Spiliopoulos S, Vasiniotis Kamarinos N, Brountzos E. Current evidence of drug-elution therapy for infrapopliteal arterial disease. World J Cardiol 2019; 11(1): 13-23
Corresponding Author of This Article
Stavros Spiliopoulos, MD, PhD, Assistant Professor, 2nd Radiology Department, Interventional Radiology Unit, Attikon University Hospital, University of Athens, Attikon University General Hospital, Athens 12461, Greece, Athens 12461, Greece. firstname.lastname@example.org
Checklist of Responsibilities for the Scientific Editor of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Current evidence of drug-elution therapy for infrapopliteal arterial disease
Stavros Spiliopoulos, Nikiforos Vasiniotis Kamarinos, Elias Brountzos
Stavros Spiliopoulos, Nikiforos Vasiniotis Kamarinos, Elias Brountzos, 2nd Radiology Department, Interventional Radiology Unit, University of Athens, Attikon University General Hospital, Athens 12461, Greece
Author contributions: Spiliopoulos S conceived the review and made critical revisions to its content; Vasiniotis Kamarinos N drafted the manuscript and made critical revisions to its content; Brountzos E drafted the manuscript and made critical revisions to its content; all authors approved the final version of the article.
Conflict-of-interest statement: The authors have no conflict of interest to declare.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Stavros Spiliopoulos, MD, PhD, Assistant Professor, 2nd Radiology Department, Interventional Radiology Unit, Attikon University Hospital, University of Athens, Attikon University General Hospital, Athens 12461, Greece, Athens 12461, Greece. email@example.com
Received: July 27, 2018 Peer-review started: July 30, 2018 First decision: October 5, 2018 Revised: October 23, 2018 Accepted: January 1, 2019 Article in press: January 1, 2019 Published online: January 26, 2019
New and sophisticated endovascular devices, such as drug-eluting stents (DES) and drug-coated balloons (DCB), provide targeted drug delivery to affected vessels. The invention of these devices has made it possible to address the reparative cascade of arterial wall injury following balloon angioplasty that results in restenosis. DESs were first used for the treatment of infrapopliteal lesions almost 20 years ago. More recently, however, DCB technology is being investigated to improve outcomes of endovascular below-the-knee arterial procedures, avoiding the need for a metallic scaffold. Today, level IA evidence supports the use of infrapopliteal DES for short to medium length lesions, although robust evidence that justifies the use of DCBs in this anatomical area is missing. This review summarizes and discusses all available data on infrapopliteal drug-elution devices and highlights the most promising future perspectives.
Core tip: Currently available level IA evidence justifies the use of infrapopliteal drug-eluting stents for short to medium length lesions in selected patients with specific anatomical criteria. The role of infrapopliteal drug-coated balloons remains to be determined.
Citation: Spiliopoulos S, Vasiniotis Kamarinos N, Brountzos E. Current evidence of drug-elution therapy for infrapopliteal arterial disease. World J Cardiol 2019; 11(1): 13-23
Infrapopliteal atherosclerotic arterial disease, either alone or combined with aortoiliac and femoropopliteal vascular disease, is the leading cause of critical limb ischemia (CLI) and severe, lifestyle-limiting, intermittent claudication (IC). In the western population, the incidence of infrapopliteal disease is strongly correlated with the prevalence of diabetes mellitus, and is continuously rising due to increased life expectancy in developed countries. Foot ulceration with tissue loss and gangrene are some of the manifestations of CLI, which may lead to major amputation if the affected arteries are not promptly revascularized. CLI is considered to be responsible for approximately 90% of the major amputations performed worldwide, and is a significant cause of morbidity and mortality[2,3]. In diabetic patients, CLI represents a medical emergency, as the concomitant foot architectural changes and potential infections can rapidly compromise limb salvage. Besides, the long vessel occlusions combined with poor distal runoff, prevalent in diabetic CLI patients, represent a considerable challenge for healthcare specialists.
Patients with ischemic rest pain, diabetic or non-healing foot ulcers, or gangrene involving any portion of the lower limbs should be evaluated with the WIFI classification system that assesses the three primary factors contributing to limb threat risk: wound (W), ischemia (I) and foot infection (FI)[6,7]. After considering these components and staging each patient, revascularization should be attempted. The WIFI classification system is depicted in Table 1. Femorodistal below-the-knee (BTK) bypass surgery with autologous vein grafts has been established in the past as the gold standard treatment for CLI. However, the presence of various underlying comorbidities, as well as the scarcity of non-diseased donor and run-off vessels, render a significant number of CLI patients unsuitable for surgery. Direct comparison data between bypass surgery and percutaneous BTK procedures are limited, with only one randomized multi-center trial available in the literature. Nevertheless, the evolution of interventional techniques, along with the development of novel devices, contributed to a paradigm shift in CLI treatment; nowadays endovascular methods can be used for multiple vessel recanalization and are related to comparable clinical outcomes for open surgery[3,8-10]. Endovascular revascularization, by virtue of its minimally-invasive nature, is characterized by decreased perioperative complications and cardiovascular stress that result in both shorter hospital stays as well as low morbidity and mortality[11,12].
Table 1 Assessment of amputation risk: wound (W), ischemia (I) and foot infection classification[6,7].
