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This study aimed to report the 5-year outcomes from the ILLUMENATE Pivotal randomized controlled trial of the lower dose (2 µg/mm 2 ) Stellarex drug-coated balloon (DCB) (Philips, formerly Spectranetics Corp, Colorado Springs, Colorado) compared with percutaneous transluminal angioplasty (PTA) for the treatment of symptomatic peripheral arterial disease. Long-term safety and effectiveness data for DCBs remains limited. The ILLUMENATE Pivotal was a prospective, randomized, multi-center, single-blinded study. Patients (Rutherford Clinical Category 2 to 4) were randomized 2:1 to Stellarex DCB or PTA. Follow-up was through 60 months. In total, 300 patients were enrolled. The mean age was 68.8 ± 10.2 years. At 60 months, freedom from a primary safety event was 69.2% in the Stellarex DCB arm and 68.2% in the PTA arm (log-rank, p = 0.623). The cumulative rate of major adverse events was 41.0% compared with 44.6% (p = 0.597), respectively. Freedom from clinically-driven target lesion revascularization (CD-TLR) was 70.3% in the Stellarex DCB arm compared with 68.2% in the PTA arm (p = 0.505). Time to first CD-TLR was 768.3 ± 478.9 days compared with 613.5 ± 453.4 days, respectively (p = 0.161). Kaplan-Meier estimates of freedom from all-cause mortality were 80.1% in the Stellarex DCB arm and 80.2% in the PTA arm (log-rank, p = 0.980). In conclusion, the 5-year results of the ILLUMENATE Pivotal randomized controlled trial add to the consistent safety data from the broader ILLUMENATE clinical program. These are the first data to report the 5-year safety and efficacy of a lower dose (2 µg/mm 2 ) DCB for the treatment of symptomatic peripheral arterial disease. Clinicaltrials.gov Registration:NCT01858428., Competing Interests: Declaration of competing interest Dr. Krishnan consultant for Medtronic and Abbott. Dr. Sachar is on the advisory board and a consultant for Medtronic and Boston Scientific. Dr. Brodmann is a Consultant for Philips. Andrew Holden is a medical advisory board member for Medtronic, Gore, Philips, Boston Scientific and a clinical investigator for Abbott, Bard-BD, Biotronik, Boston Scientific, Cagent, Cook, Efemoral, Endologix, Endospan, FluidX, Gore, Medtronic (Gore), Nectero, Philips, reflow Medical, Shape Memory, Shockwave, Terumo, and TriReme. Dr. Tarra is an employee of Philips North America, LLC. Dr. Lyden is a Consultant for BD, Boston Scientific (Merit), Contego Medical, Cordis, Endologix, Inspire MD, Medtronic, Rapid Medical, Shockwave, Penumbra, and Vivasure, holds stock in Inspire MD and Centerline Biomedical, is a board member of VIVA Physicians, and participates in research studies with Abbott (Bard), Endologix, Surmodics, W.L. Gore, Terumo Aortic, NIH, Boston Scientific, Contego Medical, Inspire MD, Reva Medical, Penumbra, Medalliance, Nectero, and Reflow Medical. The remaining authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Peripheral artery disease (PAD) can present as chronic limb threatening ischemia (CLTI) with ischemic pain and tissue loss. Progression of distal disease can lead to a "no option" or end-stage disease without traditional open or endovascular revascularization due to lack of pedal targets. Innovations in endovascular technology allow for the use of percutaneous deep vein arterialization (pDVA) to treat patients with CLTI. Purpose: We describe our experience and technique for treating four patients with end-stage PAD with pDVA. Research Design: Four patients with end-stage PAD were followed during and after pDVA creation. Technical success, complications, wound healing, and freedom from major amputation were analyzed. Data Collection and Analysis: Patient data and outcomes were collected via chart review and at time of follow up appointments in vascular surgery clinic. Results: Technical success was 100%, without post-procedural complications, and patients were continued on antiplatelet and anticoagulation. Three patients (75%) had successful wound healing, with 2 patients healing after transmetatarsal amputation (TMA), and 1 healing a distal foot ulceration that did not require surgery. One patient had worsening ischemic breakdown of a TMA, despite re-intervention on the pDVA, which required a below knee amputation (BKA). Freedom from major amputation was 75% overall, with an average follow-up time of 410 days post-procedure (Range: 113-563 days). Conclusions: Percutaneous deep vein arterialization attempts to provide blood flow to the preserved venous bed in patients with end-stage PAD. Exploration and utilization of this technique continues to expand in the modern vascular era. This case series highlights 4 patients with end-stage PVD who underwent pDVA, with 100% procedural success, and 75% limb salvage rate., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Among patients with chronic limb-threatening ischemia (CLTI) and infrapopliteal artery disease, angioplasty has been associated with frequent reintervention and adverse limb outcomes from restenosis. The effect of the use of drug-eluting resorbable scaffolds on these outcomes remains unknown., Methods: In this multicenter, randomized, controlled trial, 261 patients with CLTI and infrapopliteal artery disease were randomly assigned in a 2:1 ratio to receive treatment with an everolimus-eluting resorbable scaffold or angioplasty. The primary efficacy end point was freedom from the following events at 1 year: amputation above the ankle of the target limb, occlusion of the target vessel, clinically driven revascularization of the target lesion, and binary restenosis of the target lesion. The primary safety end point was freedom from major adverse limb events at 6 months and from perioperative death., Results: The primary efficacy end point was observed (i.e., no events occurred) in 135 of 173 patients in the scaffold group and 48 of 88 patients in the angioplasty group (Kaplan-Meier estimate, 74% vs. 44%; absolute difference, 30 percentage points; 95% confidence interval [CI], 15 to 46; one-sided P<0.001 for superiority). The primary safety end point was observed in 165 of 170 patients in the scaffold group and 90 of 90 patients in the angioplasty group (absolute difference, -3 percentage points; 95% CI, -6 to 0; one-sided P<0.001 for noninferiority). Serious adverse events related to the index procedure occurred in 2% of the patients in the scaffold group and 3% of those in the angioplasty group., Conclusions: Among patients with CLTI due to infrapopliteal artery disease, the use of an everolimus-eluting resorbable scaffold was superior to angioplasty with respect to the primary efficacy end point. (Funded by Abbott; LIFE-BTK ClinicalTrials.gov number, NCT04227899.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: No adequately powered studies exist to compare major clinical outcomes after endovascular therapy (EVT) with stent implantation vs bypass surgery (BSx) for symptomatic femoropopliteal peripheral artery disease., Objectives: This study sought to perform a pooled analysis of individual patient data from all randomized controlled trials comparing EVT vs BSx., Methods: Principal investigators of 5 of 6 available randomized controlled trials agreed to pool individual patient data. The primary endpoint was major adverse limb events, a composite of all-cause death, major amputation, or target limb reintervention. Secondary endpoints included amputation-free survival, individual major adverse limb event components, and primary patency. Early complications were bleeding, infection, or all-cause death within 30 days., Results: A total of 639 patients were analyzed with a mean age of 68.1 ± 9.1 years and 29.0% women. Baseline characteristics were comparable between groups. At 2 years, there were no significant differences between patients who received EVT and those who received BSx regarding major adverse limb events (40.1% vs 36.4%; log-rank P = 0.447; adjusted HR [aHR]: 1.04; 95% CI: 0.80-1.36), amputation-free survival (88.1% vs 90.0%; log-rank P = 0.455; aHR for death or amputation: 1.04; 95% CI: 0.63-1.71) and the other secondary endpoints except for primary patency, which was lower in patients who received EVT vs those who received BSx (51.2% vs 61.3%; log-rank P = 0.024; aHR for loss of primary patency: 1.31; 95% CI: 1.02-1.69). EVT was associated with significantly lower rates of early complications (6.8% vs 22.6%; P < 0.001) and shorter hospital stay (3.1 ± 4.2 days vs 7.4 ± 4.9 days; P < 0.001)., Conclusions: These findings further support the efficacy and safety of EVT as an alternative to BSx in patients with symptomatic femoropopliteal peripheral artery disease., Competing Interests: Funding Support and Author Disclosures Dr Enzmann has received consulting fees from the University of Innsbruck, Austria; has received honoraria for lectures from Biotronik SE and Co KG; and has received support to attend meetings from Boston Scientific. Dr Mehran has received institutional research payments from Abbott, Abiomed, Alleviant Medical, AM-Pharma, Amgen, Applied Therapeutics, Arena, AstraZeneca, BAIM, Bayer, Beth Israel Deaconess, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CellAegis, CeloNova, CERC, Chiesi, Concept Medical, CSL Behring, Cytosorbents, DSI, Duke University, Element Science, Faraday, Humacyte, Idorsia, Insel Gruppe AG, Magenta, Medtronic, Novartis, OrbusNeich, PhaseBio, Philips, Pi-Cardia, RenalPro, Shockwave, Vivasure, and Zoll; has received personal fees from Cine-Med Research and WebMD; has received consulting fees paid to the institution from Abbott, Janssen, Medtronic, and Novartis; holds equity <1% in Applied Therapeutics, Elixir Medical, Stel, and CONTROLRAD (spouse); has served on Scientific Advisory Boards for AMA, ACC (BOT Member), and SCAI (Women in Innovations Committee Member); has served as a, JAMA Associate Editor; and has served on the faculty of the Cardiovascular Research Foundation (no fee). Dr Reijnen has received consulting fees from WL Gore. Dr Krishnan has received consulting fees from Medtronic Vascular, Abbott Vascular, and Phillips. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Endovascular treatment of femoropopliteal artery disease has shifted toward drug-coated balloons (DCB). However, limited data are available regarding the safety and efficacy of DCB vs bare-metal stents (BMS)., Objectives: The purpose of this study was to compare DCB vs BMS outcomes in a propensity-adjusted, pooled analysis of 4 prospective, multicenter trials., Methods: Patient-level data were pooled from 4 prospective, multicenter studies: the IN.PACT SFA I/II and IN.PACT SFA Japan randomized controlled DCB trials and the Complete SE and DURABILITY II single-arm BMS studies. Outcomes were compared using inverse probability of treatment weighting (IPTW). Clinical endpoints were 12-month primary patency, freedom from 36-month clinically driven target lesion revascularization, and cumulative 36-month major adverse events (MAE)., Results: The primary analysis included 771 patients (288 DCB, 483 BMS). IPTW-adjusted demographic, baseline lesion, and procedural characteristics were matched between groups. The adjusted mean lesion length was 8.1 ± 4.7 cm DCB and 7.9 ± 4.5 cm BMS. The IPTW-adjusted Kaplan-Meier estimates of 12-month primary patency (90.4% DCB, 80.9% BMS, P = 0.007), freedom from 36-month clinically driven target lesion revascularization (85.6% DCB, 73.7% BMS, P = 0.001), and cumulative incidence of 36-month MAE (25.3% DCB, 38.8% BMS, P < 0.001) favored DCB. There were no statistically significant differences observed in all-cause mortality, target limb major amputation, or thrombosis through 36 months., Conclusions: In a patient-level, IPTW-adjusted pooled analysis of prospective, multicenter pivotal studies, DCB demonstrated significantly higher patency, lower revascularization and MAE rates, and no statistically significant differences in mortality, amputation, or thrombosis vs BMS. This analysis supports DCB use vs BMS in moderately complex femoropopliteal lesions amenable to both treatments., Competing Interests: Funding Support and Author Disclosures Funding was provided by Medtronic. Dr Shishehbor is a consultant and a member of advisory boards for Medtronic, Abbott Vascular, Boston Scientific, Philips, and Terumo. Prof Scheinert has received consulting fees and/or speaking honoraria from Abbott, Acotec, Alvimedica, Bayer, Boston Scientific, Cook Medical, Cardionovum, CR Bard, Gardia Medical/Allium, Medtronic, Phillips, and Upstream Peripheral Technologies. Prof Brodmann has received speaking honoraria from Bard Peripheral Vascular, Biotronik, Medtronic, Spectranetics, and VIVA Physicians; and is a consultant for Bard Peripheral Vascular, Biotronik, Medtronic, and Spectranetics. Prof Tepe has received study support from B. Braun, Biotronik, Bard, Boston Scientific, Gore, Medtronic, Cardiovascular Systems Inc (CSI), Philips, Shockwave, and Veryan. Dr Krishnan has served as a consultant to Abbott, Medtronic, and Philips. Dr Iida has received honoraria from Medtronic. Dr Laird is a part-time employee of Medtronic (employment began after the clinical study was complete). Dr Schneider has served as a member of the advisory board for Philips, Boston Scientific, and Medtronic, and has served as a consultant for Cagent, LimFlow, Medtronic, Philips, Silk Road Medical, and Surmodics. Dr Rocha-Singh is a consultant for Alucent Biomedical. Prof Zeller has received honoraria from Abbott Vascular, BIBA Medical, Biotronik, Boston Scientific Corp., Cook Medical, Efemoral, Gore & Associates, Medtronic, Philips-Spectranetics, Shockwave, and Veryan; has consulted for Boston Scientific Corp., CSI, Gore & Associates, Medtronic, Veryan, Philips-Intact Vascular, Shockwave, Bayer, and Vesper Medical Research; has received clinical trial or drug study funds from Bard Peripheral Vascular, Veryan, Biotronik, Cook Medical, Gore & Associates, Medtronic, Philips, Terumo, TriReme, Shockwave, Med Alliance, Intact Vascular, B. Braun; CSI, Boston Scientific, University of Jena, Pluristem, Philips, PQ Bypass; and has common stock with QT Medical. Drs Jain and Ando have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Sub-Optimal deployment of Self expanding interwoven stents (Supera) has been shown to increase the rate of Clinically Driven Target Lesion Revascularization (CD-TLR). Meanwhile, drug coated balloons (DCB) have been shown to reduce CD-TLR in the femoral-popliteal segment in de- novo and restenotic lesions. However, the clinical effects of vessel preparation with DCB in nominal, compressed, and elongated Supera has not been widely studied. The purpose of this study is to assess the outcomes of clinically driven re-intervention, major amputations, and mortality in relation to the use of DCB as vessel preparation in different deployment conditions (nominal, compressed, elongated) of the Supera stent. Patient chart data was collected at a single center hospital between March 2015 and May 2020. All patients were adults (≥ 18 years old) and were treated with at least one (≥ 1) Supera stent. Deployment status was extrapolated from anonymized angiograms. The primary endpoint of this study was CD-TLR. Secondary endpoints included amputation and mortality rates associated with each deployment condition. A total of 670 limbs were treated and patients were followed for 36 months. Nominal stent deployment was observed in 337 limbs, followed by elongated condition (n = 176), then by compressed conditions (n = 159). CD-TLR was observed most frequently with elongated deployment. Drug coated balloons were used as vessel prep prior to stenting and showed a protective effect regardless of deployment status; O.R = 0.44 (CI 0.30-0.66, p < .05)., (© 2022. The Author(s).)

