IMR Press / RCM / Volume 22 / Issue 3 / DOI: 10.31083/j.rcm2203070
Open Access Review
Progress on developing an effective below-the-knee drug-coated balloon
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1 Division of Vascular and Endovascular Surgery, University of California, San Francisco, CA 94143, USA
2 Division of Angiology, Medical University Graz, 8036 Graz, Austria
Academic Editor: Bernardo Cortese
Rev. Cardiovasc. Med. 2021 , 22(3), 585–595; https://doi.org/10.31083/j.rcm2203070
Submitted: 2 August 2021 | Revised: 18 August 2021 | Accepted: 25 August 2021 | Published: 24 September 2021
(This article belongs to the Special Issue Drug-Coated balloons-The “leave nothing behind” strategy)
Abstract

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.

Keywords
Drug-coated balloon
Device design
Below-the-knee
Infrapopliteal
Peripheral arterial disease
1. Introduction

Peripheral artery disease (PAD) represents a global health burden affecting 20% of the population over 80 years of age [1-3]. Its most severe form, chronic limb-threatening ischemia (CLTI) defined by ischemic rest pain, tissue loss, or gangrene is associated with a 25% incidence of limb loss and 25% risk of mortality at 1 year if left untreated [4]. Percutaneous peripheral intervention has become a vital treatment for many patients suffering from symptomatic PAD [5,6]. While CLTI often results from multilevel disease [7], the addition of infrapopliteal disease most frequently leads to lower limb amputation and continues to present the greatest challenge for effective endovascular therapies [8]. The below-the-knee (BTK) endovascular therapeutic arsenal has, heretofore, evolved from plain balloon angioplasty [9,10] to include bare metal stents [11], drug-eluting stents [12-16], bioresorbable stents [17], intravascular tacking [18], and drug-coated balloons.

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

2. 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].

Despite its broad applicability and usefulness, plain old balloon angioplasty (POBA) for the BTK arteries has produced generally suboptimal results, especially for long lesions and CTOs [21]. In their meta-analysis of infrapopliteal angioplasty, Romiti et al. [10] presented an immediate technical success as low as 89.0 ± 2.2%. Schmidt et al. [22] reported a 68.8% restenosis as early as 3 months post-intervention in 77 infrapopliteal artery lesions with a mean lesion length of 184 mm. Unfortunately, early failure is unlikely to match the need for prolonged patency required to heal foot wounds [23]. BTK POBA is also subject to elastic recoil and post-angioplasty dissection which remains unsolved in the absence of an arterial scaffold [23]. The primary patency of BTK POBA at 1 year averages 58.1 ± 4.6% with a 14% limb loss [10]. These suboptimal results have been consistent throughout more recent review. Mustapha et al. [24] reported a 63.1% primary patency and 14.9% major limb amputation at 1 year. The effect of neointimal hyperplasia or elastic recoil in small caliber and calcified distal arteries cannot be overstated. Patients with advanced disease (TransAtlantic Inter-Society Consensus (TASC) II D) [25] who are suitable candidates for an open operation could be better served by primary bypass rather than a failed attempt at POBA and this continues to be an area of active study [26,27].

The patency success of drug-eluting stents (DES) in the treatment of coronary artery disease has not followed in small peripheral arteries [28-33]. The permanence of a metallic 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].

3. Drug-coated balloon technology
3.1 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 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].

Table 1.Commonly held views on paclitaxel vs. sirolimus (or analogs).
Characteristics Paclitaxel Sirolimus (or analogs)
Drug nature Highly lipophilic Less lipophilic
Mode of action Cytotoxic Cytostatic
Safety margin 102-fold 104-fold
Therapeutic range Narrow Wide
Anti-restenotic Yes Yes
Anti-inflammatory No Yes
Coating nature Hydrophilic spacer Drug encapsulation
Coating complexity Simple Complex
Tissue absorption Fast Slow
Tissue retention Long Short
Tissue deposition Sub-intimal space with significant partition in adventitia Throughout arterial wall
Acceptance Mixed Positive
3.2 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 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.

Table 2.Coating properties.
Properties Iopromide Urea BTHC* Polysorbate/Sorbitol Polymer
Uniform drug application Yes Yes Yes NA
Limited drug loss No No Yes NA Yes
Efficient and rapid drug transfer Yes Yes No Yes Yes
Controlled drug concentration NA NA NA NA NA
Limited particulate degeneration with fragmentation No No NA Yes NA
*, n-Butyryl tri-n-hexyl citrate.

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.

4. Clinical trials of BTK-DCB
4.1 Summary of PCB clinical trials

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 ± 3.5% vs. 9.6 ± 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 ± 0.62 mm vs. 0.99 ± 0.55 mm; p < 0.001) with PCB vs. POBA [56]. Additional published clinical trials are tabulated (Tables 3 (Ref. [52-63]),4 (Ref. [52-63]),5 (Ref. [52-63]),6 (Ref. [52-63])). Comparisons of DCB and POBA have so far yielded heterogeneous results (Fig. 1).

Fig. 1.

Comparison of 12-month primary patency in DCB vs. POBA clinical trials. *, primary patency at 6 months.

