trial to prospectively evaluate a sirolimus-coated balloon for PAD, freedom from revascularization at the target lesion at 12 months for the femoropopliteal lesion subgroup was reported at 94%, slightly lower than in the SELUTION SFA trial. However, it is important to note that the median lesion length in the XTOSI trial was more than twice that in the SELUTION SFA trial (277±108 vs. 127.4±59.7 mm) and nearly all XTOSI patients had Rutherford classification 5 and 6 lesions. In contrast, the SELUTION SFA trial only included patients up to Rutherford 4, with over 97% of the patients presenting with Rutherford grade 2 or 3 lesions. This distinction is critical, since a Rutherford classification category above 3 is a known independent predictor of target lesion reintervention at 1 year after the use of DCBs (14). Furthermore, comparisons across single-arm trials cannot guide the preference of one product over another, as the study populations, treatment strategies, settings, and PAD severity vary greatly.

Second, it is commendable that the authors included clinical outcomes such as CD-TLR, major amputation, and death, along with a surrogate marker like ultrasound-assisted patency of the treated lesion. These endpoints are essential to assess the true efficacy and safety of sirolimus-coated balloons for PAD, and future trials in this field should similarly incorporate them, as has been done in the coronary field (15).

Third, this sirolimus-coated balloon appeared safe regarding distal embolization, a concern raised in the case of paclitaxel-coated balloons due to case reports of distal vasculitis and panniculitis following the treatment (16,17), although not confirmed in randomized clinical trials.

Are all sirolimus-coated balloons the same in terms of drug release, transfer, and bioavailability? We simply do not know and further head-to-head data is needed. The SELUTION SCB employs proprietary sirolimus-containing microreservoirs embedded in a biodegradable polymer, which are attached to the balloon surface through a unique cell adherent amphipathic lipid technology. This design is intended to control drug release and ensure optimal transfer and adherence of sirolimus to the target tissue. The sirolimus-coated MagicTouch balloons (Concept Medical), tested in the XTOSI trial, utilize proprietary NANOLUTE coating technology, which aims to minimize drug loss during transit, enhance rapid drug uptake into the tissue, and increase bioavailability. NANOLUTE reduces drug and excipient particle size to the nano-scale for easier tissue absorption, while a phospholipid-based carrier encapsulates the drug to improve sirolimus lipophilicity. The Sundance sirolimus-coated balloon, developed by Surmodics, utilizes a crystalline drug release (CDR) platform designed to enhance the delivery and retention of sirolimus in the arterial wall.

We are still in the early stages of the sirolimus-coated balloons era. DCBs have received a class IIa level recommendation from the 2024 guidelines of the European Society of Cardiology for the treatment of femoropopliteal lesions in patients with symptomatic PAD. However, data from randomized trials with clinical outcomes on sirolimus-coated balloons is simply lacking. Available evidence from small-sized trials is limited to surrogate endpoints, such as target lesion revascularization and patency rates. The SIRONA trial, the first randomized study comparing sirolimus- and paclitaxel-coated DCBs for PAD, was recently presented and demonstrated non-inferiority of sirolimus in terms of efficacy and safety (data not published). In this context, the data from the SELUTION SFA trial are valuable but remain preliminary. More head-to-head data from randomized controlled trials are needed in the PAD device field, as evidence from single-arm prospective studies is insufficient to guide treatment decision. Unfortunately, this limitation applies to most devices or products used to treat peripheral vessels in the endovascular setting.

A number of ongoing randomized trials with surrogate or radiological outcomes testing sirolimus-coated balloon are ongoing or have completed enrollment (18,19). The SIRolimus-coated balloon vs. standard uncoated balloon angioplasty for infrainguinal PAD (SirPAD) randomized controlled trial has just completed the enrollment of 1,200 patients. SirPAD (NCT04238546) will show whether sirolimus-coated Magic Touch balloons are non-inferior, and ultimately superior to plain old balloon to prevent hard clinical outcomes, including unplanned major amputation of the target limb and urgent target lesion revascularization for critical limb ischemia within one year of randomization (20).

In conclusion, we believe that (I) single-arm trials are useful to generate hypothesis, (II) randomized controlled trials with radiological outcomes, i.e., target lesion revascularization, are undoubtedly needed as next-level evidence, and (III) randomized controlled trials with objective clinical outcomes should be used to guide treatment and inform on cost-effectiveness. There is still some work to be done.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Cardiovascular Diagnosis and Therapy. The article has undergone external peer review.

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-484/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-484/coif). S.B. reported to have received honoraria and research grants from Concept Medical, the manufacturer of the sirolimus-coated balloons Magic Touch. S.B. is the co-principal investigator of the SirPAD trial (NCT04238546). The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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