No ulcer (ischemic rest pain)
Small, shallow ulcer on distal leg or foot without gangrene
Deeper ulcer with exposed bone, joint or tendon ± gangrenous changes limited to toes
Extensive deep ulcer, full thickness heel ulcer ± calcaneal involvement ± extensive gangrene
Ankle pressure (mmHg)
Toe pressure or TcPO2
No symptoms or signs of infection
Local infection involving only skin and subcutaneous tissue
Local infection involving deeper than skin/subcutaneous tissue
Systemic inflammatory response syndrome
Plain balloon angioplasty was the primary endovascular therapy utilized in the infrapopliteal territory. Although it appeared to be effective in the short-term, post-angioplasty elastic vessel recoil and flow-limiting dissection contributed to reocclusion and relapse of ischemic symptoms. Despite the fact that balloon angioplasty may be repeated, each procedure involves an inherent risk of technical failure and yields additional cost. Attempting to address this issue, Dorros et al pioneered the placement of the first infrapopliteal bare metal stent (BMS) 25 years ago. However, BMS application has been associated with poor outcomes in the mid-term due to the phenomenon of in-stent restenosis. Constant irritation of the vessel wall by the metal stent mesh results in inflammation, intimal hyperplasia, negative vessel remodeling and ultimate reocclusion[16,17]. Occlusion rates are high; half of the BMS become occluded within the first year and can lead to major amputation[18,19]. As a result, stenting in the infrapopliteal region has been reserved as a bail-out procedure in order to maximize acute lumen gain and avoid early vessel reocclusion.
New and sophisticated endovascular devices, such as drug-eluting stents (DES) and drug-coated balloons (DCB), provide targeted drug delivery to affected vessels. The invention of these devices has made it possible to address the reparative cascade of arterial wall injury following balloon angioplasty that results in restenosis. BTK arteries share many characteristics with coronary arteries; this fact has motivated several investigators to apply this drug-eluting technology, widely used in percutaneous coronary interventions, in the infrapopliteal territory in order to improve clinical outcomes.
DESs were introduced into clinical practice by interventional cardiologists, and demonstrated favorable outcomes regarding late lumen loss (LLL) and rate-of-repeat revascularization procedures. The comparable size of tibial to coronary arteries, and the superior efficacy of these stents compared to BMSs, led to the first clinical application of DES in the infrapopliteal arteries, with the goal of inhibiting restenosis and prolong uninterrupted blood supply to the foot. The concept of DES technology is based on covering the stent’s strut with a polymer matrix, such as silicone, polyethylene vinyl alcohol or cellulose ester, that is saturated with a specific drug. Some DESs are polymer-free, and the drug is applied directly onto the metallic strut. DESs inhibit neointimal hyperplasia and smooth muscle cell proliferation by releasing the incorporated drug into the vessel wall over a standard period of time. The pharmaceutical agents that are most commonly used are immunosuppressants of the “-olimus family,” i.e., sirolimus, everolimus and tacrolimus, or the anti-mitotic agent paclitaxel. Sirolimus (rapamycin) is a natural lipophilic macrolide compound with both immunosuppressive and antiproliferative properties. Paclitaxel is a cytotoxic and antineoplastic drug that promotes microtubule stabilization, blocking M phase of the cell cycle, thus leading to cellular death. The first clinical applications of DES in infrapopliteal arteries for the treatment of CLI demonstrated encouraging mid-term results[18,22-25].
Following these initial promising single-center studies, multicenter randomized controlled trials (RCT) (YUKON-BTX, DESTINY and ACHILLES trials), reported low infrapopliteal vessel restenosis rate, higher event-free survival and improved quality of life. These provided level IA evidence for DES use in short focal infrapopliteal lesions (< 120 mm)[26-28].
Meta-analysis of the above three multicenter RCTs confirmed these findings and demonstrated the superiority of DES over plain balloon angioplasty and BMSs. Specifically, DESs were proven to be significantly superior in terms of 1 year primary patency [80.0% vs 58.5%; number needed-to-treat (NNT) = 4.8], improvement of Rutherford-Becker class (79.0% vs 69.6%; NNT = 11.1), target lesion revascularization (TLR) events (9.9% vs 22.0%; NNT = 8.3), wound healing (76.8% vs 59.7%; 2; NNT = 5.9), and event-free survival (72.2% vs 57.3%; pooled; NNT = 6.7).
Recently, data about long-term outcomes of DES application in infrapopliteal arterial disease were published in the PADI study; the only multicenter RCT study with the long-awaited 5-year follow up data. In three vascular centers in the Netherlands, Paclitaxel-eluting stents (PES) (TAXUS Liberte; Boston Scientific, United States) were randomized vs both PTA and bail-out bare metal stenting. A total of 137 patients with CLI were included in the study. At 5 years follow-up, amputation-free survival and event-free survival rates were significantly superior in the PES group (26.2% vs 15.3%, P = 0.041 and 31.8% vs 20.4%, P = 0.043, respectively), while amputation rate was also lower for PES (19.3% vs 34.0%, P = 0.091). Survival rates were similar between the two groups, while the duplex-assessed patency rate was still significantly higher in the PES group after four years follow-up (13.5% vs 32.6%, P = 0.031). All randomized controlled trials for infrapopliteal drug-eluting technologies are analytically reported in Table 2.
Angiographic binary restenosis: DES 28% vs 57.9% in PCB; P = 0.0457
PCB 14.8 ± 5.6
PTA: Percutaneous transluminal angioplasty; CLI: Critical limb ischemia; BMS: Bare metal stent; PCB: Paclitaxel-coated balloon; DES: Drug-eluting stent; PES: Paclitaxel-eluting stent; SES: Sirolimus-eluting stent; TLR: Target lesion revascularization; CLI: Critical leg ischemia; LLL: Late lumen loss.
