Progress on developing an effective below-the-knee drug-coated balloon.

Infrapopliteal atherosclerotic disease continues to present the greatest conundrum for effective endovascular therapies. To date, conventional angioplasty has been fraught with early restenosis and recoil in these complex, long, calcified, and occlusive lesions. The success of metallic drug-eluting stents in coronary arteries has not carried over to below-the-knee arteries. Initial promise in paclitaxel-coated balloons has not been demonstrated in large randomized clinical trials. Furthermore, the potential association between paclitaxel and mortality continues to generate tremendous controversy. The goal of this review article is to discuss the evolution and challenges of drug-coated balloon (DCB) science, present the clinical results of currently available tibial DCBs, and introduce new horizons in DCB technology.

The purpose of this review is to report the progress on developing a safe and effective BTK drug-coated balloon (DCB).

Infrapopliteal vascular occlusive disease
Infrapopliteal vascular occlusive disease bestows unique clinical and anatomic challenges. First, comorbidities such as diabetes and dialysis dependence are prevalent in patients with BTK disease. Unlike its coronary counterpart, infrapopliteal artery disease tends to be diffuse, severely calcified, and involve long-segment chronic total occlusions (CTO). The lower extremity vascular bed is also relatively low flow with a high resistance to outflow [19]. In women, the higher incidence of CLTI as a presenting symptom in addition to a smaller vessel size presents an additional therapeutic challenge [20].  implant has been linked to sustained arterial inflammation, a detrimental delay in endothelial coverage, and late thrombosis. Thick struts in small, calcified, low flow distal vessels pose a significant design limitation [34]. Malapposition of DES deployed in the tibial vasculature could significantly impair drug delivery and effect [35]. Therefore, below-the-knee disease still represents an endovascular therapeutic conundrum. Can biologic therapy be used in this hostile environment to improve the results of endovascular therapy? Drug-coated balloons offer real promise to address this unmet clinical need [36,37].

Design principles
Drug-coated balloon angioplasty consists of a transfer of drug from the expanded balloon into the arterial mural surface by direct contact, followed by transport, diffusion, and uptake. Its success lies within the efficient delivery of therapeutic compounds while minimizing the need for a permanent implant [38]. However, questions persist on the dose of drug remaining in the arterial wall after balloon inflation [39]. Yazdani et al. [40] demonstrated therapeutic levels of paclitaxel in the arterial wall at 1 month without detectable plasma level after 1 day. In this swine femoral artery model, drug effect characterized by smooth muscle cell medial loss peaked at 90 days and was observed up 180 days after Lutonix balloon angioplasty. There is substantial preclinical animal evidence to demonstrate the inhibition of smooth muscle cell proliferation and neointima formation after a single DCB angioplasty [41,42]. To date, paclitaxel has proposed numer-ous advantages including its lipophilic nature associated with a fast uptake and longer retention (Table 1) [38,40,43,44]. In contrast, sirolimus presents unique questions related to its coating nature and complexity. Its slow absorption, fast elimination, and wide therapeutic range also account for some of its challenges. Nevertheless, drug is not the sole determinant of clinical response after DCB therapy [45].

Design challenges
The therapeutic success of DCB is based on a delicate balance of drug transport and transfer [45]. This balance requires an interaction between balloon, catheter, drug, and excipient [34]. Initial modifications in balloon fold geometry have proven insufficient to meaningfully enhance therapeutic level drug delivery [38]. Hence, coating appears to be the dominant design challenge in the manufacture of DCB.
Perceived ideal characteristics of utilized excipients are summarized in Table 2 [46]. Iterations of coating technology have resulted in improvement in preclinical model outcomes. Advancement in coating techniques have been geared towards increased homogeneity. When Buszman et al. [47] compared 2 generations of paclitaxel-coated balloon (PCB) coatings in their hypercholesterolemic iliofemoral porcine model, the more homogeneous second generation PCB yielded a significant reduction in percent diameter stenosis, percent area of stenosis, and neointimal proliferation. Microneedle coating generated a 1.7-fold increase in tissue retention of paclitaxel in a porcine femoral artery model when compared with amorphous/flaky-coating [48]. The goal of drug retention during tracking through a long sheath must be balanced with efficient drug transfer from the bal- loon to the artery after arrival at the target lesion. In a porcine coronary model, Kelsch et al. [49] confirmed a 30% drug loss during PCB angioplasty. Seidlitz et al. [44] presented an alarming 1% transfer of the total drug load.
A swine coronary model with very thin intima and moderately sized media is a poor model of human atherosclerotic distal peripheral vessels. In atherosclerotic animal models, the transfer of paclitaxel into arterial walls is significantly impaired. The need for higher inflation pressures to generate a pressure gradient against a rigid arterial wall to allow for efficient drug uptake may generate further arterial overstretch, injury, and dissection [38,50]. The low solubility of paclitaxel combined with low flow in a distal peripheral arterial bed may favor drug retention and uptake [41]. Slow dissolution of coating for effective drug delivery must be balanced with the risk of forming embolizing particles in end narrow vessels [51].
Although the optimal drug preparation-excipient combination for an effective BTK DCB is a work in progress, several efforts have been undertaken in recent years with varying degrees of promise.