Table 3.Devices attributes in published BTK DCB clinical trials.
Trials Device Company Drug Drug dose density (µg/mm2) Excipient
DEBELLUM [57] IN.PACT Amphirion Medtronic Paclitaxel 3.5 Urea
DEBATE-BTK [52] IN.PACT Amphirion Medtronic Paclitaxel 3.5 Urea
IDEAS-I [53] IN.PACT Amphirion Medtronic Paclitaxel 3.5 Urea
IN.PACT DEEP [58] IN.PACT Amphirion Medtronic Paclitaxel 3.5 Urea
BIOLUX P-II [54] Passeo-18 LUX BIOTRONIK Paclitaxel 3 BTHC†
BIOLUX P-III [59] Passeo-18 LUX BIOTRONIK Paclitaxel 3 BTHC†
Lutonix BTK [60] Lutonix Bard Paclitaxel 2 Polysorbate/Sorbitol
APOLLO [61] ELUTAX SV Aachen Resonance GmbH Paclitaxel 2.2 Dextran¶
Acotec [62] Litos-Tulip Acotec Scientific Paclitaxel 3 Magnesium stearate
AcoArt II-BTK [56] Litos-Tulip Acotec Scientific Paclitaxel 3 Magnesium stearate
PRESTIGE [63] Selution SLR MedAlliance SA Sirolimus 1 Polymer-based
SINGA-PACLI [55] Passeo-18 LUX BIOTRONIK Paclitaxel 3 BTHC†
†, n-Butyryl tri-n-hexyl citrate.
¶, no carrier.
IN.PACT Amphirion has been voluntary recalled. All other included devices (Passeo-18 LUX, Lutonix, ELUTAX SV, Litos-Tulip, Selution SLR) are Conformity Europeenne (CE) trademarked. None are currently Food and Drug Administration (FDA) approved.
Table 4.Patient demographics in published BTK DCB clinical trials.
Trials Patients, n* Age, years Men, % Diabetes, % Renal disease, % Rutherford stages 5–6, % or median Rutherford stage
DEBELLUM [57] 25 66 76 52 NA 8
DEBATE-BTK [52] 65 74 83 100 10.8 97.2
IDEAS-I [53] 25 67.6 80 76 44 4.5†
IN.PACT-DEEP [58] 239 73.3 76.2 75.7 8.6 85.8
BIOLUX P-II [54] 36 72.9 75 61.1 27.8 72.2
BIOLUX P-III [59] 151 72.3 73.5 62.9 36.4 63.6
Lutonix BTK [60] 287 72.9 70.4 71.1 23.7 56.1
APOLLO [61] 164 74.7 66.5 79.9 57.3 78.1
Acotec [62] 52 75.4 75 100 40 92.8
AcoArt II-BTK [56] 61 70.7 59 74 NA 54
PRESTIGE [63] 25 63.7 68 88 44 100
SINGA-PACLI [55] 70 61 61 94 54 97
*, n = patients treated with DCB.
†, Median Rutherford stage.
Table 5.Lesion characteristics in published BTK DCB clinical trials.
Trials Lesion length, mm Diameter stenosis, % Severe calcification, % Chronic total occlusion, %
DEBELLUM [57] 76 85 NA 12.2
DEBATE-BTK [52] 129 97.2 25 77.5
IDEAS-I [53] 148 85.3 NA 12
IN.PACT DEEP [58] 102 83.9 13.7 38.6
BIOLUX P-II [54] 113.1 72.5 4.7 NA
BIOLUX P-III [59] 79.2 86.2 9.8 18.4
Lutonix BTK [60] 111.8 86.7 15.1 36.1
APOLLO [61] 107.2 89.4 27 42
Acotec [62] 169 91.5 61.3 68
AcoArt II-BTK [56] 169.95 95 12.3 75
PRESTIGE [63] 191 88.9 30.3 NA
SINGA-PACLI [55] 90.3 77.2 70 35
Table 6.Clinical and anatomic outcomes of published BTK DCB clinical trials.
Trials Primary patency, % Primary patency time-point, months TLR*, % TLR* time-point, months Amputation, % Amputation time-point, months Death, % Death time-point, months LLL†, mm LLL† time-point, months
DEBELLUM [57] NA NA 5 6 5 0 0 12 0.62 6
DEBATE-BTK [52] 73 12 18 12 0 12 7.7 12 NA NA
IDEAS-I [53] 42.1 6 13.6 6 4 6 8 6 1.15 6
IN.PACT DEEP [58] 59 12 9.2 12 8.8 12 10.1 12 0.605 12
BIOLUX P-II [54] 49.2 12 34.9 12 3.3 12 NA NA 0.56 6
BIOLUX P-III [59] 86.6 12 9.1 12 9 12 NA NA NA NA
Lutonix BTK [60] 77.8 6 8.7 6 1.1 6 5 6 NA NA
APOLLO [61] 68.5 12 9.4 12 4.6 12 12.2 12 NA NA
Acotec [62] 62.1 6 10 6 0 6 7.7 6 0.51 6
AcoArt II-BTK [56] 75 12 8.9 12 1.7 6 1.7 12 0.43 6
PRESTIGE [63] 81.5 6 16.7 6 8 6 12 6 NA NA
SINGA-PACLI [55] 43 6 20 12 25 12 21 12 NA NA
*, Target-lesion revascularization.
†, Late lumen loss.
4.1.1 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%; p = 0.291) or late lumen loss (0.61 ± 0.78 mm vs. 0.62 ± 0.78 mm; p = 0.950). Moreover, binary restenosis wasn’t significantly different at 12 months (41.0% vs. 35.5%; p = 0.609). The authors also noted an alarming safety signal driven by a higher incidence of major amputations at 12 months (8.8% vs. 3.6%; p = 0.08) [58]. As a result, Medtronic (Minneapolis, MN, USA) subsequently voluntarily recalled the IN.PACT Amphirion DCB. Of note, there was no significant difference in amputation rate at 5 years (15.4% vs. 10.6%; p = 0.106) [64].