Long-term outcomes of DES placement in diabetic patients with CLI were evaluated in a clinical study that reported a 90.4% amputation-free interval at 5 and 10 years after the procedure, while survival rate was 55.5% and 36.2% at 5 and 10 years follow-up, respectively. Half of the patients (50.3%) underwent a repeat revascularization procedure due to clinical relapse at 10 years follow-up. Nevertheless, long-term data beyond a 1 year follow-up of infrapopliteal DES remain scarce, and further multicenter RCTs are required to prove whether the use of this technology can improve long-term clinical outcomes. Specifically, in a recent meta-analysis of ten studies (eight RCTs and two cohort studies), which included 927 patients assigned to either DES (484) or control treatment (443), primary patency was significantly in favor of DES at one year. However, this advantage was not evident at 3 years follow-up. The authors concluded that more high-level, long-term data are needed.
The safety and superiority of DES in short to medium length lesions has been demonstrated by level IA evidence. Nevertheless, the polymorphic nature of BTK disease, which usually presents with very long lesions (> 20 cm) and requires treatment of bifurcations and flexion points, such as the distal anterior tibial artery and the pedal arch, still has several controversies and thus requires further investigation. Specifically, the YUKON-BTX, DESTINY, and ACHILLES trials excluded patients with infrapopliteal trifurcation lesions, lesions in juxta-articular regions or lesions subject to external compression. In an attempt to address these issues, Spiliopoulos et al reported the treatment outcomes of 39 patients with infrapopliteal bifurcation disease using techniques of coronary DES placement. The mean clinical follow-up period was 47.56 ± 14.8 mo, while the mean angiographic follow-up period was 17.56 ± 12.5 mo. The application of DES across the origin of tibial vessels was proven as a safe and effective method, and was associated with satisfactory long-term angiographic and clinical outcomes. Specifically, the overall amputation-free survival and TLR-free survival at 5 years were 84.3% and 58.0%, respectively. Two-vessel primary patency (no revascularization and no > 50% angiographic restenosis of either vessel forming the target bifurcation) was 77.2%, 47.5% and 33.9%, at 12, 24 and 36 mo follow-up, while primary patency of at least one of the treated vessels was 84.0%, 65.5% and 54.5%, at 12, 24 and 36 mo. In a study that was published the following year, similar results were reported of 54.5% two-vessel primary patency and 81.8% one-vessel primary patency at 6 mo.
Another challenging issue commonly faced by medical providers is the deployment of DES in anatomic flexion points. Severe compression resulting in DES fracture at the distal third of the anterior tibial artery has been related to in-stent restenosis/reocclusion, as well as the inability to recanalize the lesion with either endovascular or surgical means. Therefore, stent placement in this area, as well as the pedal arteries, must be avoided. The concern of treating infrapopliteal DES in-stent restenosis/reocclusion has also been addressed. In a retrospective analysis of 367 patients treated with infrapopliteal DES, 54 cases of DES occlusion were noted (re-occlusion rate 11.4% within a 7 year study period), and the technical success of uneventful endovascular recanalization of DES occlusions was 90.7%. The authors concluded that intraluminal recanalization of infrapopliteal DES occlusions is safe and not technically demanding in the majority of cases.
DES occlusions have been studied using optical coherence tomography (OCT), which reveals in-stent neoatherosclerosis. The concept that antiproliferative properties of DES alter endothelial formation and function has been discussed but never proven. However, it’s thought that these properties result in increased lipid insudation and macrophage activation, which precipitate both atherosclerosis of the neointima and vascular lumen loss[37,38]. Furthermore, the stent’s durable polymer matrix acts as a source of continuous vessel irritation that triggers a local inflammatory reaction and can precipitate in-stent thrombosis. In the field of coronary disease, the phenomenon of neoatherosclerosis following both bare metal or DES has been correlated with very late acute stent thrombosis, and many authors advocate the prescription of long-term dual antiplatelet therapy to avoid late thrombotic events. Nevertheless, late stent thrombosis has never been investigated following infrapopliteal BMS placement and, therefore, whether this phenomenon is as frequent as in cases of DES placement remains to be addressed. However, according to current knowledge, the need for long-term antiplatelet coverage to reduce the risk of acute or late thrombosis after DES placement might pose some restrictions on the use of these devices. Tepe et al have investigated the administration of GP IIb/IIIa blockade with sirolimus-eluting stents (SES), bare-metal stents and PTA. SES were correlated with significantly reduced restenosis, as the 6 mo restenosis rate was 9%, 67%, and 75%, respectively.
The development of novel DES with biodegradable polymer technology aims to improve vessel re-endothelialization and further decrease complications. Initial outcomes of the application of bioabsorbable DES in 33 patients suffering from either CLI (68.4%) or claudication due to infrapopliteal vessel disease were excellent. The primary patency rates were 96% and 84.6%, and freedom from clinically-driven target lesion revascularization rates were 96% at 12 and 24 mo, respectively. Although mean lesion length was only 19.2 ± 11.6 mm, most likely due to the current availability of very short bioabsorbable DES, these results may soon lead to the implementation of this technology for CLI management.
Furthermore, a new generation of polymer-free, dedicated BTK DES is presently under investigation. Specifically, the Alvimedica Cre8TM BTK is a polymer-free, balloon-expandable platform-loaded stent with the AmphilimusTM antirestenotic agent (Sirolimus + Fatty Acid). Futhermore, the Angiolite BTK sirolimus-eluting peripheral stent (iVascular, Spain) is another balloon-expandable device consisting of a cobalt chromium alloy coated with a mix of sirolimus and last generation biostable fluorinated acrylate polymer. Clinical results from these devices are pending.