Background: Paclitaxel-coated balloons have shown safety and efficacy in the short- to intermediate-term; however, long-term data remain limited., Objectives: To report late safety and efficacy outcomes for a low-dose paclitaxel drug-coated balloon (DCB) compared with percutaneous transluminal angioplasty (PTA) in femoropopliteal lesions from a large randomized controlled trial (RCT)., Methods: ILLUMENATE Pivotal is a multicenter, single-blind RCT conducted across 43 US and EU centers to examine the safety and efficacy of the Stellarex DCB for the treatment of femoropopliteal disease. Assessments were recorded for all active patients at 36 and 48 months. Vital status of patients formally exited from the study was also collected., Results: Primary patency through 36 months for patients treated with DCB was significantly higher compared with PTA (p=0.016). The primary safety endpoint through 36 months was 77.4% and 72.4%, respectively (p=0.377). Kaplan-Meier analysis indicated that a higher proportion of DCB subjects were event-free compared with PTA at all study visits. The rate of major adverse event (MAE) through 48 months was 32.9% in the DCB group and 37.9% in the PTA group (p=0.428). No differences in the rate of mortality were evident through 48 months of follow-up with 15.6% in the DCB group and 15.2% in the PTA group (p=0.929)., Conclusions: Stellarex DCB was associated with significantly higher patency compared with PTA through 3 years with no mortality difference detected through 4 years. The data from the ILLUMENATE Pivotal RCT support the long-term safety and efficacy of the low-dose Stellarex DCB.