4.1.2 Lutonix-BTK

The Lutonix balloon demonstrated a trend toward improved freedom from major amputation 6 months post-intervention (95.5% vs. 93.8%; p = 0.268). However, the primary efficacy endpoint of combined vessel occlusion, clinically driven-TLR (CD-TLR), and above-ankle amputation was only superior in the proximal-segment DCB group (76% vs. 62.9%; p = 0.0085) [60]. In femoropopliteal revascularization, a “slow-flow phenomenon” has been observed after DCB angioplasty and associated with worse 6-month primary patency (71% vs. 91%; p = 0.09), freedom from TLR (71% vs. 97%; p < 0.01), and amputation free-survival (71% vs. 95%; p = 0.02) [65]. The incidence of “slow-flow phenomenon” after infrapopliteal POBA has been reported as high as 18.6% and its occurrence has been associated with reduced 2-year major limb amputation (60% vs. 86%; p < 0.01) and decreased wound healing (77% vs. 91%; p = 0.03) [66]. Perhaps, the consequences of slow flow after PCB angioplasty could be even more pronounced in smaller, distal arteries and therefore result in the observed better results of PCB in proximal and larger tibial vessels. At 1 year, there was no longer a statistical difference in the primary efficacy endpoint between DCB and POBA (60.3% vs. 60.9%; p = 0.54). The Lutonix balloon is still awaiting U.S. Food and Drug Administration (FDA) approval for the tibial vasculature.

4.1.3 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].

4.2 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 [70-75]. 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 [79-85].

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 [88-90]. 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 [30,93-96]. 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].

4.3 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].

5. Future directions
5.1 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].

Table 7.Planned BTK DCB clinical trials.
Trial Clinicaltrials.gov identifier Device Company Design Patients, n Primary endpoint
PRISTINE NCT04534257 Selution SLR MedAlliance SA Single arm 75 6-month TLR*
SELUTION BTK IDE NA Selution SLR MedAlliance SA FDA IDE 330 NA
STEP NA Selution SLR MedAlliance SA Single arm 20 Freedom from occlusion at 30 days
Future BTK Asia-Choke NCT04511247 MagicTouch DCB Concept Medical Randomized 219 6-month primary patency
Future BTK EU NA MagicTouch DCB Concept Medical NA 153 NA
LIMES Germany-Teichgraber NCT04772300 MagicTouch DCB Concept Medical Randomized 244 Compositive of 6-month primary patency and limb salvage
Debate BTK DUelL-Liistro NA MagicTouch DCB Concept Medical Randomized 172 6-month LLL†
SWING NCT04107298 SUNDANCE DCB Surmodics Single arm 35 6-month LLL†
*, Target-lesion revascularization.
†, Late lumen loss.
5.2 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).

5.3 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 SUNDANCETM 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).

5.4 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].

5.5 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].

6. 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 run-off [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].

7. 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.

Acknowledgment

The authors would like to thank all the peer reviewers for their opinions and suggestions.

Funding

This research received no external funding.

Conflict of interest

PAS has served as a consultant for Silk Road Medical, Surmodics, Boston Scientific, Medtronic, Philips, CSI, Cagent, Cordis, and LimFlow. MB is a consultant for Medtronic, BD Bard, Boston Scientific, Biotronik, and Cook Medical.

