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 numerous 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].

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 balloon 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 2013, DEBATE-BTK compared PCB with POBA with encouraging results. Both target-lesion revascularization (18% vs. 43%; p = 0.002) and binary restenosis (27% vs. 74%; p 0.001) were significantly lower in limbs treated with PCB [52]. In the following years, IDEAS-1 evaluated DES against PCB. While there was no significant difference in target-lesion revascularization (TLR) between groups (p = 0.65), arteries treated with PCB exhibited significantly higher post-procedure residual stenosis (24.8 $\pm$ 3.5% vs. 9.6 $\pm$ 2.2%; p 0.0001) and subsequent binary restenosis at 6 months (57.9% vs. 28%; p = 0.0457) [53]. In BIOLUX P-II, the Passeo-18 LUX (Biotronik, Berlin, Germany) drug-releasing balloon catheter showed no significant difference in 6-month patency loss (17.1% vs. 26.1%; p = 0.298) or major amputation (3.3% vs. 5.6%; p = 0.631) compared with POBA [54]. More recently, Patel et al. [55] related a similarly low 6-month primary patency after Passeo-18 LUX BTK angioplasty compared with POBA (43% vs. 38%; p = 0.48). AcoArt II (Acotec, Beijing, China) BTK reported a significantly superior 6-month primary patency (75.0% vs. 28.3%; p 0.001) and late lumen loss (0.43 $\pm$ 0.62 mm vs. 0.99 $\pm$ 0.55 mm; p 0.001) with PCB vs. POBA [56]. Additional published clinical trials are tabulated (Tables 3 (Ref. [52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63]),4 (Ref. [52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63]),5 (Ref. [52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63]),6 (Ref. [52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63])). Comparisons of DCB and POBA have so far yielded heterogeneous results (Fig. 1).

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 meta-analysis 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 follow-up 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].

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].

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].

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).

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${}^{TM}$ 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).

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].

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].