Background: The objective of the RANGER II SFA long lesion cohort analysis was to evaluate the safety and effectiveness of the Ranger drug-coated balloon (DCB) in patients with lesion lengths greater than 100 mm., Methods: Patients from the RANGER II SFA randomized controlled trial and long balloon sub-study were included in the long lesion cohort if their baseline lesion measurement was > 100 mm and if they had been treated with a RANGER DCB. Patients had symptomatic lower limb peripheral artery disease and Rutherford classification 2-4 symptomatology. The endpoints of interest included the 12-month target lesion primary patency and freedom from major adverse events (MAEs).Additional patient outcomes including changes in Rutherford classification were also evaluated., Results: A total of 129 patients met the inclusion criteria and were included in the long lesion cohort. Mean lesion length was 144.5 ± 31.7 mm. Seventy-five lesions had Peripheral Arterial Calcium Scoring System (PACSS) grades 3 (33.3%, 43/129) and 4 (24.8%, 32/129). The Kaplan-Meier estimate of the primary patency rate at 12 months was 88.0%. The rate of freedom from MAEs at 12 months was 95.1% (117/123; 95% CI: 89.7%, 98.2%); all MAEs were clinically driven target lesion revascularization (4.9%, 6/123). The 12-month mortality rate was 2.4% (3/125)., Conclusions: Patients with lesions > 100 mm treated with Ranger DCBs demonstrated excellent 1-year safety and efficacy results, comparable to those of the overall RANGER II SFA randomized clinical trial. This suggests that the Ranger DCB can provide consistent results regardless of lesion length. (ClinicalTrials.gov Identifier: NCT03064126) .

Background: Drug-coated balloons (DCB) are frequently used to treat femoropopliteal artery disease. However, patency loss occurs in ≥10% of patients within 12 months posttreatment with poor understanding of the underlying mechanisms., Objectives: The authors sought to investigate the determinants of DCB failure in femoropopliteal disease., Methods: Data from randomized clinical trials (IN.PACT SFA, MDT-2113 SFA Japan) and 2 prespecified imaging cohorts of the IN.PACT Global Clinical Study were included. Influential procedural characteristics were evaluated by an independent angiographic core laboratory. The primary endpoint was DCB failure (patency loss during follow-up). Additional endpoints were binary restenosis and clinically driven target lesion revascularization. Multivariable analyses evaluated the clinical, anatomical, and procedural predictors of DCB failure., Results: Included were 557 participants with single lesions and 12-month core laboratory-adjudicated duplex ultrasonography. Key clinical characteristics were as follows: mean age 68.8 years, 67.5% male, 87.6% with hypertension, 76.9% with hyperlipidemia, 40.5% with diabetes mellitus, 90.5% in Rutherford Classification Category (RCC) 2 to 3, and 9.5% in RCC 4 to 5. Average length and reference vessel diameter (RVD) were 16.37 cm and 4.66 mm, respectively; 49.7% of lesions were totally occluded. In multivariable analysis, only residual stenosis >30% was associated with patency loss, whereas residual stenosis >30% and smaller preprocedure RVD were associated with increased binary restenosis risk. RCC >3 and residual stenosis >30% were associated with increased 12-month clinically driven target lesion revascularization risk., Conclusions: Patency loss after DCB treatment was influenced by procedural and clinical factors. Residual stenosis >30%, smaller preprocedure RVD, and higher RCC may be considered predictors of increased risk of DCB failure and its components in femoropopliteal artery disease. (Randomized Trial of IN.PACT Admiral® Drug Coated Balloon vs Standard PTA for the Treatment of SFA and Proximal Popliteal Arterial Disease [INPACT SFA I]; NCT01175850; IN.PACT Admiral Drug-Coated Balloon vs. Standard Balloon Angioplasty for the Treatment of Superficial Femoral Artery [SFA] and Proximal Popliteal Artery [PPA] [INPACT SFA II]; NCT01566461; MDT-2113 Drug-Eluting Balloon vs. Standard PTA for the Treatment of Atherosclerotic Lesions in the Superficial Femoral Artery and/or Proximal Popliteal Artery [MDT-2113 SFA]; NCT01947478; IN.PACT Global Clinical Study; NCT01609296)., Competing Interests: Funding Support and Author Disclosures The clinical studies included in this analysis were sponsored and funded by Medtronic. Data were transferred for independent analysis to the Baim Institute for Clinical Research, and the analysis was funded by Medtronic. Dr Krishnan has served as a consultant to Abbott and Medtronic. Dr Schneider has served as a member of the advisory board for Philips, Boston Scientific, and Medtronic; and has served as a consultant for Cagent, Cardiovascular Systems, Inc, Intact Vascular, Medtronic, Profusa, Silk Road Medical, and Surmodics. Dr Brodmann has received speaker honoraria from Bard Peripheral Vascular, Biotronik, Medtronic, Spectranetics, and VIVA Physicians; and is a consultant for Bard Peripheral Vascular, Biotronik, Medtronic, and Spectranetics. Dr Micari is a compensated consultant for Medtronic and Boston Scientific. Dr Sachar has served as a consultant for, an advisory board member for, and has received compensation for educational programs from Boston Scientific and Medtronic; has received funds for research or clinical trials from Abbott Vascular, Bard Peripheral Vascular, Cook Medical, W.L. Gore and Associates, Medtronic, Terumo, and Veryan; and is a major shareholder of Contego Medical. Dr Scheinert is a compensated consultant for Abbott, Acotec, Alvimedica, Bayer, Boston Scientific, Cook Medical, Cardionovum, CR Baird, Gardia Medical/Allium, Medtronic, Phillips, and Upstream Peripheral Technologies. Dr Doros is an employee of the Baim Institute for Clinical Research, which was funded by Medtronic to conduct the present analysis. Dr Tepe has received research grants from Medtronic; and is a compensated advisory board member for Medtronic. Dr Laird is an employee of Medtronic; has served on the advisory board for Abbott Vascular and Boston Scientific; has served as a consultant for Abbott Vascular, Bard/Becton Dickinson, Boston Scientific, Medtronic, and Philips; and has received speaker fees from Medtronic. Dr Zeller has received speaking honoraria from Abbott Vascular, Bard Peripheral Vascular, Biotronik, Boston Scientific, Cook Medical, Cordis, GLG, W.L. Gore & Associates, Medtronic, Philips, Spectranetics, Straub Medical, TriReme, Veryan, and VIVA Physicians; is a consultant for Abbott Vascular, Bard Peripheral Vascular, Boston Scientific, Cook Medical, W.L. Gore & Associates, Medtronic, and Spectranetics; and his clinic has received study funds or funds for research or clinical trials from 480 Biomedical, Abbott Vascular, B. Braun, Bard Peripheral Vascular, Bayer Pharma, Biotronik, Caveo Med, Contego Medical, Cook Medical, CSI, W.L. Gore & Associates, Innora, Intact Vascular, Medtronic, Mercator, Philips, Pluristem, Shockwave, Spectranetics, Terumo, TriReme, and Veryan. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: First-generation drug-coated balloons (DCBs) have significantly reduced the rate of restenosis compared with balloon angioplasty alone; however, high rates of bailout stenting and dissections persist. The Chocolate Touch DCB is a nitinol constrained balloon designed to reduce acute vessel trauma and inhibit neointima formation and restenosis., Methods: Patients with claudication or ischemic rest pain (Rutherford class 2-4) and superficial femoral or popliteal disease (≥70% stenosis) were randomized 1:1 to Chocolate Touch or Lutonix DCB at 34 sites in the United States, Europe, and New Zealand. The primary efficacy end point was DCB success, defined as primary patency at 12 months (peak systolic velocity ratio <2.4 by duplex ultrasound without clinically driven target lesion revascularization in the absence of clinically driven bailout stenting). The primary safety end point was freedom from major adverse events at 12 months, a composite of target limb-related death, major amputation, or reintervention. Both primary end points were tested for noninferiority, and if met, sequential superiority testing for efficacy followed by safety was prespecified. An independent clinical events committee, and angiographic and duplex ultrasound core laboratories blinded to treatment allocation reviewed all end points., Results: A total of 313 patients were randomized to Chocolate Touch (n=152) versus Lutonix DCB (n=161). Follow-up at 1 year was available in 94% of patients. The mean age was 69.4±9.5 years, the average lesion length was 78.1±46.9 mm, and 46.2% had moderate-to-severe calcification. The primary efficacy rates of DCB success at 12 months was 78.8% (108/137) with Chocolate Touch and 67.7% (88/130) with Lutonix DCB (difference, 11.1% [95% CI, 0.6-21.7]), meeting noninferiority ( P noninferiority <0.0001) and sequential superiority ( P superiority =0.04). The primary safety event rate was 88.9% (128/144) with Chocolate Touch and 84.6% (126/149) with Lutonix DCB ( P noninferiority <0.001; P superiority =0.27)., Conclusions: In this prospective, multicenter, randomized trial, the second-generation Chocolate Touch DCB met both noninferiority end points for efficacy and safety and was more effective than Lutonix DCB at 12 months for the treatment of femoropopliteal disease., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02924857.

