Sirolimus coated balloons in peripheral arterial disease, what’s next?

Sirolimus-coated balloons (SCB) have been shown to be a feasible option to paclitaxel coated balloons (PCB) in treating peripheral arterial disease (PAD) (1-5). Sirolimus is a macrolide compound, which was initially used as an immunosuppressant with antiproliferative properties. It acts by reversibly putting the cell into resting phase, G_{0 (cytostatic)}, retaining its viability (6). Besides its anti-inflammatory and anti-restenotic effects, Sirolimus has a wide therapeutic safety margin (6).

The Selution SLRÔ (M. A. MedAlliance SA, Nyon, Switzerland) SCB mixes sirolimus with a biodegradable polymer poly(lactic-co-glycolic acid), which forms micro-reservoirs, thus allowing for a sustained release over a 90-day period into the arterial wall whilst minimising circulatory loss and distal embolization (1). This helps in inhibiting the neointimal hyperplasia and restenosis process, which typically only starts to occur from 2 to 3 months following the barotrauma of angioplasty (7).

PCBs have been the mainstay of drug coated balloons (DCB) in endovascular PAD treatment. The results of the 2018 meta-analysis by Katsanos et al. have led some to worry about the safety of the use of paclitaxel devices (8). It was suggested treatment with the use of paclitaxel devices would lead to an increase in mortality for patients with femoropopliteal (FP) disease in the medium term. Since then, there have been other studies to show no such association (9,10). This subsequently led the US Food and Drug Administration to issue an update that “the data does not support an excess mortality risk for paclitaxel-coated devices.” (11). Despite this, there were also concerns about aneurysmal formation after paclitaxel use, especially used in the subintimal space (12,13). A postulated mechanism of paclitaxel-anerusymal degeneration may be due to the high concentration and rapid onset of action of paclitaxel delivered (13). Another concern of PCBs is the possibility of distal embolization resulting in increased risk of amputations (14,15). Although, in rabbit iliac models, it is suggested that, SCBs showed more even distribution, with deeper tissue penetration and higher drug concentrations within distal skeletal muscles compared to PCBs, also postulating a possibility for distal embolization with SCBs (16). This finding was not formerly noted in SCBs, and the risk of distal embolization associated with PCBs appears underestimated when compared to current evidence. Besides, the use of rabbit iliac to study atherosclerosis is not ideal as porcine models are considered to have greater similarity to human physiology (17). SCBs also typically use micro or nano particles in micro-reservoirs with Cell Adherent Technology amphipathic transfer membrane on the balloon surface which don’t cause significant downstream vascular changes, as shown with a reduced incidence of slow-flow phenomenon (18). Whilst in the FP segment, DCBs have shown their effectiveness, this has not been the case in the below-the-knee (BTK) segment (4,5). Thus, this has led many to start considering alternatives to paclitaxel as a drug coated device for use in the peripheral vasculature (Table 1).

The first-in-human trial of the of Selution SLR™ SCB titled “First-in-Human, Single-Arm SELUTION Sustained-Limus-Release Drug-Eluting Balloon Trial in Femoropopliteal Lesions” (SELUTION FIM) (NCT02941224) was performed for treatment of FP lesions (1). The patients had a mean lesion length of 64.3 mm, of which 30% were complete total occlusion. Results were promising with a target lesion revascularization (TLR) rate of 2.3%, no major lower extremity limb amputation (LEA) or death and improvement in 1 or more categories on the Rutherford Classification in 73% of patients at 6 months. Primary patency (PP) rate was 88.4% and freedom from restenosis was 91.2%. Improvement was experienced in 1 or more categories on the Rutherford Classification from baseline in 78% and 84% of patients at 12- and 24-month respectively and 85% freedom from TLR at 12-month post procedure. No incidence of major LEA or death were reported at 2 years (19). This study was small (n=50) and comprised of only claudicants.