References
[1]
Sampson UK, Fowkes FG, McDermott MM, Criqui MH, Aboyans V, Norman PE, et al. Global and regional burden of death and disability from peripheral artery disease: 21 world regions, 1990 to 2010. Global Heart. 2014; 9: 145–158.e121.
[2]
Scully RE, Arnaoutakis DJ, DeBord Smith A, Semel M, Nguyen LL. Estimated annual health care expenditures in individuals with peripheral arterial disease. Journal of Vascular Surgery. 2018; 67: 558–567.
[3]
Selvin E, Erlinger TP. Prevalence of and Risk Factors for Peripheral Arterial Disease in the United States. Circulation. 2004; 110: 738–743.
[4]
Abu Dabrh AM, Steffen MW, Undavalli C, Asi N, Wang Z, Elamin MB, et al. The natural history of untreated severe or critical limb ischemia. Journal of Vascular Surgery. 2015; 62: 1642–1651.e3.
[5]
Shishehbor MH, Jaff MR. Percutaneous Therapies for Peripheral Artery Disease. Circulation. 2016; 134: 2008–2027.
[6]
Bosiers M, Hart JP, Deloose K, Verbist J, Peeters P. Endovascular therapy as the primary approach for limb salvage in patients with critical limb ischemia: experience with 443 infrapopliteal procedures. Vascular. 2006; 14: 63–69.
[7]
Conte MS, Bradbury AW, Kolh P, White JV, Dick F, Fitridge R, et al. Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia. European Journal of Vascular and Endovascular Surgery. 2019; 58: S1–S109.
[8]
Graziani L, Jaff MR. Drug-eluting balloons: are these failed solutions for the treatment of below-the-knee peripheral artery disease? Annals of Vascular Surgery. 2014; 28: 1078–1079.
[9]
Greenfield AJ. Femoral, popliteal, and tibial arteries: percutaneous transluminal angioplasty. American Journal of Roentgenology. 1980; 135: 927–935.
[10]
Romiti M, Albers M, Brochado-Neto FC, Durazzo AES, Pereira CAB, De Luccia N. Meta-analysis of infrapopliteal angioplasty for chronic critical limb ischemia. Journal of Vascular Surgery. 2008; 47: 975–981.
[11]
Biondi-Zoccai GGL, Sangiorgi G, Lotrionte M, Feiring A, Commeau P, Fusaro M, et al. Infragenicular Stent Implantation for below-the-Knee Atherosclerotic Disease: Clinical Evidence from an International Collaborative Meta-Analysis on 640 Patients. Journal of Endovascular Therapy. 2009; 16: 251–260.
[12]
Rastan A, Brechtel K, Krankenberg H, Zahorsky R, Tepe G, Noory E, et al. Sirolimus-Eluting Stents for Treatment of Infrapopliteal Arteries Reduce Clinical Event Rate Compared to Bare-Metal Stents. Journal of the American College of Cardiology. 2012; 60: 587–591.
[13]
Scheinert D, Ulrich M, Scheinert S, Sax J, Braunlich S, Biamino G. Comparison of sirolimus-eluting vs. bare-metal stents for the treatment of infrapopliteal obstructions. EuroIntervention. 2006; 2: 169–174.
[14]
Bosiers M, Scheinert D, Peeters P, Torsello G, Zeller T, Deloose K, et al. Randomized comparison of everolimus-eluting versus bare-metal stents in patients with critical limb ischemia and infrapopliteal arterial occlusive disease. Journal of Vascular Surgery. 2012; 55: 390–398.
[15]
Fusaro M, Cassese S, Ndrepepa G, Tepe G, King L, Ott I, et al. Drug-eluting stents for revascularization of infrapopliteal arteries: updated meta-analysis of randomized trials. JACC: Cardiovascular Interventions. 2013; 6: 1284–1293.
[16]
Feiring AJ, Krahn M, Nelson L, Wesolowski A, Eastwood D, Szabo A. Preventing leg amputations in critical limb ischemia with below-the-knee drug-eluting stents: the PaRADISE (PReventing Amputations using Drug eluting StEnts) trial. Journal of the American College of Cardiology. 2010; 55: 1580–1589.
[17]
Varcoe RL, Schouten O, Thomas SD, Lennox AF. Experience with the Absorb Everolimus-Eluting Bioresorbable Vascular Scaffold in Arteries below the Knee: 12-Month Clinical and Imaging Outcomes. JACC: Cardiovascular Interventions. 2016; 9: 1721–1728.
[18]
Geraghty PJ, Adams G, Schmidt A, Cardenas J, Lichtenberg M, Wissgott C, et al. Six-month pivotal results of tack optimized balloon angioplasty using the Tack Endovascular System in below-the-knee arteries. Journal of Vascular Surgery. 2021; 73: 918–929.e5.
[19]
Torii S, Mustapha JA, Narula J, Mori H, Saab F, Jinnouchi H, et al. Histopathologic Characterization of Peripheral Arteries in Subjects with Abundant Risk Factors. JACC: Cardiovascular Imaging. 2019; 12: 1501–1513.
[20]
McDermott MM, Greenland P, Liu K, Criqui MH, Guralnik JM, Celic L, et al. Sex differences in peripheral arterial disease: leg symptoms and physical functioning. Journal of the American Geriatrics Society. 2003; 51: 222–228.
[21]
Söder HK, Manninen HI, Jaakkola P, Matsi PJ, Räsänen HT, Kaukanen E, et al. Prospective trial of infrapopliteal artery balloon angioplasty for critical limb ischemia: angiographic and clinical results. Journal of Vascular and Interventional Radiology. 2000; 11: 1021–1031.
[22]
Schmidt A, Ulrich M, Winkler B, Klaeffling C, Bausback Y, Bräunlich S, et al. Angiographic patency and clinical outcome after balloon-angioplasty for extensive infrapopliteal arterial disease. Catheterization and Cardiovascular Interventions. 2010; 76: 1047–1054.
[23]
Karnabatidis D, Spiliopoulos S, Katsanos K, Siablis D. Below-the-knee drug-eluting stents and drug-coated balloons. Expert Review of Medical Devices. 2012; 9: 85–94.
[24]
Mustapha JA, Finton SM, Diaz-Sandoval LJ, Saab FA, Miller LE. Percutaneous Transluminal Angioplasty in Patients with Infrapopliteal Arterial Disease: Systematic Review and Meta-Analysis. Circulation: Cardiovascular Interventions. 2016; 9: e003468.