Peripheral artery disease (PAD) can often present with chronic limb threatening ischemia (CLTI), including ischemic rest pain and severe tissue loss. Progression of PAD can lead to "no option" or end-stage disease in which there are no traditional open or endovascular interventions available for revascularization. This cohort of patients have a poor prognosis, with a major amputation rate of 40% and mortality of up to 20% at six months. For this patient population, surgical deep vein arterialization (DVA) is offered as an attempt to provide blood flow to the distal preserved venous bed and reverse the ischemic process. Surgical DVA has traditionally been offered as an option and was pioneered by Herb Dardik. The evolution of endovascular technology has allowed for percutaneous DVA (pDVA). Using ultrasound and fluoroscopic guidance, an arteriovenous channel is created between a tibial artery and vein and reinforced with covered stent grafts to increase distal limb perfusion with the goals of improving wound healing and amputation-free survival. Lysis of venous valves with a valvulotome also aids with reversal of flow into the distal venous system. Investigations of percutaneous deep vein arterialization are underway with one device, the LimFlow System (LimFlow SA, Paris, France), which is undergoing feasibility trials. Here we present the current clinical indications, feasibility, results, and our institutional experience with the use of percutaneous deep vein arterialization.

We assessed the clinical outcomes of patients with critical limb-threatening ischemia (CLTI) who underwent interwoven nitinol stent (Supera) implantation for significant stenoses of the femoropopliteal segment. In this retrospective cohort study, 116 consecutive patients with CLTI who were treated with Supera stents between September 2015 and March 2020 were included in this analysis. Primary endpoint analysis was completed for amputation-free survival, target lesion revascularization (TLR), and mortality. After a mean follow-up time of 3.4 years, 21 (18%) patients had undergone amputations, 3 (2.6%) died, and, overall, the amputation-free survival rate was 81%. TLR occurred in 21 (18%) patients, resulting in the freedom from target lesion revascularization of 82%. The average Wagner score for all patients was 2.8 ± 1.1. A subgroup analysis of 57 patients revealed a median ulcer size of 3.0 cm 2 [1.65, 9.0], with complete healing for 45 patients by 20 months. The Wagner score of this subgroup decreased by an average of 3.4 ± .9 points. Supera stents can be used together with other endovascular therapies and are a safe and effective treatment modality for CLTI.

Objective: To perform a meta-analysis of two concordant randomized controlled trials (RCTs) examining the long-term, 4-year safety profile of the Stellarex drug-coated balloon (DCB) vs percutaneous transluminal angioplasty (PTA) for the treatment of peripheral artery disease., Methods: An independent, third-party, meta-analysis of homogeneous, patient-level data from the ILLUMENATE Pivotal and ILLUMENATE EU RCTs was performed to assess mortality (time to death) in patients treated for symptomatic femoropopliteal disease. The Kaplan-Meier (KM) methodology was used to estimate hazard rates [HRs] of all-cause mortality, and Cox proportional hazard modeling was used to assess predictors of mortality. All serious adverse events, including deaths, were adjudicated by an independent, blinded clinical events committee., Results: In total, 589 (419 DCB; 170 PTA) patients were included in the pooled analysis of the ILLUMENATE Pivotal and ILLUMENATE EU RCTs. The median follow-up was 1735 days (interquartile range, 1434-1829 days), equivalent to 4.75 years. Vital status compliance was >95% in each RCT. The total number of deaths through 4 years was 81 of 589 (13.8%): 58 of 419 (13.8%) in the DCB arm and 23 of 170 (13.5%) in the PTA arm. The 1-year KM estimate of all-cause mortality was 1.9% ± 0.7% (estimate ±standard error) in those treated with DCB vs 1.2% ± 0.9% in those treated with PTA. At 2, 3, and 4 years, the respective KM estimates were 6.6% ± 1.2% vs 4.9% ± 1.7%, 9.3% ± 1.4% vs 9.9% ± 2.4%, and 14.0% ± 1.7% vs 14.4% ± 2.8% (P = .864). There were no significant differences in clinical events committee-adjudicated deaths between the two cohorts. In multivariate analysis, predictors of 4-year mortality were age (HR, 1.048; 95% confidence interval [CI], 1.026-1.071; P < .0001), renal insufficiency (HR, 2.440; 95% CI, 1.566-3.800; P < .0001), and lesion length (HR, 1.004; 95% CI, 1.000-1.008; P = .041). Neither paclitaxel exposure (DCB vs PTA; HR, 1.086; 95% CI, 0.709-1.664; P = .705) nor dose (mg; HR, 1.043; 95% CI, 0.971-1.119; P = .248) was the predictor of all-cause mortality at 4 years., Conclusions: This systematic meta-analysis of two concordant ILLUMENATE RCTs shows no difference in all-cause mortality through 4 years between Stellarex DCB and PTA, confirming the acceptable, long-term safety profile of the Stellarex DCB., (Copyright © 2021. Published by Elsevier Inc.)

Background: Drug coated balloon (DCB) angioplasty significantly reduces reintervention rates in patients with symptomatic femoropopliteal peripheral artery disease (PAD). However, stand-alone DCB use in long, severely calcified lesions is frequently associated with vessel recoil and/or high-grade dissections necessitating provisional stent implantation., Objectives: Assess the safety and effectiveness of a vessel preparation strategy with directional atherectomy (DA) prior to DCB angioplasty in patients with symptomatic severely calcified femoropopliteal PAD., Methods: REALITY (NCT02850107) prospectively enrolled subjects at 13 multinational centers with 8-36 cm femoropopliteal stenoses or occlusions with bilateral vessel wall calcification treated with DA prior to DCB angioplasty. The primary effectiveness endpoint was 12-month primary patency, and the primary safety endpoint was freedom from major adverse events through 30 days. Independent angiographic and duplex core laboratories assessed outcomes and a Clinical Events Committee adjudicated events., Results: A total of 102 subjects were enrolled; one lesion was treated per subject. The mean lesion length was 17.9 ± 8.1 cm, 39.0% were chronic total occlusions (mean lesion length 22.6 ± 8.6 cm); 86.2% of lesions exhibited moderate to severe bilateral calcification. Provisional stents were implanted in 8.8% (9/102) of subjects. Twelve-month primary patency rate was 76.7% (66/86) and freedom from CD-TLR rate was 92.6% (87/94). No device or procedure related deaths and one index-limb major amputation were reported., Conclusions: Plaque excision with DA in patients with symptomatic severely calcified femoropopliteal arterial disease prior to DCB angioplasty is a safe and effective treatment strategy with a low provisional stent rate., (© 2021 Wiley Periodicals LLC.)

