Sirolimus coated balloon for the treatment of femoropopliteal lesions: the new kid on the block is getting older ‘step by step’

Iida and colleagues report on the results of the SELUTION SFA Japan trial, which was a prospective multicenter single-arm trial, studying the safety and effectiveness of sirolimus-coated balloons for the treatment of mild-to-moderate complexity femoropopliteal disease in a Japanese population (1). The authors studied 134 patients with symptomatic peripheral artery disease (PAD) with Rutherford categories (RC) 2 to 4, performing core lab adjudication for the interpretation of angiographic findings and clinical events. The results should be considered in the context of the current approaches for the endovascular treatment of femoropopliteal disease.

Atherosclerotic lesions in the femoropopliteal axis are the most common causes for lifestyle limiting claudication or critical limb threatening ischemia (CLTI). While medical treatment represents the cornerstone for the treatment of all patients with PAD, supervised exercise training is an important component for the treatment of patients with lifestyle limiting claudication. Endovascular treatment, on the other hand, has emerged as the first line strategy to alleviate symptoms and salvage limb tissue in this context (2-5). Currently, a plethora of different modalities for lesion preparation and treatment exist aiming to regain tissue perfusion by endovascular revascularization techniques. However, no consensus exists for the best way to treat femoropopliteal lesions, which would include the choice of both lesion preparation techniques and tools for the definitive endovascular treatment, depending on patient and lesion specific parameters.

Paclitaxel-coated balloons have demonstrated anti-restenotic action, reducing clinically driven target-lesion revascularization (TLR) rates in femoropopliteal segments compared to plain old balloon angioplasty (POBA) (6,7). Therefore, based on evidence from randomised controlled trials, the use of paclitaxel emerged as the standard of care for the treatment of femoropopliteal lesions in patients with symptomatic PAD who undergo endovascular revascularization treatment. In December 2018, however, a meta-analysis of randomised controlled trials indicated mortality increase in PAD patients treated with paclitaxel-coated devices (8). Despite some limitations in terms of device types heterogeneity, different paclitaxel dosages, and confounders with patients characteristics, this publication caused warnings issued by the US Food and Drug Administration (FDA), Healthcare products Regulatory Agency (MHRA) and UK Medicines. However, as patient level data from the randomised controlled trials included in the original meta-analysis alongside with longer-term outcome data became available, the strength of the adverse mortality signal diminished. In the same direction, analysis of real-world data demonstrated that there was no significant increase in all-cause mortality associated with the use of paclitaxel-coated devices. Thus, the SAFE-PAD study [168,553 patients, 70,584 (41.9%) treated with paclitaxel coated devices] demonstrated that up to 6.3 years, paclitaxel-coated devices are not associated with increased mortality rates (9). Similarly, in a time-dependent Cox regression analysis, conducted in 64,771 patients who underwent endovascular revascularization procedures, with 3,324 of them receiving at least one paclitaxel-coated device, no statistical increase in mortality was observed for a period of up to 11 years (10). Based on this accumulating evidence, warning issues have meanwhile been removed and in 2023 the FDA sent a letter to healthcare providers stating that the risk of mortality associated with paclitaxel to treat PAD can no longer be supported (https://www.fda.gov/medical-devices/letters-health-care-providers/update-paclitaxel-coated-devices-treat-peripheral-arterial-disease-unlikely-increase-risk-mortality). However, ongoing research in this field showed that paclitaxel devices may be associated with increased risk for amputation in patients with CLTI (11).

The above-mentioned safety issues and concerns for application of paclitaxel-coated devices with peripheral endovascular revascularization procedures and the large-scale experience with sirolimus coated stents and balloons with percutaneous coronary interventions, contributed to the development and application of sirolimus coated balloons for lower limb interventions. From a pathophysiologic point of view, paclitaxel is associated with pro-inflammatory and cytotoxic action, causing cell necrosis (12). This is associated with a narrower therapeutic window compared to sirolimus, which exhibits cytostatic and not cytotoxic and additional anti-inflammatory effects (13). Sirolimus drug transfer into the arterial wall, on the other hand, also needs to be considered, as this may pose a pharmacologic challenge, which needs to be addressed (14). Importantly, beyond pharmacological considerations, the success of drug-coated balloons is also related to the technical execution during the endovascular revascularization procedure, which includes lesion preparation, proper pre-dilation with gradual increase of the inflation pressure with a recommended inflation time of 2–3 minutes to avoid dissections and appropriate vessel sizing.

Currently two sirolimus-coated balloons are available and have obtained FDA approval for the treatment of symptomatic PAD treatment, including the Magic-Touch™ (Concept Medical Inc., Surat, India) and the Selution SLR™ (Med.Alliance, SA, Mont-sur-Rolle, Switzerland) drug-coated balloons (15). Selution SLR™ combines the use micro-reservoirs, made of a biodegradable polymer intermixed with sirolimus at a dose density of 1 µg/mm², to increase drug uptake into the arterial wall. Micro-reservoirs are coated onto the balloon with a proprietary amphipathic transfer membrane that contains and protects them during balloon insertion, lesion crossing, and subsequent balloon inflation. During inflation, the transfer membrane containing the micro-reservoirs adheres to the vessel lumen, preventing flaking into the vasculature and providing sustained release of the drug into the arterial wall. Promising 6-month data for its safety and effectiveness to inhibit restenosis with freedom from angiographic restenosis of >90% were reported within a previous single-arm trial for femoropopliteal lesions (16). In addition, promising single-arm data exist on the efficacy of sirolimus-coated balloons for the treatment of complex and calcified femoral (17) and below-the-knee lesions (18).