[25]
Jaff MR, White CJ, Hiatt WR, Fowkes GR, Dormandy J, Razavi M, et al. An Update on Methods for Revascularization and Expansion of the TASC Lesion Classification to Include below-the-Knee Arteries: a Supplement to the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Journal of Endovascular Therapy. 2015; 22: 663–677.
[26]
Lo RC, Darling J, Bensley RP, Giles KA, Dahlberg SE, Hamdan AD, et al. Outcomes following infrapopliteal angioplasty for critical limb ischemia. Journal of Vascular Surgery. 2013; 57: 1455–1454.
[27]
Giles KA, Pomposelli FB, Spence TL, Hamdan AD, Blattman SB, Panossian H, et al. Infrapopliteal angioplasty for critical limb ischemia: relation of TransAtlantic InterSociety Consensus class to outcome in 176 limbs. Journal of Vascular Surgery. 2008; 48: 128–136.
[28]
AbuRahma AF, Beasley M, Davis M, Adams E, Lee A, Shapiro J, et al. Use of drug-eluting stents in patients with critical limb ischemia and infrapopliteal arterial disease: a real-world single-center experience. Journal of vascular surgery. 2021. (in press)
[29]
Baumann F, Engelberger RP, Willenberg T, Do D, Kalka C, Baumgartner I, et al. Infrapopliteal lesion morphology in patients with critical limb ischemia: implications for the development of anti-restenosis technologies. Journal of Endovascular Therapy. 2013; 20: 149–156.
[30]
Rastan A, Tepe G, Krankenberg H, Zahorsky R, Beschorner U, Noory E, et al. Sirolimus-eluting stents vs. bare-metal stents for treatment of focal lesions in infrapopliteal arteries: a double-blind, multi-centre, randomized clinical trial. European Heart Journal. 2011; 32: 2274–2281.
[31]
Liu X, Zheng G, Wen S. Drug-eluting stents versus control therapy in the infrapopliteal disease: a meta-analysis of eight randomized controlled trials and two cohort studies. International Journal of Surgery. 2017; 44: 166–175.
[32]
Siablis D, Karnabatidis D, Katsanos K, Diamantopoulos A, Spiliopoulos S, Kagadis GC, et al. Infrapopliteal Application of Sirolimus-eluting versus Bare Metal Stents for Critical Limb Ischemia: Analysis of Long-term Angiographic and Clinical Outcome. Journal of Vascular and Interventional Radiology. 2009; 20: 1141–1150.
[33]
Deloose K, Bosiers M, Peeters P. One year outcome after primary stenting of infrapopliteal lesions with the CHROMIS DEEP stent in the management of critical limb ischaemia. EuroIntervention. 2009; 5: 318–324.
[34]
Ang H, Koppara TR, Cassese S, Ng J, Joner M, Foin N. Drug-coated balloons: technical and clinical progress. Vascular Medicine. 2020; 25: 577–587.
[35]
Spiliopoulos S, Kamarinos NV, Brountzos E. Current evidence of drug-elution therapy for infrapopliteal arterial disease. World Journal of Cardiology. 2019; 11: 13–23.
[36]
Fanelli F, Cannavale A. Endovascular treatment of infrapopliteal arteries: angioplasty vs stent in the drug-eluting era. European Radiology. 2014; 24: 793–798.
[37]
Teichgräber U. 24-Month Registry Results on Drug-Coated Balloon Angioplasty below the Knee: strong enough Evidence to Convince the Sceptics? CardioVascular and Interventional Radiology. 2021; 44: 19–20.
[38]
Gray WA, Granada JF. Drug-coated balloons for the prevention of vascular restenosis. Circulation. 2010; 121: 2672–2680.
[39]
Gongora CA, Shibuya M, Wessler JD, McGregor J, Tellez A, Cheng Y, et al. Impact of Paclitaxel Dose on Tissue Pharmacokinetics and Vascular Healing: a Comparative Drug-Coated Balloon Study in the Familial Hypercholesterolemic Swine Model of Superficial Femoral in-Stent Restenosis. JACC: Cardiovascular Interventions. 2015; 8: 1115–1123.
[40]
Yazdani SK, Pacheco E, Nakano M, Otsuka F, Naisbitt S, Kolodgie FD, et al. Vascular, downstream, and pharmacokinetic responses to treatment with a low dose drug-coated balloon in a swine femoral artery model. Catheterization and Cardiovascular Interventions. 2014; 83: 132–140.
[41]
Speck U, Cremers B, Kelsch B, Biedermann M, Clever YP, Schaffner S, et al. Do pharmacokinetics explain persistent restenosis inhibition by a single dose of paclitaxel? Circulation: Cardiovascular Interventions. 2012; 5: 392–400.
[42]
Buerke M, Guckenbiehl M, Schwertz H, Buerke U, Hilker M, Platsch H, et al. Intramural delivery of Sirolimus prevents vascular remodeling following balloon injury. Biochimica Et Biophysica Acta. 2007; 1774: 5–15.
[43]
Levin AD, Vukmirovic N, Hwang C, Edelman ER. Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel. Proceedings of the National Academy of Sciences of the United States of America. 2004; 101: 9463–9467.
[44]
Seidlitz A, Kotzan N, Nagel S, Reske T, Grabow N, Harder C, et al. In vitro determination of drug transfer from drug-coated balloons. PLoS ONE. 2013; 8: e83992.
[45]
Kolachalama VB, Pacetti SD, Franses JW, Stankus JJ, Zhao HQ, Shazly T, et al. Mechanisms of tissue uptake and retention in zotarolimus-coated balloon therapy. Circulation. 2013; 127: 2047–2055.
[46]
Rykowska I, Nowak I, Nowak R. Drug-Eluting Stents and Balloons-Materials, Structure Designs, and Coating Techniques: A Review. Molecules. 2020; 25: 4624.
[47]
Buszman PP, Tellez A, Afari ME, Peppas A, Conditt GB, Rousselle SD, et al. Tissue uptake, distribution, and healing response after delivery of paclitaxel via second-generation iopromide-based balloon coating: a comparison with the first-generation technology in the iliofemoral porcine model. JACC: Cardiovascular Interventions. 2013; 6: 883–890.
[48]