Objective: To compare the safety and efficacy between the SpiderFX EPD and Emboshield NAV6 filter in the collection of embolic debris created from lower limb atherectomy procedures in patients with PAD., Materials and Methods: Between January 2014 and October 2015, 507 patients with symptomatic peripheral artery disease were treated with directional atherectomy (SilverHawk), rotational atherectomy (JetStream), or laser atherectomy (Turbo Elite) based on operator discretion. Emboshield NAV6 ( n  = 161) and SpiderFX ( n  = 346) embolic protection devices were used with each of the 3 atherectomy devices. The primary study endpoint was 30-day freedom from major adverse events (MAEs). An MAE was defined as death, MI, TVR, thrombosis, dissection, distal embolization, perforation at the level of the filter, and unplanned amputation. A descriptive comparison of the MAE rates between Emboshield NAV6 and SpiderFX embolic protection devices was conducted., Results: The freedom from major adverse event (MAE) rate was 92.0% (CI: 86.7%, 95.7%) in patients who received an Emboshield NAV6 filter compared to 91.6% (CI: 88.2%, 94.3%) in patients who received the SpiderFX filter ( p =0.434). The lower limit of 86.7% freedom from major adverse event rate in the Emboshield NAV6 group was above the performance goal of 83% ( p < 0.0008)., Conclusions: There were no significant clinical outcome differences between Emboshield NAV6 and SpiderFX EPD filters in the treatment of lower extremities. This evaluation indicates the safety and efficacy to use either filter device to treat PAD patients with lower extremity lesions., Competing Interests: There are no conflicts of interest., (Copyright © 2021 Prakash Krishnan et al.)

Peripheral artery disease (PAD) remains a major cause of morbidity and future cardiovascular events despite advancement in the surgical interventions and optimal medical therapy. The aim of our study is to evaluate the efficacy and safety of anticoagulation (AC) therapy for reducing cardiovascular and limb events in patients with PAD. PUBMED, Medline, and Cochrane Library were searched through 2020 for randomized clinical trials comparing major adverse cardiovascular events (MACE) and risk of major bleeding (MB), between AC and standard of care (SOC) therapy, among patients with PAD. Meta-analysis was performed using weighted pooled absolute risk difference (RD) with 95% confidence interval (CI) and fixed effects model for overall and sub-groups of full dose (FD) and low dose (LD) AC therapies. Amongst 17,684 patients from 7 different studies, the addition of AC to SOC therapy was associated with MACE reduction (RD -0.022, 95% CI -0.033 to -0.012, p <0.001) and increased MB (RD 0.02, 95% CI 0.014 to 0.025, p <0.001). For FD, MACE reduction was (RD -0.021, 95% CI -0.042 to 0.001, p = 0.061) and MB (RD 0.036, 95% CI 0.025 to 0.047, p <0.001). For LD, MACE reduction was (RD -0.023, 95% CI -0.035 to -0.011, p <0.001) and MB (RD 0.011, 95% CI 0.005 to 0.017, p <0.001). In conclusion, addition of AC to the current SOC therapy can mitigate future MACE events in patients with PAD albeit at risk of increased bleeding. LD AC is associated with an efficacy/safety net benefit compared to FD AC therapy., (Copyright © 2021. Published by Elsevier Inc.)

Background: Our aim was to review the current literature of the use of directional atherectomy (DA) in the treatment of lower extremity critical-limb ischemia., Methods: A search for relevant literature was performed in PubMed and PubMed Central on 16 April 2020, sorted by best match. Three searches across two databases were performed. Articles were included that contained clinical and procedural data of DA interventions in lower extremity critical-limb ischemia patients. All studies that were systematic reviews were excluded., Results: Eleven papers were included in this review. Papers were examined under several parameters: primary patency and secondary patency, limb salvage/amputation, technical/procedural success, complications/periprocedural events, and mean lesion length. Primary and secondary patency rates ranged from 56.3% to 95.0% and 76.4% to 100%, respectively. Limb salvage rates ranged from 69% to 100%. Lesion lengths were highly varied, representing a broad population, ranging from 30 ± 33 mm to 142.4 ± 107.9 mm., Conclusions: DA may be a useful tool in the treatment of lower extremity critical-limb ischemia.

Background: Paclitaxel drug-coated balloons (DCB) prevent recurrent claudication after angioplasty, yet data from randomized trials with incomplete follow-up have raised uncertainty regarding long-term mortality., Objectives: To evaluate the effect of paclitaxel exposure on the long-term safety and efficacy of angioplasty of femoropopliteal artery lesions in the combined IN.PACT randomized trials., Methods: The IN.PACT randomized trials (SFA, N = 331 and Japan, N = 100) each compared the DCB with standard percutaneous transluminal angioplasty (PTA) for claudication, and consented patients for 5 and 3 years, respectively. To address long-term safety, sites were requested to obtain vital status follow-up. In the pooled, updated data set, we examined the association between randomized treatment and mortality by cumulative incidence and hazard ratio (HR), and freedom from clinically driven target lesion revascularization (CD-TLR). Multivariable Cox regression with adjustment for baseline characteristics was used to evaluate the dose effect. Causes of death were adjudicated by a blinded clinical events committee that included oncologists with paclitaxel expertise., Results: The rate of long-term vital status ascertainment increased from 81% to 97% for DCB and from 85% to 97% for PTA in the IN.PACT SFA trial. The cumulative incidence of mortality was 14.7% DCB versus 12.0% PTA at 5 years, HR 1.39, log-rank p = .286. Paclitaxel dose (mg) was not an independent predictor of mortality (HR 1.02, p = .381), but was an independent predictor of reduced risk of CD-TLR (HR 0.79; p < .001). Causes of death did not differ by treatment arm., Conclusions: In pooled randomized trial data with updated vital status ascertainment, paclitaxel was associated with improved efficacy but was not associated with increased mortality., (© 2020 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Objectives: To assess 24-month outcome differences based on sex in symptomatic femoro-popliteal arterial disease of patients treated with drug-coated balloon (DCB)., Background: Peripheral artery disease affects over 12 million people in the United States. Drug-coated balloons have shown to be effective in treating patients with symptomatic femoropopliteal arterial occlusive disease. Debate remains regarding its safety and efficacy in female gender. We investigated the differential treatment effect between genders., Methods: Patients (93 females and 102 males) with symptomatic femoropopliteal arterial disease treated with DCB from November 2014 to November 2015 were included in this retrospective study. We compared the resting ankle-brachial indices (ABIs) and peak systolic velocities (PSVs) by arterial duplex between the male and female patients at 6, 12, and 24 months postintervention., Results: Females had significantly smaller vessels (4.70 ± 0.9, P = .02) and higher body mass index (BMI; 30.0 ± 3.7, P = .002) than males. Females had significantly decreased ABI and PSV at the 6-month (ABI: 0.90 ± 0.15, P = .05 and PSV: 188.30 ± 103.1, P = .02), 12-month (ABI: 0.86 ± 0.15, P < .0001 and PSV: 219.10 ± 100.10, P = .001), and at 24-month (ABI: 0.84 ± 0.2, P = .0001 and PSV: 251.0 ± 135.9, P < .0001) intervals when compared to males. Females had increased clinically driven target lesion revascularization (TLR) at 6 months (females = 8 vs males = 4, P = .22), 12 months (females = 12 vs males = 4, P = .02), and 24 months (females = 14 vs males = 6, P = .03). In simple logistic regression analysis, BMI, age, reference vessel diameter (RVD), and gender were strongly associated with target lesion restenosis. The final model included the above and it produced the following odds ratios (ORs): BMI (OR = 1.07, 95% confidence interval [CI]: 0.98-1.2), age (OR: 1.0, CI: 0.96-1.03), RVD (OR: 1.6, CI: 1.02-2.4), and gender (OR: 3.5, CI: 1.6-7.8)., Conclusion: Females treated with DCBs have significantly decreased ABI, PSVs, and an increased rate of TLR than their male counterparts.