The cost-effectiveness of DES should indeed be placed under scrutiny; the direct cost of DES is higher than that of a plain balloon, while most CLI patients suffer from long multilevel tibial vessel lesions that cannot be treated with the short DES presently available. However, despite the increased direct cost, DESs appear cost-effective for the management of long infrapopliteal lesions due to the significantly reduced number of re-interventions that are required. It is generally accepted that the direct cost-reduction resulting from deeper market penetration, combined with the development of longer devices, would further improve DES cost-effectiveness.
DCBs were first introduced in coronary artery procedures, and the applications of this technology have subsequently been expanded with the goal of confronting the endovascular treatment obstacles of femoropopliteal artery atherosclerotic disease. Today, there is strong level IA evidence derived from multiple multicenter RCTs and their meta-analysis demonstrating that femoropopliteal angioplasty using DCB significantly reduces restenosis rates. This new technology to inhibit neointimal hyperplasia by administering a single dose of an antiproliferative agent within the vessel wall without the use of a permanent metallic scaffold (“leave nothing behind” concept) is rather appealing for the infrapopliteal vascular bed. As previously discussed, the distal third of the anterior tibial artery is not readily amenable to stent placement due to the compressive forces of the osseous and musculotendinous tissues in this area that can lead to stent deformations and fractures, and ultimately decreased patency rates. DCB could provide a valid solution to such limitations presented by the utilization of DES in this territory. Furthermore, long lesions can be easily treated with DCBs as the available lengths reach up to 150 mm. DCB combines balloon angioplasty with local, high-dose, cytotoxic drug delivery. The drug is coated on the balloon using special excipients, and is delivered within the arterial layers during balloon inflation to both achieve a uniform application to the vessel wall and promote the death of smooth muscle cells in the media. This allows for early intimal re-endothelialization and vessel healing. The pharmaceutical agent that is most commonly used in DCB is paclitaxel, owing to its lipophilic properties that can generate high local tissue concentrations. Although the application of DCB is less likely to compromise any future surgical revascularization procedures and can achieve a drug distribution to the target lesion that is not affected by malapposition, as in the case of DES, available evidence about the efficacy of DCB in the BTK territory has been conflicting[44-47]. Despite the initial promising results deriving from single-center studies, two industry-driven, large-scale, multicenter RCT studies failed to prove any clinical or angiographic superiority of DCB over plain PTA. Precisely, the IN.PACT DEEP study was a prospective, multicenter, RCT designed to undergo independent clinical event adjudication as well as angiographic and wound core laboratory analysis. The trial included 358 CLI patients that were randomized 2:1 to receive IN.PACT AmphirionTM paclitaxel-coated balloon (Medtronic, USA) or PTA. Despite randomization of a considerably large population, significant baseline differences were noted between the two arms in important parameters, such mean lesion length (10.2 cm for DCB vs 12.9 cm for control, P = 0.002), impaired inflow (40.7% for DCB vs 28.8% for control, P = 0.035), and previous target limb revascularization (32.2% for vs 21.8% for control, P = 0.047). No statistically significant differences were detected in the primary efficacy outcomes of clinically-driven target lesion revascularization (CD-TLR: 9.2% PCB vs 13.1% control, P = 0.291) and late lumen loss (LLL: 0.61 ± 0.78 mm for PCB vs 0.62 ± 0.78 mm for control, P = 0.950) at 1 year follow-up. The composite primary safety endpoint (6 mo all-cause mortality, major amputation, and CD-TLR) was similar between PCB (17.7%) and control (15.8%), and the non-inferiority hypothesis was met (P = 0.021). However, major amputations at 12 mo were more than double in the PCB arm and on the verge of statistical significance (8.8% vs 3.6%, P = 0.080). After safety issues were raised, the study was interrupted, and the AmphirionTM paclitaxel-coated balloon was withdrawn from the market. It has been suggested that distal embolization due to loss of balloon coating during insertion may have contributed to these poor outcomes. The company is currently recruiting patients in an RCT to investigate a novel PCB for BTK use. In the BIOLUX P-II multicenter RCT study, 72 patients were randomized in a 1:1 ratio to undergo treatment with either the Passeo-18 Lux DCB (Biotronik AG, Switzerland) or Passeo-18 PTA. In this trial, the primary endpoint of 6 mo patency loss was not significantly inferior in the DCB group vs plain balloon angioplasty (17.1% vs 26.1%, respectively, P = 0.298), while major amputations were also similar (3.3% vs 5.6% at 12 mo, respectively). The 30 d composite primary safety endpoint (all-cause mortality, target extremity major amputation, target lesion thrombosis, and target vessel revascularization) was marginally superior in the DCB group (0% PCB vs 8.3% PTA, P = 0.239). The authors would like to comment that the patency rates of plain balloon angioplasty in both studies were unexpectedly high, taking into consideration reported data from previous infrapopliteal plain balloon angioplasty studies, a fact that potentially contributed to the inability to prove the anti-restenotic effect of PCB. The reason for this discrepancy remains to be clarified. Outcomes from a new generation of DCB are also pending. Lutonix® 014 DCB (paclitaxel dose 2 µg/mm2) has been tested in a large-scale multicenter, single-arm registry, which included 314 patients from 26 sites and 12 countries. Patients suffered from either CLI or claudication due to infrapopliteal disease. Interim 6 mo results demonstrated an excellent safety profile, as freedom from major adverse limb events and perioperative death was 98.6% at 30 d and 96.0% at 6 mo, while freedom from TLR was 87.9% at 6 mo. The final 24 mo results are expected in late 2019. The RangerTM (Boston Scientific Corporation, United States), a new-generation 2 µg/mm2 DCB, is also under investigation. The single-center, open-label prospective trial sponsored by Boston Scientific has enrolled 30 CLI patients with infrapopliteal disease treated with the Ranger DCB. The study’s efficacy primary outcome measures will be primary patency at 6 mo follow-up (no stenosis > 50% of the target lesion measured by quantitative vascular angiography). The safety outcome measurement will be the number of deaths and major amputations at 6 mo follow-up. The estimated study completion date is November 2018.