Tzafriri AR, Muraj B, Garcia-Polite F, Salazar-Martín AG, Markham P, Zani B, et al. Balloon-based drug coating delivery to the artery wall is dictated by coating micro-morphology and angioplasty pressure gradients. Biomaterials. 2020; 260: 120337.
[49]
Kelsch B, Scheller B, Biedermann M, Clever YP, Schaffner S, Mahnkopf D, et al. Dose response to Paclitaxel-coated balloon catheters in the porcine coronary overstretch and stent implantation model. Investigative Radiology. 2011; 46: 255–263.
[50]
Stolzenburg N, Breinl J, Bienek S, Jaguszewski M, Löchel M, Taupitz M, et al. Paclitaxel-Coated Balloons: investigation of Drug Transfer in Healthy and Atherosclerotic Arteries - first Experimental Results in Rabbits at Low Inflation Pressure. Cardiovascular Drugs and Therapy. 2016; 30: 263–270.
[51]
Speck U, Stolzenburg N, Peters D, Scheller B. How does a drug-coated balloon work? Overview of coating techniques and their impact. The Journal of Cardiovascular Surgery. 2016; 57: 3–11.
[52]
Liistro F, Porto I, Angioli P, Grotti S, Ricci L, Ducci K, et al. Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia. Circulation. 2013; 128: 615–621.
[53]
Siablis D, Kitrou PM, Spiliopoulos S, Katsanos K, Karnabatidis D. Paclitaxel-Coated Balloon Angioplasty Versus Drug-Eluting Stenting for the Treatment of Infrapopliteal Long-Segment Arterial Occlusive Disease. JACC: Cardiovascular Interventions. 2014; 7: 1048–1056.
[54]
Zeller T, Beschorner U, Pilger E, Bosiers M, Deloose K, Peeters P, et al. Paclitaxel-Coated Balloon in Infrapopliteal Arteries: 12-Month Results from the BIOLUX P-II Randomized Trial (BIOTRONIK’S-first in Man study of the Passeo-18 LUX drug releasing PTA Balloon Catheter vs. the uncoated Passeo-18 PTA balloon catheter in subjects requiring revascularization of infrapopliteal arteries). JACC: Cardiovascular Interventions. 2015; 8: 1614–1622.
[55]
Patel A, Irani FG, Pua U, Tay KH, Chong TT, Leong S, et al. Randomized Controlled Trial Comparing Drug-coated Balloon Angioplasty versus Conventional Balloon Angioplasty for Treating below-the-Knee Arteries in Critical Limb Ischemia: the SINGA-PACLI Trial. Radiology. 2021; 300: 715–724.
[56]
Jia X, Zhuang B, Wang F, Gu Y, Zhang J, Lu X, et al. Drug-Coated Balloon Angioplasty Compared with Uncoated Balloons in the Treatment of Infrapopliteal Artery Lesions (AcoArt II–BTK). Journal of Endovascular Therapy. 2021; 28: 215–221.
[57]
Fanelli F, Cannavale A, Boatta E, Corona M, Lucatelli P, Wlderk A, et al. Lower Limb Multilevel Treatment with Drug-Eluting Balloons:6-Month Results from the DEBELLUM Randomized Trial. Journal of Endovascular Therapy. 2012; 19: 571–580.
[58]
Zeller T, Baumgartner I, Scheinert D, Brodmann M, Bosiers M, Micari A, et al. Drug-Eluting Balloon Versus Standard Balloon Angioplasty for Infrapopliteal Arterial Revascularization in Critical Limb Ischemia. Journal of the American College of Cardiology. 2014; 64: 1568–1576.
[59]
Tepe G, Wang J, Corpataux J, Pua U, Binkert CA, Moscovic M, et al. BIOLUX P-III Passeo-18 Lux all-Comers Registry: 24-Month Results in below-the-Knee Arteries. CardioVascular and Interventional Radiology. 2021; 44: 10–18.
[60]
Mustapha JA, Brodmann M, Geraghty PJ, Saab F, Settlage RA, Jaff MR, et al. Drug-Coated vs Uncoated Percutaneous Transluminal Angioplasty in Infrapopliteal Arteries: Six-Month Results of the Lutonix BTK Trial. Journal of Invasive Cardiology. 2019; 31: 205–211.
[61]
Teichgräber U, Lehmann T, Thieme M, Wahl K, Stelzner C, Bormann A, et al. Drug-Coated Balloon Angioplasty of Infrapopliteal Lesions in Patients with Critical Limb Ischaemia: 1-Year Results of the APOLLO Trial. CardioVascular and Interventional Radiology. 2019; 42: 1380–1390.
[62]
Liistro F, Angioli P, Ventoruzzo G, Ducci K, Reccia MR, Ricci L, et al. Randomized Controlled Trial of Acotec Drug-Eluting Balloon Versus Plain Balloon for below-the-Knee Angioplasty. JACC: Cardiovascular Interventions. 2020; 13: 2277–2286.
[63]
Tang TY, Yap C, Soon SXY, Chan SL, Lee QS, Yap HY, et al. World’s first Experience Treating TASC II C and D Tibial Occlusive Disease Using the Selution SLR Sirolimus-Eluting Balloon: Six-Month Results from the PRESTIGE Study. Journal of Endovascular Therapy. 2021; 28: 555–566.
[64]
Zeller T, Micari A, Scheinert D, Baumgartner I, Bosiers M, Vermassen FEG, et al. The in.PACT DEEP Clinical Drug-Coated Balloon Trial. JACC: Cardiovascular Interventions. 2020; 13: 431–443.
[65]
Shirai S, Hirano K, Mori S, Makino K, Honda Y, Tsutsumi M, et al. Frequency, predictors, and effect of the slow-flow phenomenon after drug-coated balloon angioplasty for femoropopliteal lesions. Heart and Vessels. 2021. (in press)
[66]
Tokuda T, Hirano K, Sakamoto Y, Takimura H, Kobayashi N, Araki M, et al. Incidence and clinical outcomes of the slow-flow phenomenon after infrapopliteal balloon angioplasty. Journal of Vascular Surgery. 2017; 65: 1047–1054.
[67]
Ipema J, Huizing E, Schreve MA, de Vries JPM, Ünlü Ç. Editor’s Choice – Drug Coated Balloon Angioplasty vs. Standard Percutaneous Transluminal Angioplasty in below the Knee Peripheral Arterial Disease: a Systematic Review and Meta-Analysis. European Journal of Vascular and Endovascular Surgery. 2020; 59: 265–275.
[68]
Cassese S, Ndrepepa G, Liistro F, Fanelli F, Kufner S, Ott I, et al. Drug-Coated Balloons for Revascularization of Infrapopliteal Arteries: a Meta-Analysis of Randomized Trials. JACC: Cardiovascular Interventions. 2016; 9: 1072–1080.
[69]