Purpose: To investigate the cellular and extracellular changes induced by drug-coated balloons (DCB) in the treatment of superficial femoral artery (SFA) restenosis, and to compare histopathological features with those observed after plain old balloon angioplasty (POBA) from the same patients., Methods and Results: Plaque samples for five patients with SFA restenosis (first-time) after POBA were collected using atherectomy and DCB. These samples constitute the POBA restenosis group. The same five patients developed recurrent restenosis (RR) after DCB, at the same intervention site. These SFA-RR lesions were again treated using atherectomy and POBA. These samples constitute the DCB restenosis group. DCB restenosis group plaques showed significant reduction in neointima, smooth muscle cells, fibroblast densities, and Ki67 index; and increase in caspase 3, features of apoptosis and type III collagen deposition in comparison to the POBA restenosis group., Conclusion: Plaque tissue from the DCB restenosis group show reductions in neointimal thickness, cellularity, and cellular proliferation, along with increased apoptosis, and Type III collagen content. These results suggest a different mechanistic pathway for DCB restenosis, in which neointimal proliferation is reduced but reparative fibrosis is increased. The treatment for SFA-RR after DCB may therefore benefit from different forms of therapy including scaffolding, rather than recurrent anti-proliferative therapy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: A recent summary-level meta-analysis comprising randomized, controlled trials (RCTs) of femoropopliteal paclitaxel-coated balloon and stent intervention identified excess late mortality in the paclitaxel-treated patients., Methods: We evaluated the safety of the Stellarex drug-coated balloon (DCB) for femoropopliteal artery disease with an independently performed meta-analysis of patient-level data from all patients in the Stellarex femoropopliteal clinical program. To compare mortality after DCB or uncoated percutaneous transluminal angioplasty (PTA), we aggregated data from 2 RCTs comprising 419 patients treated with DCB and 170 patients treated with PTA. In an additional analysis, data were aggregated from 6 poolable Stellarex DCB studies (2 RCTs, 3 single-arm studies, and 1 registry). All serious adverse events including deaths were adjudicated by a blinded, third-party, independent Clinical Events Committee. Kaplan-Meier estimates in the RCTs were compared with restricted mean survival time. Predictors of death were assessed with hazard ratios (HRs) and Cox proportional hazards modeling., Results: Baseline characteristics were similar in the patients treated with DCB and PTA in the pooled RCT analysis, with the exception that the DCB cohort was younger (67.4±9.7 versus 69.4±9.4 years, P =0.02), smoked more frequently (86.6% versus 78.8%, P =0.02), and were less often treated for recurrent lesions (8.8% versus 14.7%, P =0.04). In the RCTs, patients treated with DCB had all-cause mortality rates that were not different from those of patients treated with PTA (Kaplan-Meier estimates 1.8±0.7% versus 1.3±0.9%, 6.5±1.2% versus 5.9±1.9%, and 9.3±1.5% versus 9.9±2.4% at 1, 2, and 3 years, respectively, P =0.86). All-cause mortality rates were similar in a 1906-patient pooled nonrandomized DCB data set (Kaplan-Meier estimates of 2.1%, 4.9%, and 7.0% at 1, 2, and 3 years, respectively). Clinical Events Committee-adjudicated causes of death were balanced between the DCB and PTA cohorts. Multivariable Cox modeling identified age (HR, 1.06; 95% CI, 1.04-1.08; P <0.001), diabetes mellitus (HR, 1.42; 95% CI, 1.01-2.00; P =0.04), congestive heart failure (HR, 1.88; 95% CI, 1.12-3.16; P =0.02), and renal insufficiency (HR, 2.00; 95% CI, 1.33-3.01; P <0.001) as predictors of mortality. Paclitaxel exposure was unrelated to mortality (HR, 1.04; 95% CI, 0.98-1.10; P =0.23)., Conclusions: The mortality rates for patients treated with the DCB and uncoated PTA were indistinguishable over 3-year follow-up. Additional patient-level, adequately powered meta-analyses with larger RCT data sets will be needed to confirm the generalizability of these findings., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02110524, NCT01858363, NCT01858428, NCT03421561, NCT01912937, NCT01927068, and NCT02769273.

Diabetes mellitus (DM) and chronic kidney disease (CKD) separately are known to facilitate the progression of medial arterial calcification (MAC) in patients with symptomatic peripheral artery disease (PAD), but their combined effect on MAC and associated mediators of calcification is not well studied. The association of MAC and calcification inducer bone morphogenetic protein (BMP-2) and inhibitor fetuin-A, with PAD, is well known. Our aim was to investigate the association of MAC with alterations in BMP-2 and fetuin-A protein expression in patients with PAD with DM and/or CKD. Peripheral artery plaques (50) collected during directional atherectomy from symptomatic patients with PAD were evaluated, grouped into no-DM/no-CKD ( n = 14), DM alone ( n = 10), CKD alone ( n = 12), and DM+CKD ( n = 14). MAC density was evaluated using hematoxylin and eosin, and alizarin red stain. Analysis of inflammation, neovascularization, BMP-2 and fetuin-A protein density was performed by immunohistochemistry. MAC density, inflammation grade and neovessel content were significantly higher in DM+CKD versus no-DM/no-CKD and CKD ( p < 0.01). BMP-2 protein density was significantly higher in DM+CKD versus all other groups ( p < 0.01), whereas fetuin-A protein density was significantly lower in DM+CKD versus all other groups ( p < 0.001). The combined presence of DM+CKD may be associated with MAC severity in PAD plaques more so than DM or CKD alone, as illustrated in this study, where levels of calcification mediators BMP-2 and fetuin-A protein were related most robustly to DM+CKD. Further understanding of mechanisms involved in mediating calcification and their association with DM and CKD may be useful in improving management and developing therapeutic interventions.

Background: Microvascular blood flow (MBF) impairment in patients with lower extremity arterial disease (LEAD) is associated with more severe major adverse limb events (MALE). The contribution of ticagrelor, a P2Y12 antagonist and an adenosine enhancer, on blood viscosity (BV) and BV-dependent MBF in LEAD is unknown. The aim of the trial is to investigate the effects of ticagrelor on BV, and explore the association of BV-dependent MBF in participants with LEAD and type 2 diabetes (T2DM)., Methods: Randomized, double-blind, double-dummy, crossover trial design that compares treatment with aspirin 81 mg/ticagrelor placebo, aspirin 81 mg/ticagrelor 90 mg twice daily and aspirin placebo/ticagrelor 90 mg twice daily on high-shear (300 s -1 ) and low-shear (5 s -1 ) BV, and laser Doppler flowmetry (LDF) in the dorsum of the feet of participants with T2DM., Results: We randomized 70 (45% female) participants aged (mean ± SD) 72 ± 9 years. The duration of LEAD was 12.3 ± 10.3 years, and 96.9% reported intermittent claudication symptoms. Use of statins was 93% (high-intensity 43%, moderate intensity 49%), renin-angiotensin-aldosterone system inhibitors (75%) and beta-blockers (61%). Treatment with ticagrelor with or without aspirin reduced high-shear BV by 5%, in both cases, while aspirin monotherapy increased high-shear BV by 3.4% (p < 0.0001). Ticagrelor with or without aspirin reduced low-shear BV by 14.2% and 13.9% respectively, while aspirin monotherapy increased low-shear BV by 9.3% (p < 0.0001). The combination of ticagrelor and aspirin increased MBF in the left foot compared to the other two treatments (p = 0.02), but not in the right foot (p = 0.25)., Conclusions: Ticagrelor should be considered in the treatment of microvascular disease in patients with LEAD and T2DM. Trial registration Registration number: NCT02325466, registration date: December 25, 2014.