DES VS DCB FOR INFRAPOPLITEAL ARTERIAL DISEASE
In 2014, Siablis et al sought to compare the efficacy of the two emerging drug-eluting technologies for long infrapopliteal lesions. The authors randomized 50 CLI patients to receive DES or DCB infrapopliteal treatment. Among the inclusion criteria was a minimum lesion length of 70 mm. The primary endpoint of 6 mo angiographic > 50% restenosis, adjudicated by quantitative vessel analysis, was significantly less in the DES group (28% vs 57.9%, P = 0.0457). Nonetheless, LLL, TLR and major amputation rates at 6 mo follow-up were similar between the two study groups. This is the only study directly comparing infrapopliteal DES vs DCB that reported that DCBs are associated with increased vessel restenosis at 6 mo, even though LLL was similar between the two groups. The authors can assume that reduced binary restenosis following DES deployment was due to a significantly superior initial luminal gain compared to DCB angioplasty. In addition, they can also assume that for small-vessel disease, maximizing the initial luminal gain could lead to less short-term binary restenosis. Nevertheless, better vessel preparation using atherectomy devices or less traumatic semi-compliant balloon catheters could also improve infrapopliteal DCB angioplasty outcomes. Indeed, the combination of DCB use with debulking atherectomy devices for the management of long, heavily calcified femoropopliteal de novo or restenotic lesions is supported by an increasing level of evidence. Orbital and directional atherectomy have been employed to remove occlusive intimal or neointimal tissue, allowing DCB to act directly on the vessel wall. Moreover, in a recent Bayesian network meta-analysis by Katsanos et al, data from RCTs investigating all endovascular treatment options for BTK arterial disease were elaborated. In total, 16 RCTs with 1,805 patients were analyzed. Median follow-up was 1 year. The authors created a network of comparisons between infrapopliteal DES, DCB, plain balloon angioplasty and BMS, and calculated the cumulative rank probabilities to provide hierarchies of these treatments. Outcomes were found to be stable upon sensitivity and meta-regression analyses. No significant publication bias or inconsistency was detected. DESs were found to significantly reduce restenosis, amputations and revascularization procedures compared to BMSs and plain balloon angioplasty. Specifically, DES reduced restenosis compared with BMS [OR 0.26, 95%Credible Interval (CrI): 0.12 to 0.51] and plain balloon angioplasty (Odds Ratio (OR) 0.22, 95%CrI: 0.11 to 0.45), and also reduced TLR compared with plain balloon angioplasty (OR 0.41, 95%CrI: 0.22 to 0.75) and BMS (OR 0.26, 95%CrI: 0.15 to 0.45) (quality of evidence high). DCBs reduced TLR compared with plain balloon angioplasty (OR 0.55, 95%CrI: 0.34 to 0.90) and BMS (OR 0.35, 95%CrI: 0.18 to 0.67) (quality of evidence low to moderate), while plain balloon angioplasty resulted in significantly less TLR than BMS (OR 0.63, 95%CrI: 0.40 to 0.99) (level of evidence high). Furthermore, DES significantly reduced limb amputations compared with plain balloon angioplasty (OR 0.58, 95%CrI: 0.35 to 0.96), DCB (OR 0.51, 95%CrI: 0.26 to 0.98), or BMS (OR 0.38, 95%CrI: 0.19 to 0.72) (quality of evidence moderate to high), and improved wound healing compared with plain balloon angioplasty (OR 2.02, 95%CrI: 1.01 to 4.07) or BMS (OR 3.45, 95%CrI: 1.41 to 8.73) (quality of evidence high). The abovementioned high level of evidence establishes DES as the dominant endovascular treatment modality for BTK disease, although these outcomes mainly relate to short-to-medium length lesions and short-to-midterm follow-up.
DRUG INFUSION CATHETERS
New elution technologies for BTK treatment include catheters that can deliver therapeutic agents directly to the vessel wall, eliminating drug loss in the circulation. The Occlusion Perfusion Catheter (Advanced Catheter Therapies, Chattanooga, TN) is a universal delivery catheter capable of delivering paclitaxel to the media by forming a treatment chamber between two occlusion balloons. Results from a small multi-center study are promising. Moreover, the infusion of dexamethasone in the adventitia of infrapopliteal arteries is also being studied. The LIMBO-PTA prospective, multicenter RCT is currently recruiting CLI patients (up to 120 participants) in up to 30 sites throughout Europe and the US in order to document the effects of adventitial delivery of dexamethasone via the Bullfrog Micro-Infusion Device (Mercator MedSystems, Inc., United States) after balloon angioplasty of infrapopliteal lesions. Patients will be randomized 1:1 to receive either the active treatment or control therapy. The study is currently recruiting patients, and the estimated study completion date is February 2020.