Zeller T, Jaff MR. Favorable Angiographic Outcome after Treatment of Infrapopliteal Lesions with Drug-Coated Balloons without Clinical Benefit: what we Learn from a Meta-Analysis. JACC: Cardiovascular Interventions. 2016; 9: 1081–1082.
[70]
Schroeder H, Werner M, Meyer D, Reimer P, Krüger K, Jaff MR, et al. Low-Dose Paclitaxel-Coated Versus Uncoated Percutaneous Transluminal Balloon Angioplasty for Femoropopliteal Peripheral Artery Disease: one-Year Results of the ILLUMENATE European Randomized Clinical Trial (Randomized Trial of a Novel Paclitaxel-Coated Percutaneous Angioplasty Balloon). Circulation. 2017; 135: 2227–2236.
[71]
Rosenfield K, Jaff MR, White CJ, Rocha-Singh K, Mena-Hurtado C, Metzger DC, et al. Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease. The New England Journal of Medicine. 2015; 373: 145–153.
[72]
Tepe G, Laird J, Schneider P, Brodmann M, Krishnan P, Micari A, et al. Drug-Coated Balloon Versus Standard Percutaneous Transluminal Angioplasty for the Treatment of Superficial Femoral and Popliteal Peripheral Artery Disease. Circulation. 2015; 131: 495–502.
[73]
Scheinert D, Duda S, Zeller T, Krankenberg H, Ricke J, Bosiers M, et al. The LEVANT i (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC: Cardiovascular Interventions. 2014; 7: 10–19.
[74]
Schmidt A, Piorkowski M, Görner H, Steiner S, Bausback Y, Scheinert S, et al. Drug-Coated Balloons for Complex Femoropopliteal Lesions: 2-Year Results of a Real-World Registry. JACC: Cardiovascular Interventions. 2016; 9: 715–724.
[75]
Krishnan P, Faries P, Niazi K, Jain A, Sachar R, Bachinsky WB, et al. Stellarex Drug-Coated Balloon for Treatment of Femoropopliteal Disease: Twelve-Month Outcomes from the Randomized ILLUMENATE Pivotal and Pharmacokinetic Studies. Circulation. 2017; 136: 1102–1113.
[76]
Zeller T, Rastan A, Macharzina R, Tepe G, Kaspar M, Chavarria J, et al. Drug-coated balloons vs. drug-eluting stents for treatment of long femoropopliteal lesions. Journal of Endovascular Therapy. 2014; 21: 359–368.
[77]
Korosoglou G, Lichtenberg M, Celik S, Andrassy J, Brodmann M, Andrassy M. The evolving role of drug-coated balloons for the treatment of complex femoropopliteal lesions. The Journal of Cardiovascular Surgery. 2018; 59: 51–59.
[78]
Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Karnabatidis D. Risk of Death Following Application of Paclitaxel‐Coated Balloons and Stents in the Femoropopliteal Artery of the Leg: a Systematic Review and Meta‐Analysis of Randomized Controlled Trials. Journal of the American Heart Association. 2018; 7: e011245.
[79]
Schneider PA, Laird JR, Doros G, Gao Q, Ansel G, Brodmann M. Mortality not Correlated with Paclitaxel Exposure: an Independent Patient-Level Meta-analysis of a Drug-Coated Balloon. Journal of the American College of Cardiology. 2019; 73: 2550–2563.
[80]
Holden A, Varcoe RL, Jaff MR, Schneider PA, Tepe G, Zeller T. Paclitaxel and Mortality: the Dose Argument is Critical. Journal of Endovascular Therapy. 2019; 26: 467–470.
[81]
Rocha-Singh KJ, Duval S, Jaff MR, Schneider PA, Ansel GM, Lyden SP, et al. Mortality and Paclitaxel-Coated Devices. Circulation. 2020; 141: 1859–1869.
[82]
Schneider PA, Varcoe RL, Secemsky E, Schermerhorn M, Holden A. Update on paclitaxel for femoral-popliteal occlusive disease in the 15 months following a summary level meta-analysis demonstrated increased risk of late mortality and dose response to paclitaxel. Journal of Vascular Surgery. 2021; 73: 311–322.
[83]
Nordanstig J, James S, Andersson M, Andersson M, Danielsson P, Gillgren P. Mortality with Paclitaxel-Coated Devices in Peripheral Artery Disease. Journal of Vascular Surgery. 2020; 383: 2538–2546.
[84]
Secemsky EA, Barrette E, Bockstedt L, Bonaca MP, Hess CN, Hanson T, et al. Long-Term Safety of Drug-Coated Devices for Peripheral Revascularisation. EuroIntervention. 2020. (in press)
[85]
Gutierrez JA, Rao SV, Jones WS, Secemsky EA, Aday AW, Gu L, et al. Survival and Causes of Death among Veterans with Lower Extremity Revascularization with Paclitaxel‐Coated Devices: Insights from the Veterans Health Administration. Journal of the American Heart Association. 2021; 10: e018149.
[86]
Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Paraskevopoulos I, Karnabatidis D. Risk of Death and Amputation with Use of Paclitaxel-Coated Balloons in the Infrapopliteal Arteries for Treatment of Critical Limb Ischemia: a Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of Vascular and Interventional Radiology. 2020; 31: 202–212.
[87]
Katsanos K, Spiliopoulos S, Teichgräber U, Kitrou P, Del Giudice C, Björkman P, et al. Risk of Major Amputation Following Application of Paclitaxel Coated Balloons in the Lower Limb Arteries: a Systematic Review and Meta-Analysis of Randomised Controlled Trials. European Journal of Vascular and Endovascular Surgery. 2021. (in press)
[88]
Dinh K, Limmer AM, Chen AZL, Thomas SD, Holden A, Schneider PA, et al. Mortality Rates After Paclitaxel-Coated Device Use in Patients With Occlusive Femoropopliteal Disease: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of Endovascular Therapy. 2021. (in press)
[89]
Schneider PA, Varcoe RL. Re: Risk of Death and Amputation with Use of Paclitaxel-Coated Balloons in the Infrapopliteal Arteries for Treatment of Critical Limb Ischemia: a Systematic Review and Meta-analysis of Randomized Controlled Trials. Journal of Vascular and Interventional Radiology. 2020; 31: 1030–1032.
[90]