Background While randomized trials have demonstrated the superiority of drug-coated balloon (DCB) angioplasty versus standard percutaneous transluminal angioplasty (PTA) in patients with femoropopliteal peripheral artery disease, the long-term durability of DCB angioplasty remains uncertain. Methods and Results IN.PACT SFA is a prospective, multicenter, randomized single-blinded trial (Randomized Trial of IN.PACT Admiral Paclitaxel-Coated Percutaneous Transluminal Angioplasty [PTA] Balloon Catheter vs Standard PTA for the Treatment of Atherosclerotic Lesions in the Superficial Femoral Artery [SFA] and/or Proximal Popliteal Artery [PPA]) that enrolled 331 subjects with symptomatic (Rutherford 2-4) femoropopliteal lesions. Subjects were randomly assigned 2:1 to the IN.PACT Admiral DCB or PTA. Assessments through 5 years included freedom from clinically driven target lesion revascularization, the primary safety end point, and major adverse events. Through 5 years, patients treated with the IN.PACT Admiral DCB demonstrated a sustained treatment effect with superior freedom from clinically driven target lesion revascularization when compared with PTA (Kaplan-Meier estimate of 74.5% versus 65.3%; log-rank P=0.020). The primary safety composite was achieved in 70.7% of subjects in the DCB and 59.6% in the PTA groups ( P=0.068). The major adverse event rate was 42.9% for DCB and 48.1% for PTA ( P=0.459). There were no device- or procedure-related deaths in either group as adjudicated by an independent and blinded Clinical Events Committee. Conclusions The IN.PACT SFA randomized trial demonstrates that the IN.PACT Admiral DCB continues to perform better than PTA through 5 years with higher freedom from clinically driven target lesion revascularization. The sustained safety and effectiveness profile of this DCB supports its use as a preferred treatment choice compared with PTA for femoropopliteal lesions. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01175850 (IN.PACT SFA phase I) and NCT01566461 (IN.PACT SFA phase II).

Background: Bivalirudin may be an effective alternative anticoagulant to heparin for use in percutaneous peripheral interventions. We aimed to compare the safety and efficacy of bivalirudin versus heparin as the procedural anticoagulant agent in patients undergoing percutaneous peripheral intervention., Methods: For this meta-analysis and systematic review, we conducted a search in PubMed, Medline, Embase, and Cochrane for all the clinical studies in which bivalirudin was compared to heparin as the procedural anticoagulant in percutaneous peripheral interventions. Outcomes studied included all-cause mortality, all-bleeding, major and minor bleeding, and access site complications., Results: Eleven studies were included in the analysis, totaling 20,137 patients. There was a significant difference favoring bivalirudin over heparin for all-cause mortality (risk ratio 0.58, 95% CI 0.39-0.87), all-bleeding (risk ratio 0.62, 95% CI 0.50-0.78), major bleeding (risk ratio 0.61, 95% CI 0.39-0.96), minor bleeding (risk ratio 0.66, 95% CI 0.47-0.92), and access site complications (risk ratio 0.66, 95% CI 0.51-0.84). There was no significant difference in peri-procedural need for blood transfusions (risk ratio 0.79, 95% CI 0.57-1.08), myocardial infarction (risk ratio 0.87, 95% CI 0.59-1.28), stroke (risk ratio 0.77, 95% CI 0.59-1.01), intracranial bleeding (risk ratio 0.77, 95% CI 0.29-2.02), or amputations (OR 0.75, 95% CI 0.53-1.05)., Conclusion: Our meta-analysis suggests that bivalirudin use for percutaneous peripheral interventions is associated with lower all-cause mortality, bleeding, and access site complications as compared to heparin. Further large randomized trials are needed to confirm the current results.

Background: The aim of this study was to compare 1-year outcomes for patients with femoropopliteal in-stent restenosis using directional atherectomy guided by intravascular ultrasound (IVUS) versus directional atherectomy guided by angiography., Methods and Results: This was a retrospective analysis for patients with femoropopliteal in-stent restenosis treated with IVUS-guided directional atherectomy versus directional atherectomy guided by angiography from a single center between March 2012 and February 2016. Clinically driven target lesion revascularization was the primary endpoint and was evaluated through medical chart review as well as phone call follow up., Conclusions: Directional atherectomy guided by IVUS reduces clinically driven target lesion revascularization for patients with femoropopliteal in-stent restenosis.

Background: Randomized controlled trials have reported favorable 1-year outcomes with drug-coated balloons (DCBs) for the treatment of symptomatic peripheral arterial disease when compared with standard percutaneous transluminal angioplasty (PTA). Evidence remains limited on the durability of the treatment effect with DCBs in the longer term., Methods and Results: IN.PACT SFA is a single-blind, randomized trial (Randomized Trial of IN.PACT Admiral Paclitaxel-Coated Percutaneous Transluminal Angioplasty [PTA] Balloon Catheter vs Standard PTA for the Treatment of Atherosclerotic Lesions in the Superficial Femoral Artery [SFA] and/or Proximal Popliteal Artery [PPA]) that enrolled 331 patients with symptomatic (Rutherford 2-4) femoropopliteal lesions up to 18 cm in length. Patients were randomized 2:1 to receive treatment with DCB or PTA. The 36-month assessments included primary patency, freedom from clinically driven target lesion revascularization, major adverse events, and functional outcomes. At 36 months, primary patency remained significantly higher among patients treated with DCB compared with PTA (69.5% versus 45.1%; log rank P <0.001). The rates of clinically driven target lesion revascularization were 15.2% and 31.1% ( P =0.002) for the DCB and PTA groups, respectively. Functional outcomes were similarly improved between treatment groups even though subjects in the DCB group required significantly fewer reinterventions versus those in the PTA group ( P <0.001 for target lesion revascularization, P =0.001 for target vessel revascularization). There were no device- or procedure-related deaths as adjudicated by an independent Clinical Events Committee., Conclusions: Three-year results demonstrate a durable and superior treatment effect among patients treated with DCB versus standard PTA, with significantly higher primary patency and lower clinically driven target lesion revascularization, resulting in similar functional improvements with reduced need for repeat interventions., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01175850 for IN.PACT SFA phase I in the European Union and NCT01566461 for IN.PACT SFA phase II in the United States., (© 2018 The Authors.)

Objectives: To propose a classification system for characterizing angiographic femoropopliteal artery restenosis patterns associated with common endovascular modalities., Background: Peripheral artery disease is a worldwide issue affecting millions of people. Despite a myriad of endovascular technologies available to treat peripheral artery disease of the femoropopliteal arteries, restenosis remains a common failure mode. Characterizing common patterns of restenosis is important to discern the potential impact of baseline patient, lesion, and procedural characteristics, as well as treatment modalities on either the primary success or the failure patterns associated with restenosis., Methods: Studies included in the analysis were from previous core laboratory-adjudicated femoropopliteal artery disease trials and registries reflecting a wide array of treatment modalities., Results: From the subjects enrolled and analyzed, there were 403 total angiograms for analysis and adjudication. Target lesion revascularization images of the 32 validation cases were evaluated for index treated length, diameter stenosis, and lesion morphology characteristics. The following lesion types are proposed: Type 1 "Focal" pattern, which may be "Edge Proximal" or "Edge Distal" depending on location; a Type 2 "Multifocal" pattern which may also exhibit edge restenosis, but may also be "Edge Bilateral"; a Type 3 "Moderate" pattern and a Type 4 "Diffuse" pattern; and finally, a Type 5 "Occlusion"., Conclusions: A classification system that enables healthcare professionals to anticipate and describe failures following the index procedure, thereby impacting the choice of options for retreatment, may facilitate consistency and standardization within the heterogeneous field of endovascular device treatments for the femoropopliteal artery., (© 2017 Wiley Periodicals, Inc.)