IN.PACT DEEP
In the initial study of IN.PACT Amphirion against POBA, the IN.PACT DEEP trial investigators failed to demonstrate a superiority of DCB in clinically-driven TLR (9.2% vs. 13.1%;

Systematic reviews and meta-analyses
The lack of clear benefit of PCB has since then been confirmed by Ipema et al. [67] in their review of 10 studies including 1593 patients. The authors did not reveal a significant difference in their primary outcomes of 12-month limb salvage or secondary endpoints (survival, restenosis, TLR, amputation-free survival). Similarly, Cassese et al. [68] showed no difference in clinical outcomes with a favorable  late lumen loss (LLL) at 12 months in 641 patients enrolled in 5 clinical trials comparing PCB with POBA. In this study, the discordance between angiographic and clinical results of PCB in BTK arteries raised additional concerns related to the reliability of angiographic findings in small calcified arteries, and the merit of angiographic success [69].

Failure of paclitaxel
Although paclitaxel has consistently shown improved efficacy over conventional devices in the treatment of femoropopliteal disease, its success in tibial disease so far is rather modest [70][71][72][73][74][75]. The effectiveness of DCB in the treatment of long complex femoropopliteal lesions [76,77] has not carried onto the infrapopliteal vasculature. No significant difference was demonstrated in 12-month binary restenosis between IN.PACT and POBA. In Lutonix BTK, the combined freedom from amputation, unhealed wounds, rest pain, target-vessel occlusion, and CD-target-vessel revascularization was not significantly different between groups (76% vs. 62.9%; p = 0.13).
In 2018, the highly controversial summary-level metaanalysis by Katsanos et al. [78] noted an increased late mortality in patients with femoropopliteal disease treated with paclitaxel devices. The FDA issued a first warning letter to physicians in January 2019 and eventually convened an advisory panel in June 2019. Patient-level data analyses questioning this mortality signal along with its mechanism swiftly followed [79][80][81][82][83][84][85].
In 2020, Katsanos et al. [86] focused on PCBs targeting infrapopliteal disease. In this second systematic review and meta-analysis of randomized controlled trials, PCBs were associated with significantly worse outcomes using a composite endpoint of amputation-free survival (86.3% vs. 90.6%; p = 0.008). Although no significant differences were encountered when separating all-cause death (odds ratio (OR) = 1.39 [0.94-2.07]; p = 0.10) or major amputation (OR = 1.63 [0.92-2.90]; p = 0.09), the authors commented on the need for adequately powered multicenter studies with long-term followup data. More recently, the same group reported a significantly higher amputation rate after PCB angioplasty in CLTI patients (hazard ratio = 1.56 [1.04-2.33]; p = 0.03). In this systematic review and meta-analysis, the authors hypothesized that both paclitaxel systemic release, and an underlying inflammatory process were responsible for an observed 4% crude risk of major amputation [87]. Several systematic reviews and meta-analysis with contradictory findings consequently followed [88][89][90]. But this turmoil led to a natural decrease in paclitaxel use in the wide medical community along with a reconsideration of its role in the treatment algorithm of PAD. The further identification of mechanistic shortcomings of paclitaxel including its potential for downstream release and distal embolization [87,91] along with an ongoing debate on its systemic safety supported by limited animal studies [92] led to a growing interest in favor of sirolimus or its analogs.
In fact, "limus" drug has already displaced paclitaxel in the coronary world as the preferred antiproliferative agent. "Limus" drugs have already been used in tibial drug-eluting stents [30,[93][94][95][96]. In YUKON-BTK, 1-year primary patency was significantly improved in DES compared with bare-metal stents (80.6% vs. 55.6%; p = 0.004). The primary endpoint of freedom from target vessel revascularization, myocardial infarction, and death similarly favored the DES group [12,30]. The Destiny trial also revealed a primary patency advantage of the Everolimus polymer-coated Xience V stent in contrast to bare-metal stenting (85.2% vs. 54.5% at 1 year; p = 0.0001) [14,97]. The "limus" analog Everolimus has also being used in a drug-eluting bioresorbable vascular scaffold in tibial vessels with an impressive 8% incidence of binary restenosis after a mean 24-month period [98]. While "limus"-based technology presents some challenges in drug dose density and tissue uptake [99], they may offer an effective therapeutic solution to this clinical puzzle. Pharmacokinetic differences between paclitaxel and sirolimus (or analogs) are summarized in Table 1 [38,43].

SELUTION SLR
The SELUTION SLR consists of a sirolimus-coated balloon that utilizes micro-reservoirs made of biodegradable polymer. Its purpose is to achieve controlled and sustained drug release via a long-term tissue distribution. In the pilot physician-initiated, prospective, non-randomized, single arm PRESTIGE, the investigators assessed the safety and efficacy of the SELUTION SLR in TASC II C and D tibial occlusive disease. The authors presented favorable 6-month freedom from CD-TLR (83.3%), primary patency (81.5%) and amputation free-survival (84%) in high-risk CLTI patients with long lesions (mean lesion length 191 mm). Wound healing was achieved in 81% of patients at 6 months in the 25 included patients with Rutherford class 5 wounds [63].