Bonassi S. Letter by Bonassi Regarding Article, “Risk of Death Following Application of Paclitaxel‐Coated Balloons and Stents in the Femoropopliteal Artery of the Leg: a Systematic Review and Meta‐Analysis of Randomized Controlled Trials”. Journal of the American Heart Association. 2019; 8: e012315.
[91]
Granada JF, Ferrone M, Melnick G, Crookall L, Schulz-Jander D, Tunev S, et al. Downstream Paclitaxel Released Following Drug-Coated Balloon Inflation and Distal Limb Wound Healing in Swine. JACC: Basic to Translational Science. 2021; 6: 416–427.
[92]
Ohtsu T, Sasaki Y, Tamura T, Miyata Y, Nakanomyo H, Nishiwaki Y, et al. Clinical pharmacokinetics and pharmacodynamics of paclitaxel: a 3-hour infusion versus a 24-hour infusion. Clinical Cancer Research. 1995; 1: 599–606.
[93]
Prado Jr GFA, Abizaid AAC, Meireles GC, Sarmento-Leite R, Prudente M, Cantarelli M, et al. Comparative clinical performance of two types of drug-eluting stents with abluminal biodegradable polymer coating: five-year results of the DESTINY randomized trial. Revista Portuguesa De Cardiologia. 2021; 40: 71–76.
[94]
Costa JR, Chamié D, Abizaid AAC, Ribeiro E, Meireles GC, Prudente M, et al. Intravascular imaging comparison of two metallic limus-eluting stents abluminally coated with biodegradable polymers: IVUS and OCT results of the DESTINY trial. The International Journal of Cardiovascular Imaging. 2017; 33: 161–168.
[95]
Lemos PA, Abizaid AAC, Meireles GC, Sarmento-Leite R, Prudente M, Cantarelli M, et al. Metallic Limus-Eluting Stents Abluminally Coated with Biodegradable Polymers: Angiographic and Clinical Comparison of a Novel Ultra-Thin Sirolimus Stent Versus Biolimus Stent in the DESTINY Randomized Trial. Cardiovascular Therapeutics. 2015; 33: 367–371.
[96]
Scheinert D, Katsanos K, Zeller T, Koppensteiner R, Commeau P, Bosiers M, et al. A Prospective Randomized Multicenter Comparison of Balloon Angioplasty and Infrapopliteal Stenting with the Sirolimus-Eluting Stent in Patients with Ischemic Peripheral Arterial Disease. Journal of the American College of Cardiology. 2012; 60: 2290–2295.
[97]
Franzone A, Stabile E, Trimarco B, Esposito G. Peripheral drug-eluting technology. Cardiology Clinics. 2015; 33: 151–162.
[98]
Varcoe RL, Thomas SD, Lennox AF. Three-Year Results of the Absorb Everolimus-Eluting Bioresorbable Vascular Scaffold in Infrapopliteal Arteries. Journal of Endovascular Therapy. 2018; 25: 694–701.
[99]
Brattström C, Säwe J, Jansson B, Lönnebo A, Nordin J, Zimmerman JJ, et al. Pharmacokinetics and safety of single oral doses of sirolimus (rapamycin) in healthy male volunteers. Therapeutic Drug Monitoring. 2000; 22: 537–544.
[100]
Amlani V, Falkenberg M, Nordanstig J. The current status of drug-coated devices in lower extremity peripheral artery disease interventions. Progress in Cardiovascular Diseases. 2021; 65: 23–28.
[101]
Cremers B, Toner JL, Schwartz LB, von Oepen R, Speck U, Kaufels N, et al. Inhibition of neointimal hyperplasia with a novel zotarolimus coated balloon catheter. Clinical Research in Cardiology. 2012; 101: 469–476.
[102]
Albrecht T, Speck U, Baier C, Wolf K, Böhm M, Scheller B. Reduction of stenosis due to intimal hyperplasia after stent supported angioplasty of peripheral arteries by local administration of paclitaxel in swine. Investigative Radiology. 2007; 42: 579–585.
[103]
Serruys PW, Chevalier B, Dudek D, Cequier A, Carrié D, Iniguez A, et al. A bioresorbable everolimus-eluting scaffold versus a metallic everolimus-eluting stent for ischaemic heart disease caused by de-novo native coronary artery lesions (ABSORB II): an interim 1-year analysis of clinical and procedural secondary outcomes from a randomised controlled trial. Lancet. 2015; 385: 43–54.
[104]
Serruys PW, Chevalier B, Sotomi Y, Cequier A, Carrié D, Piek JJ, et al. Comparison of an everolimus-eluting bioresorbable scaffold with an everolimus-eluting metallic stent for the treatment of coronary artery stenosis (ABSORB II): a 3 year, randomised, controlled, single-blind, multicentre clinical trial. Lancet. 2016; 388: 2479–2491.
[105]
Cortese B, Granada JF, Scheller B, Schneider PA, Tepe G, Scheinert D, et al. Drug-coated balloon treatment for lower extremity vascular disease intervention: an international positioning document. European Heart Journal. 2016; 37: 1096–1103.
[106]
Conte MS, Geraghty PJ, Bradbury AW, Hevelone ND, Lipsitz SR, Moneta GL, et al. Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia. Journal of Vascular Surgery. 2009; 50: 1462–1463.
[107]
Brodmann M, Choke E, Holden A. BTK Drug-Coated Balloons: Can They Clear the Hurdle? Endovasc Today. 2021; 20: 58–62.
[108]
Bonaca MP, Bauersachs RM, Hiatt WR. Rivaroxaban in Peripheral Artery Disease after Revascularization. Reply. The New England Journal of Medicine. 2020; 383: 2090–2091.
[109]
Kang IS, Lee W, Choi BW, Choi D, Hong M, Jang Y, et al. Semiquantitative assessment of tibial artery calcification by computed tomography angiography and its ability to predict infrapopliteal angioplasty outcomes. Journal of Vascular Surgery. 2016; 64: 1335–1343.
[110]
Kobayashi N, Hirano K, Yamawaki M, Araki M, Sakai T, Sakamoto Y, et al. Characteristics and clinical outcomes of repeat endovascular therapy after infrapopliteal balloon angioplasty in patients with critical limb ischemia. Catheterization and Cardiovascular Interventions. 2018; 91: 505–514.
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