In a recent issue of the Journal of the American College of Cardiology: Cardiovascular Interventions, Iida et al. attempted to shed more light on the role of SCBs in the treatment of FP disease with a large, single-am, prospective, multicenter trial evaluating the Selution SLR™ SCB (3). A total of 134 Rutherford 2–4 patients were enrolled in this study. Patients with chronic kidney disease (CKD) stage 4 or worse were excluded. The primary endpoint was PP of the target lesion at 12 months, which was defined as the absence of restenosis by duplex ultrasound or clinically driven target lesion revascularisation. The PP rate was 83.5% [95% confidence interval (CI): 75.8–89.5%] at 12 months, with a cumulative MAE rate was 6.7%, including 5 deaths and 4 clinically-driven target lesion revascularizations (CD-TLRs). There were no investigational device or procedural related deaths and no amputations. The authors summarised that the Selution SLR™ SCB was an effective and safe in treating symptomatic FP disease.

One of the strengths of this study is the number of patients as it is currently the largest prospective trial and was adjudicated by an independent core laboratory. The results further reinforce the results from the study by Zeller et al. with comparable PP rates (87.9% vs. 88.4%) (1). There was also very few lost to follow ups, allowing for the primary end point to be reached in a majority of patients. The study included an Asian population which allows for some applicability of the results to a wider scope of patients of patients with almost 60.3% being diabetics. There was a long treatment length (170.2±57.0 mm) and very low rates of bail-out stenting (1.5%, n=2). Once again, the safety outcomes of this study validate the safety profile of the study with no procedural deaths or that related to the investigational device. Likewise, there were no LEAs.

Nonetheless, this also highlights some of the deficiencies of this study population and its wider applicability. The study focused on mainly claudicants with a mean ankle brachial index (ABI) of 0.73±0.16. Similar to SELTUION FIM study, which also treated Rutherford class 2 or 3 patients, 97.8% of patients in this study being Rutherford class 2 or 3 (3). This could have been one of the reasons why there would be no LEA. Chronic limb threatening ischaemia (CLTI) which occurs due to occlusive arterial disease causing tissue loss and ischaemic rest pain, is the most severe manifestation of PAD (20). This is associated with a high mortality and major LEA rates (21). The primary aim of treatment for CLTI is early revascularisation to aid in wound healing and to reduce the risk of major LEA, which results in mobility impairment and poorer quality of life (20). Unlike these 2 trials, the recent Xtreme Touch-Neo [MagicTouch PTA (Concept Medical)] Sirolimus Coated Balloon (XTOSI) pilot study enrolled mianly patients with Rutherford class 5–6. With complex FP [mean length of 277 mm, 45% chronic total occlusions (CTOs)] and BTK lesions, the 6-month SFA PP was reported at 88.2% and 78.6% at 12 months (2). In their 3-year update, For FP lesions, the freedom from CD-TLR was 92.9%, freedom from major amputation was 93.3%, amputation free survival (AFS) was 70%, with an overall survival of 70%. Regarding BTK lesions, the freedom from CD-TLR was 77.8%, freedom from major amputation was 81.0%, AFS was 58.6%, with an overall survival of 58.6% (22). The results of the ongoing FUTURE SFA trial (NCT04511234), which is the first trial comparing an SCB (MagicTouch PTA) versus uncoated balloon for SFA lesions are awaited as it is foreseen that the majority of patients recruited will be CLTI patient as in Asia the prevailing indication for lower limb angioplasty is CLTI (23).

The PRESTIGE trial (NCT04071782), a pilot prospective, non-randomised, single-arm, multi-investigator single-centre study was carried out by Tang et al. to investigate the efficacy and safety of Selution SLR™ SCB in TASC II C and D occlusive BTK lesions in patients with CLTI (4). Twenty five patients who had Rutherford 5 wounds, with 33 atherosclerotic lesions of TASC II C (54.5%) and D (45.5%) aetiology were enrolled. The mean lesion length was 190.6 mm. Technical success was 100% with a tibial PP at 6 months of 81.5% and freedom from CD-TLR at 83.3%. One major LEA and 3 deaths occurred. 81.8% of patients had an improvement of at least 1 Rutherford category by 6 months. The authors concluded that Selution SLR™ SCB was safe and efficacious in treating BTL occlusive lesions with good technical and clinical success with high patency and AFS (4).