Level IA evidence supports the use of infrapopliteal DES for short-to-medium length lesions. New developments in DES, such as bioabsorbable, polymer-free or even longer self-expanding DES, could maximize outcomes. Large trials to prove their superiority over other endovascular technologies in longer lesions are required. DCBs are a very appealing endovascular solution for infrapopliteal artery disease due to their inherent features, which enable metal-free inhibition of vessel restenosis. However, data to prove the superiority of DCBs over plain balloon angioplasty are scarce. In a single-institution randomized comparison with DES in long infrapopliteal lesions, DES resulted in significantly less 6 mo binary restenosis. Multicenter RCTs and long-term results from large-scale registries are awaited in order to justify the use of DCBs in BTK disease. New-generation drug elution and drug infusion devices are also under investigation.
Manuscript source: Invited manuscript
Specialty type: Cardiac and cardiovascular systems
Country of origin: Greece
Peer-review report classification
Grade A (Excellent): 0
Grade B (Very good): B, B
Grade C (Good): C
Grade D (Fair): 0
Grade E (Poor): 0
P- Reviewer: Korosoglou G, Iacoviello M, Okutucu S S- Editor: Ji FF L- Editor: Filipodia E- Editor: Song H
Graziani L, Silvestro A, Bertone V, Manara E, Andreini R, Sigala A, Mingardi R, De Giglio R. Vascular involvement in diabetic subjects with ischemic foot ulcer: a new morphologic categorization of disease severity.Eur J Vasc Endovasc Surg. 2007;33:453-460.
Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG; TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).J Vasc Surg. 2007;45 Suppl S:S5-67.
Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss L, Golzarian J, Gornik HL, Jaff MR, Moneta GL, Olin JW, Stanley JC, White CJ, White JV, Zierler RE; American College of Cardiology Foundation Task Force; American Heart Association Task Force. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA Guideline Recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2013;61:1555-1570.
Karnabatidis D, Spiliopoulos S, Katsanos K, Siablis D. Below-the-knee drug-eluting stents and drug-coated balloons.Expert Rev Med Devices. 2012;9:85-94.
Spiliopoulos S, Theodosiadou V, Katsanos K, Kitrou P, Kagadis GC, Siablis D, Karnabatidis D. Long-Term Clinical Outcomes of Infrapopliteal Drug-Eluting Stent Placement for Critical Limb Ischemia in Diabetic Patients.J Vasc Interv Radiol. 2015;26:1423-1430.
Mills JL Sr, Conte MS, Armstrong DG, Pomposelli FB, Schanzer A, Sidawy AN, Andros G; Society for Vascular Surgery Lower Extremity Guidelines Committee. The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System: risk stratification based on wound, ischemia, and foot infection (WIfI).J Vasc Surg. 2014;59:220-34.e1-2.
Aboyans V, Ricco JB, Bartelink MEL, Björck M, Brodmann M, Cohnert T, Collet JT, Czerny M, De Carlo M, Debus S, Espinola-Klein C, Kahan T, Kownator S, Mazzolai L, Naylor AR, Roffi M, Röther J, Sprynger M, Tendera M, Tepe G, Venermo M, Vlachopoulos C, Desormais I; ESC Scientific Document Group. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS).Eur Heart J. 2018;39:763-816.
Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, Fowkes FG, Gillepsie I, Ruckley CV, Raab G, Storkey H; BASIL trial participants. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial.Lancet. 2005;366:1925-1934.
Verzini F, De Rango P, Isernia G, Simonte G, Farchioni L, Cao P. Results of the "endovascular treatment first" policy for infrapopliteal disease.J Cardiovasc Surg (Torino). 2012;53:179-188.
Hicks CW, Najafian A, Farber A, Menard MT, Malas MB, Black JH 3rd, Abularrage CJ. Below-knee endovascular interventions have better outcomes compared to open bypass for patients with critical limb ischemia.Vasc Med. 2017;22:28-34.
Söder HK, Manninen HI, Jaakkola P, Matsi PJ, Räsänen HT, Kaukanen E, Loponen P, Soimakallio S. Prospective trial of infrapopliteal artery balloon angioplasty for critical limb ischemia: angiographic and clinical results.J Vasc Interv Radiol. 2000;11:1021-1031.
Nasr MK, McCarthy RJ, Hardman J, Chalmers A, Horrocks M. The increasing role of percutaneous transluminal angioplasty in the primary management of critical limb ischaemia.Eur J Vasc Endovasc Surg. 2002;23:398-403.
Katsanos K, Spiliopoulos S, Krokidis M, Karnabatidis D, Siablis D. Does below-the-knee placement of drug-eluting stents improve clinical outcomes?J Cardiovasc Surg (Torino). 2012;53:195-203.
Dorros G, Hall P, Prince C. Successful limb salvage after recanalization of an occluded infrapopliteal artery utilizing a balloon expandable (Palmaz-Schatz) stent.Cathet Cardiovasc Diagn. 1993;28:83-88.
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.
Epstein SE, Speir E, Unger EF, Guzman RJ, Finkel T. The basis of molecular strategies for treating coronary restenosis after angioplasty.J Am Coll Cardiol. 1994;23:1278-1288.
Herrman JP, Hermans WR, Vos J, Serruys PW. Pharmacological approaches to the prevention of restenosis following angioplasty. The search for the Holy Grail? (Part I).Drugs. 1993;46:18-52.
Siablis D, Kraniotis P, Karnabatidis D, Kagadis GC, Katsanos K, Tsolakis J. Sirolimus-eluting versus bare stents for bailout after suboptimal infrapopliteal angioplasty for critical limb ischemia: 6-month angiographic results from a nonrandomized prospective single-center study.J Endovasc Ther. 2005;12:685-695.