Beyond PRESTIGE
After encouraging initial clinical results, the SELUTION SLR is currently under investigation in Asia (PRISTINE) and Austria (STEP). The SELUTION SLR BTK IDE trial will debut enrollment in the U.S. and Europe this calendar year (Table 7). Sirolimus-coated balloons may provide an alternative to PCBs in other forms [100].

MagicTouch DCB
In an effort to improve the lipophilic profile and bioavailability of sirolimus, Concept Medical has developed nanolute technology. This proprietary design relies on the conversion of sirolimus into sub-micron sized particles and its encapsulation into a phospholipid drug carrier. In the XTOSI first in man clinical trial presented at Leipzig Intervention Course (LINC) 2020, investigators reported a 74% primary patency at 6 months in 30 BTK lesions. Further trial results including FUTURE BTK Asia, FUTURE BTK EU, LIMES Germany, and DEBATE BTK-DUelL are awaited (Table 7).

Surmodics Sundance
The Surmodics Sundance balloon presents a unique hydrophilic shaft coating and is currently being investigated. The SWING trial (A Prospective, Multi-Center, Single-Arm, Feasibility Study to Access the Safety and Performance WIth the SUNDANCE T M DruG Coated Balloon (Surmodics, Inc., Eden Prairie, MN, USA) for the Treatment of De Novo or Restenotic Lesions in Infra-Popliteal Arteries) will be reporting a primary endpoint of 6-month late lumen loss (Table 7).

Substitute "limus" drug
Sirolimus is not the only member of the "limus" family to have shown promise in the search for an optimal DCB. The highly lipophilic nature of zotarolimus and potential for enhanced drug uptake has been tested in a porcine coronary overstretch model. In this preclinical evaluation, zotarolimus-coated balloons demonstrated a significant reduction in inflammation scores, and neointimal area when compared with control polymer coated stents without drug or zotarolimus-eluting stents [101].

Alternative methods of drug delivery
Novel therapeutic modalities have emerged with the goals of minimizing arterial injury while designing an effective platform for antiproliferative drug delivery.
Administration of antiproliferative drug dissolved in contrast medium has shown promise in reducing restenosis due to neointimal hyperplasia in a porcine artery overstretch model [102]. In this light, the Mercator Bullfrog catheter was developed to directly administer "limus" drugs in the arterial bed. In the TANGO trial presented at Transcatheter Cardiovascular Therapeutics (TCT) 2020, temsirolimus was used in 41 patients with TASC II B-C-D infrapopliteal lesions. The investigators reported a significant improvement in remaining transverse lumen area which assesses late lumen loss along the entire length of the treated artery when compared with 20 controls (24% vs. 46%) at 6-month follow-up.
The appeal of an effective device without the need for a permanent metallic implant has been explored in the coronary arteries. In ABSORB II, an Everolimus-containing poly-D, L-lactide scaffold initially demonstrated promising results with no significant difference in the composite endpoint of 1-year cardiac death, myocardial infarction, or target lesion revascularization vs. the best in-class DES Xience (Abbott, Chicago, IL, USA) [103]. In contrast, the significantly higher rate of target-lesion failure at two years led to its withdrawal [104]. Below the knee, excellent early results were noted with an astoundingly low binary restenosis (6%) and CD-TLR (4% at 2 years) [17]. Primary patency (81.1%) and freedom from CD-TLR (87.3%) have remained satisfactory at 36 months [98].

Limitations
Several limitations prevail in the study and design of an effective BTK DCB. High-fidelity models incorporating flow are lacking [45]. Compressive forces created by adjacent bones, muscles, and tendons are rarely accounted for [23,105]. Study endpoints are heterogeneous and challenging to interpret [106]. The impact of vessel preparation and balloon inflation protocol on technical and clinical outcomes remains unknown, particularly to treat lesions with poor runoff [50,105,107]. Efficacy may vary based on lesion location, length, and pattern of calcification. The role and potential advantage of BTK DCB in the treatment of high-risk lesions or restenosis is still undefined. Drivers of clinical success in PAD span beyond devices and include the management of underlying metabolic disorders as well as optimal and standardized wound care. Finally, paradigm shifts in post-procedural antithrombotic and antiplatelet therapy may play a larger role in success after high-risk infrapopliteal revascularization [108].

Conclusions
The endeavor to develop additional tools in the management of infrapopliteal occlusive disease is driven by limited efficacy of currently available devices [105]. Improvements in device design, drug delivery, possibly drug choices, along with the identification of demographic and lesion risk factors will allow for patient-specific targeted and effective therapy delivery [29,109,110].

Author contributions
Conceptualization-REK and PAS; investigation-REK and PAS; resources-REK, MB, and PAS; writing-original draft preparation-REK and PAS; writing-review and editing-REK, MB, and PAS; visualization-REK, MB, and PAS; supervision-MB and PAS; project administration-REK and PAS. All authors have read and agreed to the published version of the manuscript.

Ethics approval and consent to participate
Not applicable.