Most of the patients in the trial by Iida et al. had TASC A (48.5%), or B (38.1%) and only 17.2% were CTO (3). This likely correlates of the clinical condition of the patients. CTOs represent a challenging subset of PAD that sometimes require complex endovascular techniques. CTOs are due to severe, concentric intimal thickening or occlusive thrombi organized from cyclic episodic ruptures with subsequent healing (24). There may be arterial calcifications that further compound such lesion. All these may in turn act against maintaining patency post endovascular treatment. It would be interesting to the effects of SCBs on CTO lesions.

Patients with stage 4 CKD or higher were excluded and only 6.9% of patients had CKD (3). Renal impairment especially end stage renal failure (ESRF) presents another challenge in revascularisation. In addition to slow healing, a high rate of infection and a higher operative risk due to co-morbidities, there is a higher prevalence of vascular calcification in ESRF patients (25). As there is usually concomitant diabetes these patients may often have diffuse and distal disease that make endovascular procedures more complex and reduces the likelihood of success (25). It would be interesting to see the efficacy of the Selution SLR™ SCB in a similar population to that in the XTOSI study where 20% of the patients had ESRF. Finally, almost 98.5% of patients had de novo lesions. Once again, this may restrict the applicability of Iida et al.’s study to patients who have recurrent lesions.

The latest results from the Prospective Registry to Investigate the Safety and efficacy of the Treatment with the SELUTION Sirolimus Drug Coated Balloon in TASC II C and D athero-occlusive Infra-iNguinal disease in patients with chronic limb threatening ischemia from Singapore (PRISTINE) (NCT04534257) may shed some light on some of these queries on the effect of the Selution SLR™ SCB on CLTI patients with TASC II C and D lesions (5). The PRISTINE registry is a prospective, non-randomized, observational, single-arm, single-centre study, which includes patients with a Ruthford classification between four and six, and TASC II C or D lesions. The primary endpoints were freedom from mortality, major amputation and CD-TLR, and procedure-related mortality through to 30 days, and to six months. 75 patients were treated. Seven had Rutherford 4, 51 had Rutherford 5 and 17 had Rutherford 6 disease. Majority of the patients had never smoked (n=48; 64.0%). 68 (91.0%) patients had diabetes mellitus, 28 (37.0%) had end-stage renal failure. 112 atherosclerotic lesions were treated [TASC II C =54 (48.2%), TASC II D =58 (51.8%)], of which 76 (67%) de novo) with a 100% technical success was achieved. The mean lesion length treated was 22.4±13.9 cm. Primary vessel patencies at 6 and 12 months were 64/86 (74%) and 43/74 (58%) respectively. The freedom from CD-TLR at 6 and 12 months were 72/86 (84%) and 55/74 (74%) respectively. AFS was 61/73 (84.0%; 5 deaths (6.8%) and 7 major LEAs) at 6 months and 53/73 (72.6%; 12 deaths (16.4%) and 8 major LEAs) at 12 months. Mean Rutherford score improved from 5.1±0.55 at baseline to 1.1±2.05 (P<0.05) and there was a wound healing rate of 38/48 (79%) at one year (5). The PRISTINE study comprised of everyday Asian patients in Asia who were frail with multiple comorbidities and had few exclusion criteria, unlike many of the DCB randomised controlled trials in the peripheral vasculature. It represented a common set of patients treated by a range of vascular surgeons of varying expertise. Moreover, considering the that 99/122 (88.4%) had moderate to severe calcification, an acceptable PP rate was maintained. This may suggest that the sirolimus may still be taken into the vessel wall despite the barrier.

Nevertheless, interest and research in SCBs is starting to pick up and the study by Iida et al. reinforces the growing evidence pool on the efficacy and safety of SCBs as an endovascular option for treating FP disease. Further studies are required to establish its efficacy in a wider variety and number of patients as well as its comparison to PCBs especially in CLTI patients and the BTK disease. The long-term outcomes of the SCB studies are also coming in and we await these results. Both of which present with challenges that current endovascular treatments do not have the best answers to.

Acknowledgments

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-24-425/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-425/coif). T.Y.T. reports that he had previously received physician initiated grants and travelling bursary to speak from MedAlliance when he conducted the PRESTIGE and PRISTINE trials. The other authors have 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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