Siablis D, Karnabatidis D, Katsanos K, Kagadis GC, Kraniotis P, Diamantopoulos A, Tsolakis J. Sirolimus-eluting versus bare stents after suboptimal infrapopliteal angioplasty for critical limb ischemia: enduring 1-year angiographic and clinical benefit.J Endovasc Ther. 2007;14:241-250.
Karnabatidis D, Spiliopoulos S, Diamantopoulos A, Katsanos K, Kagadis GC, Kakkos S, Siablis D. Primary everolimus-eluting stenting versus balloon angioplasty with bailout bare metal stenting of long infrapopliteal lesions for treatment of critical limb ischemia.J Endovasc Ther. 2011;18:1-12.
Duda SH, Poerner TC, Wiesinger B, Rundback JH, Tepe G, Wiskirchen J, Haase KK. Drug-eluting stents: potential applications for peripheral arterial occlusive disease.J Vasc Interv Radiol. 2003;14:291-301.
Marx SO, Jayaraman T, Go LO, Marks AR. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells.Circ Res. 1995;76:412-417.
Commeau P, Barragan P, Roquebert PO. Sirolimus for below the knee lesions: mid-term results of SiroBTK study.Catheter Cardiovasc Interv. 2006;68:793-798.
Bosiers M, Deloose K, Verbist J, Peeters P. Percutaneous transluminal angioplasty for treatment of ''below-the-knee'' critical limb ischemia: early outcomes following the use of sirolimus-eluting stents.J Cardiovasc Surg (Torino). 2006;47:171-176.
Falkowski A, Poncyljusz W, Wilk G, Szczerbo-Trojanowska M. The evaluation of primary stenting of sirolimus-eluting versus bare-metal stents in the treatment of atherosclerotic lesions of crural arteries.Eur Radiol. 2009;19:966-974.
Rastan A, Tepe G, Krankenberg H, Zahorsky R, Beschorner U, Noory E, Sixt S, Schwarz T, Brechtel K, Böhme C, Neumann FJ, Zeller T. Sirolimus-eluting stents vs. bare-metal stents for treatment of focal lesions in infrapopliteal arteries: a double-blind, multi-centre, randomized clinical trial.Eur Heart J. 2011;32:2274-2281.
Bosiers M, Scheinert D, Peeters P, Torsello G, Zeller T, Deloose K, Schmidt A, Tessarek J, Vinck E, Schwartz LB. Randomized comparison of everolimus-eluting versus bare-metal stents in patients with critical limb ischemia and infrapopliteal arterial occlusive disease.J Vasc Surg. 2012;55:390-398.
Scheinert D, Katsanos K, Zeller T, Koppensteiner R, Commeau P, Bosiers M, Krankenberg H, Baumgartner I, Siablis D, Lammer J, Van Ransbeeck M, Qureshi AC, Stoll HP; ACHILLES Investigators. A prospective randomized multicenter comparison of balloon angioplasty and infrapopliteal stenting with the sirolimus-eluting stent in patients with ischemic peripheral arterial disease: 1-year results from the ACHILLES trial.J Am Coll Cardiol. 2012;60:2290-2295.
Katsanos K, Spiliopoulos S, Diamantopoulos A, Siablis D, Karnabatidis D, Scheinert D. Wound Healing Outcomes and Health-Related Quality-of-Life Changes in the ACHILLES Trial: 1-Year Results From a Prospective Randomized Controlled Trial of Infrapopliteal Balloon Angioplasty Versus Sirolimus-Eluting Stenting in Patients With Ischemic Peripheral Arterial Disease.JACC Cardiovasc Interv. 2016;9:259-267.
Katsanos K, Spiliopoulos S, Diamantopoulos A, Karnabatidis D, Sabharwal T, Siablis D. Systematic review of infrapopliteal drug-eluting stents: a meta-analysis of randomized controlled trials.Cardiovasc Intervent Radiol. 2013;36:645-658.
Spreen MI, Martens JM, Knippenberg B, van Dijk LC, de Vries JPM, Vos JA, de Borst GJ, Vonken EPA, Bijlstra OD, Wever JJ, Statius van Eps RG, Mali WPTM, van Overhagen H. Long-Term Follow-up of the PADI Trial: Percutaneous Transluminal Angioplasty Versus Drug-Eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia.J Am Heart Assoc. 2017;6:pii: e004877.
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.Int J Surg. 2017;44:166-175.
Spiliopoulos S, Fragkos G, Katsanos K, Diamantopoulos A, Karnabatidis D, Siablis D. Long-term outcomes following primary drug-eluting stenting of infrapopliteal bifurcations.J Endovasc Ther. 2012;19:788-796.
Werner M, Scheinert S, Bausback Y, Bräunlich S, Ulrich M, Piorkowski M, Scheinert D, Schmidt A. Bifurcation stenting after failed angioplasty of infrapopliteal arteries in critical limb ischemia: techniques and short-term follow-up.Catheter Cardiovasc Interv. 2013;82:E522-E528.
Karnabatidis D, Katsanos K, Spiliopoulos S, Diamantopoulos A, Kagadis GC, Siablis D. Incidence, anatomical location, and clinical significance of compressions and fractures in infrapopliteal balloon-expandable metal stents.J Endovasc Ther. 2009;16:15-22.
Spiliopoulos S, Theodosiadou V, Fragkos G, Diamantopoulos A, Katsanos K, Siablis D, Karnabatidis D. Feasibility of endovascular recanalization of occluded infrapopliteal drug-eluting stents.J Endovasc Ther. 2014;21:392-399.