In the present multi-center study by Iida et al. (1) 134 patients with symptomatic PAD due to femoral or popliteal disease underwent endovascular revascularization using the Selution SLR™ sirolimus-coated balloon. Mean age was 73.8±6.9 years, and 60.3% of the patients had diabetes mellitus. The trial allowed the inclusion of patients with RC 2 to 4, thus including patients with ischemic resting pain (RC 4). However, the vast majority (97.8%) of the patients had lifestyle-limiting claudication. In addition, 36.6% of the patients had only moderate claudication, and data on the duration of symptomatic claudication or performance supervised exercise training prior to the endovascular procedure are not provided. In terms of lesion complexity, lesions with mild-to-moderate complexity were selected. Indeed, only lesions with a length of <20 cm were allowed for enrollment and the mean lesion length was 127.4±59.7 mm. In addition, 23 (14.6%) of the patients were excluded after initial inclusion to the trial, presumably due to the presence of long or complex lesions, resulting in a patient cohort with selected lesions. Although lesion calcification was semi-quantitatively assessed for every lesion within the trial and 26.9% exhibited severe calcification, three patients (2.2%) were excluded due to failed balloon expansion during pre-dilation treatment. In addition, only 17.2% of the lesions were chronic total occlusions (CTOs), whereas involvement of the popliteal segment was noted in 47% of the treated lesions. Overall, most of the patients had Trans-Atlantic Inter-Society Consensus (TASC) A or B lesions (86.6%). During endovascular treatment, technical success was observed in all cases and only 5.2% and 1.5% of the patients required additional post-dilatation or bail-out stenting, respectively.

During 12 months of follow-up, the primary patency rate was 83.5%, and the freedom from clinically driven TLR was 97.0%. The major adverse event rate was 6.7%, driven by 4 TLRs and 5 deaths, none of which were related to the index procedure. In addition, no major amputations occurred during the study period. It needs to be mentioned, however, that the sample size included in this study cannot allow for analysis of patient safety due to toxicity issues. In addition, ankle-brachial index data improved significantly from 0.73±0.16 at baseline to 0.96±0.14 at 30 days after the procedure and remained high at 12 months (0.94±0.13).

The study by Iida et al. (1) provides evidence that the Selution SLR™ sirolimus coated balloon has good mid-term effectiveness for the treatment of non-complex TASC A and B femoropopliteal lesions, which allow for adequate balloon expansion during pre-dilation and without the need for advanced lesion preparation techniques as atherectomy or lithotripsy. Notably, the sirolimus coated ballon exhibited relatively similar results to paclitaxel coated devices, which were tested within a randomized controlled study in lesions with similar complexity by the same authors (19).

Paclitaxel coated balloons have already demonstrated the efficacy in more complex femoropopliteal lesions either as a stand-alone therapy option after predilation (20) or in combination with lesion preparation tools, such as atherectomy (21-24). In addition, the superiority of paclitaxel coated balloons compared to POBA has been demonstrated in randomized controlled trials, so that paclitaxel coated balloons are part of the current clinical practice with endovascular revascularization procedures in patients with femoropopliteal disease. Despite some limitations of the present trial, like the inclusion of short and simple lesions and the lack of statistical power for the evaluation of patient safety issues, the study takes an important step forward, towards the implementation of sirolimus coated technologies, as a part of a treatment algorithm for the endovascular treatment of femoropopliteal lesions. However, more trials will be necessary in this direction, (I) studying the effectiveness of sirolimus coated devices in complex and calcified femoropopliteal lesions, in combination with lesion preparation tools as atherectomy or lithotripsy, (II) comparing the effectiveness of sirolimus coated devices with POBA within randomized controlled trials, and (III) assessing the non-inferiority of sirolimus-coated devices compared to well-established paclitaxel coated devices, which is currently being addressed within the SIRONA randomized controlled trial (25). In addition, (IV) retrospective population-based trials would be useful to evaluate the safety of sirolimus versus paclitaxel-coated balloons in large patient cohorts. Furthermore, future trials need to expand not only on fem-pop but also on below-the-knee lesions, thus allowing for inclusion of more patients with resting pain and patients with wound healing disorders. This evidence will possibly be provided by the Selution BTK study, which is currently enrolling patients (G210342-NCT05055297). With this broad study program, the way may be paved for the use of sirolimus-coated devices as an alternative for the treatment of femoropopliteal and BTK disease compared to paclitaxel-coated devices.

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-24-406/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-406/coif). C.R. reports that he received honoraria from: Avinger, Biotronik, BD Bard, Cordis, Daichii-Sankyo, Inari, Novartis, Shockwave, Veryan, consulted for: BD Bard, Boston Scientific Corp., Veryan, Shockwave and received institutional Grants for research, clinical trial, or drug studies from: Avinger, Biotronik, Boston Scientific Corp., Veryan, Med Alliance. G.K. reports that he received modest speaker honoraria from Philips, Cordis, Boston scientific and BARD Peripheral Vascular Inc., and institutional grants from Philips and Bard Peripheral Vascular Inc. 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.

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