Nakazawa G, Otsuka F, Nakano M, Vorpahl M, Yazdani SK, Ladich E, Kolodgie FD, Finn AV, Virmani R. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents.J Am Coll Cardiol. 2011;57:1314-1322.
Paraskevopoulos I, Spiliopoulos S, Davlouros P, Karnabatidis D, Katsanos K, Alexopoulos D, Siablis D. Evaluation of below-the-knee drug-eluting stents with frequency-domain optical coherence tomography: neointimal hyperplasia and neoatherosclerosis.J Endovasc Ther. 2013;20:80-93.
Tepe G, Schmehl J, Heller S, Brechtel K, Heuschmid M, Fenchel M, Kramer U, Miller S, Claussen CD. Drug eluting stents versus PTA with GP IIb/IIIa blockade below the knee in patients with current ulcers--The BELOW Study.J Cardiovasc Surg (Torino). 2010;51:203-212.
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 Cardiovasc Interv. 2016;9:1721-1728.
Katsanos K, Karnabatidis D, Diamantopoulos A, Spiliopoulos S, Siablis D. Cost-effectiveness analysis of infrapopliteal drug-eluting stents.Cardiovasc Intervent Radiol. 2013;36:90-97.
Katsanos K, Spiliopoulos S, Paraskevopoulos I, Diamantopoulos A, Karnabatidis D. Systematic Review and Meta-analysis of Randomized Controlled Trials of Paclitaxel-Coated Balloon Angioplasty in the Femoropopliteal Arteries: Role of Paclitaxel Dose and Bioavailability.J Endovasc Ther. 2016;23:356-370.
Schmidt A, Piorkowski M, Werner M, Ulrich M, Bausback Y, Bräunlich S, Ick H, Schuster J, Botsios S, Kruse HJ, Varcoe RL, Scheinert D. First experience with drug-eluting balloons in infrapopliteal arteries: restenosis rate and clinical outcome.J Am Coll Cardiol. 2011;58:1105-1109.
Liistro F, Porto I, Angioli P, Grotti S, Ricci L, Ducci K, Falsini G, Ventoruzzo G, Turini F, Bellandi G, Bolognese L. 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.
Zeller T, Baumgartner I, Scheinert D, Brodmann M, Bosiers M, Micari A, Peeters P, Vermassen F, Landini M, Snead DB, Kent KC, Rocha-Singh KJ; IN. PACT DEEP Trial Investigators. Drug-eluting balloon versus standard balloon angioplasty for infrapopliteal arterial revascularization in critical limb ischemia: 12-month results from the IN.PACT DEEP randomized trial.J Am Coll Cardiol. 2014;64:1568-1576.
Zeller T, Beschorner U, Pilger E, Bosiers M, Deloose K, Peeters P, Scheinert D, Schulte KL, Rastan A, Brodmann M. 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 Cardiovasc Interv. 2015;8:1614-1622.
Herten M, Stahlhoff S, Imm B, Schönefeld E, Schwindt A, Torsello GB. [Drug-coated balloons in the treatment of peripheral artery disease (PAD). History and current level of evidence].Radiologe. 2016;56:240-253.
Randomized Study of IN. PACT 014 Paclitaxel-Coated Percutaneous Transluminal Angioplasty Balloon Catheter vs Standard Percutaneous Transluminal Angioplasty for the Treatment of Chronic Total Occlusions in the Infrapopliteal Arteries.
In: ClinicalTrials.gov [Internet]. Bethesda (MD): U.S. National Library of Medicine. Available from: URL: https://clinicaltrials.gov/ct2/show/NCT02963649 ClinicalTrials.gov Identifier: NCT02963649.
Thieme M, Lichtenberg M, Brodmann M, Cioppa A, Scheinert D. Lutonix® 014 DCB global Below the Knee Registry Study: interim 6-month outcomes.J Cardiovasc Surg (Torino). 2018;59:232-236.
An Efficacy and Safety Study to Evaluate Ranger Drug-eluting Balloon for Below the Knee Angioplasty in Patients With Critical Limb Ischemia.
In: ClinicalTrials.gov [Internet]. Bethesda (MD): U.S. National Library of Medicine. Available from: URL: https://clinicaltrials.gov/ct2/show/record/NCT02856230 ClinicalTrials.gov Identifier: NCT02856230.
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: the IDEAS randomized controlled trial.JACC Cardiovasc Interv. 2014;7:1048-1056.
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.J Cardiovasc Surg (Torino). 2018;59:51-59.
Katsanos K, Kitrou P, Spiliopoulos S, Diamantopoulos A, Karnabatidis D. Comparative Effectiveness of Plain Balloon Angioplasty, Bare Metal Stents, Drug-Coated Balloons, and Drug-Eluting Stents for the Treatment of Infrapopliteal Artery Disease: Systematic Review and Bayesian Network Meta-analysis of Randomized Controlled Trials.J Endovasc Ther. 2016;23:851-863.
Bunch F, Walker C, Kassab E, Carr J. A universal drug delivery catheter for the treatment of infrapopliteal arterial disease: Results from the multi-center first-in-human study.Catheter Cardiovasc Interv. 2018;91:296-301.
LIMBO-PTA: Lower-Limb Adventitial Infusion of DexaMethasone Via Bullfrog to Reduce Occurrence of Restenosis After Percutaneous Transluminal Angioplasty Revascularization In: ClinicalTrials.gov [Internet].
Bethesda (MD): U.S. National Library of Medicine. Available from: URL: https://clinicaltrials.gov/ct2/show/record/NCT02479555 ClinicalTrials.gov Identifier: NCT02479555.