Background: Drug-coated balloons (DCBs) are a predominant revascularization therapy for symptomatic femoropopliteal artery disease. Because of the differences in excipients, paclitaxel dose, and coating morphologies, varying clinical outcomes have been observed with different DCBs. We report the results of 2 studies investigating the pharmacokinetic and clinical outcomes of a new DCB to treat femoropopliteal disease., Methods: In the ILLUMENATE Pivotal Study (Prospective, Randomized, Single-Blind, U.S. Multi-Center Study to Evaluate Treatment of Obstructive Superficial Femoral Artery or Popliteal Lesions With A Novel Paclitaxel-Coated Percutaneous Angioplasty Balloon), 300 symptomatic patients (Rutherford class 2-4) were randomly assigned to DCB (n=200) or standard angioplasty (percutaneous transluminal angioplasty [PTA]) (n=100). The primary safety end point was freedom from device- and procedure-related death through 30 days, and freedom from target limb major amputation and clinically driven target lesion revascularization through 12 months. The primary effectiveness end point was primary patency through 12 months. In the ILLUMENATE PK study (Pharmacokinetic Study of the Stellarex Drug-Coated Angioplasty Balloon), paclitaxel plasma concentrations were measured after last DCB deployment and at prespecified times (at 1, 4, 24 hours and at 7 and 14 days postprocedure) until no longer detectable., Results: In the ILLUMENATE Pivotal Study, baseline characteristics were similar between groups: 50% had diabetes mellitus, 41% were women, mean lesion length was 8.3 cm, and 44% were severely calcified. The primary safety end point was met (92.1% for DCB versus 83.2% for PTA, P =0.025 for superiority) and the primary patency rate was significantly higher with DCB (76.3% for DCB versus 57.6% for PTA, P =0.003). Primary patency per Kaplan-Meier estimates at day 365 was 82.3% for DCB versus 70.9% for PTA ( P =0.002). The rate of clinically driven target lesion revascularization was significantly lower in the DCB cohort (7.9% versus 16.8%, P =0.023). Improvements in ankle-brachial index, Rutherford class, and quality of life were comparable, but the PTA cohort required twice as many revascularizations. Pharmacokinetic outcomes showed that all patients had detectable paclitaxel levels after DCB deployment that declined within the first hour (54.4±116.9 ng/mL to 1.4±1.0 ng/mL)., Conclusions: The data demonstrate superior safety and effectiveness of the Stellarex DCB in comparison with PTA, and plasma levels of paclitaxel fall to low levels within 1 hour., Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifiers: NCT01858428 and NCT01912937., (© 2017 The Authors.)

Objectives: This study sought to identify an algorithm for the use of distal embolic protection on the basis of angiographic lesion morphology and vascular anatomy for patients undergoing atherectomy for femoropopliteal lesions., Background: Atherectomy has been shown to create more embolic debris than angioplasty alone. Distal embolic protection has been shown to be efficacious in capturing macroemboli; however, no consensus exists for the appropriate lesions to use distal embolic protection during atherectomy., Methods: Patients with symptomatic lower extremity peripheral artery disease treated with atherectomy and distal embolic protection were evaluated to identify potential predictors of DE. Plaque collected from the SilverHawk nose cone subset was sent to pathology for analysis to evaluate the accuracy of angiography in assessing plaque morphology., Results: Significant differences were found in lesion length (142.1 ± 62.98 vs. 56.91 ± 41.04; p = 0.0001), low-density lipoprotein (82.3 ± 40.3 vs. 70.9 ± 23.2; p = 0.0006), vessel runoff (1.18 ± 0.9 vs. 1.8 ± 0.9; p = 0.0001), chronic total occlusion (131 vs. 10; p = 0.001), in-stent restenosis (33 vs. 6; p = 0.0081), and calcified lesions (136 vs. 65; p < 0.001). In simple logistic regression analysis lesion length, reference vessel diameter, chronic total occlusion, runoff vessels, and in-stent restenosis were found to be strongly associated with macroemboli. Angiographic assessment of plaque morphology was accurate. Positive predictive value of 92.31, negative predictive value of 95.35, sensitivity of 92.31, and specificity of 95.35 for calcium; positive predictive value of 95.56, negative predictive value of 100, sensitivity of 100, and specificity of 92.31 for atherosclerotic plaque. Thrombus/in-stent restenosis was correctly predicted., Conclusions: Chronic total occlusion, in-stent restenosis, thrombotic, calcific lesions >40 mm, and atherosclerotic lesions >140 mm identified by peripheral angiography necessitate concomitant filter use during atherectomy to prevent embolic complications., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Anvar Babaev has an investigator’s agreement with Cardiovascular Systems, Inc (CSI). Akiko Maehara is employed at the Cardiovascular Research Foundation, which receives funding from CSI. Brad Martinsen is employed by CSI.

Background and Aims: Neointimal cellular proliferation of fibroblasts and myofibroblasts is documented in coronary artery restenosis, however, their role in peripheral arterial disease (PAD) restenosis remains unclear. Our aim was to investigate the role of fibroblasts, myofibroblasts, and collagens in restenotic PAD., Methods: Nineteen PAD restenotic plaques were compared with 13 de novo plaques. Stellate cells (H&E), fibroblasts (FSP-1), myofibroblasts (α-actin/vimentin/FSP-1), cellular proliferation (Ki-67), and apoptosis (caspase-3 with poly ADP-ribose polymerase) were evaluated by immunofluorescence. Collagens were evaluated by picro-sirius red stain with polarization microscopy. Smooth muscle myosin heavy chain (SMMHC), IL-6 and TGF-β cytokines were analyzed by immunohistochemistry., Results: Restenotic plaques demonstrated increased stellate cells (2.7 ± 0.15 vs.1.3 ± 0.15) fibroblasts (2282.2 ± 85.9 vs. 906.4 ± 134.5) and myofibroblasts (18.5 ± 1.2 vs.10.6 ± 1.0) p = 0.0001 for all comparisons. In addition, fibroblast proliferation (18.4% ± 1.2 vs.10.4% ± 1.1; p = 0.04) and apoptosis (14.6% ± 1.3 vs.11.2% ± 0.6; p = 0.03) were increased in restenotic plaques. Finally, SMMHC (2.6 ± 0.12 vs.1.4 ± 0.15; p = 0.0001), type III collagen density (0.33 ± 0.06 vs. 0.17 ± 0.07; p = 0.0001), IL-6 (2.08 ± 1.7 vs.1.03 ± 2.0; p = 0.01), and TGF-β (1.80 ± 0.27 vs. 1.11 ± 0.18; p = 0.05) were increased in restenotic plaques., Conclusions: Our study suggests proliferation and apoptosis of fibroblast and myofibroblast with associated increase in type III collagen may play a role in restenotic plaque progression. Understanding pathways involved in proliferation and apoptosis in neointimal cells, may contribute to future therapeutic interventions for the prevention of restenosis in PAD., Competing Interests: The authors declared that they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Smooth muscle cell proliferation and extracellular matrix formation are responsible for disease progression in de novo and restenotic atherosclerosis. Internal elastic lamella (IEL) layer maintains the structural integrity of intima, and disruption of IEL may be associated with alterations in neointima, type III collagen deposition, and lesion progression in restenosis. Nineteen restenotic plaques (12 patients) procured during peripheral interventions were compared with 13 control plaques (12 patients) without restenosis. Hematoxylin & Eosin and elastic trichrome stains were used to measure length and percentage of IEL disruption, cellularity, and inflammation score. Type I and III collagens, smooth muscle cell (smc), fibroblast density, and nuclear proliferation (Ki67) percentage were evaluated by immunohistochemistry. IEL disruption percentage (28 ± 3.6 vs 6.1 ± 2.4; p = 0.0006), type III collagen content (0.33 ± 0.06 vs 0.17 ± 0.07; p = 0.0001), smc density (2014 ± 120 vs 923 ± 150; p = 0.0001), fibroblast density (2,282 ± 297 vs 906 ± 138; p = 0.0001), and Ki67 percentage (21.6 ± 2 vs 8.2 ± 0.65; p = 0.0001) were significantly increased in restenotic plaques compared to de novo plaques. Logistic regression analysis identified significant correlation between IEL disruption and neointimal smc density (r = 0.45; p = 0.01) and with type III collagen deposition (r = 0.61; p = 0.02) in restenosis. Increased IEL disruption may trigger cellular proliferation, altering collagen production, and enhancing restenotic neointima. In conclusion, understanding the pathologic and molecular basis of restenosis and meticulous-guided interventions oriented to minimize IEL damage may aid to reduce neointimal proliferation and the occurrence of restenosis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To investigate the impact on restenosis rates of deep injury to the adventitial layer during directional atherectomy., Methods: Between 2007 and 2010, 116 consecutive patients (mean age 69.6 years; 56 men) with symptomatic femoropopliteal stenoses were treated with directional atherectomy at a single center. All patients had claudication and TASC A/B lesions in the superficial femoral or popliteal arteries. Histopathology analysis of atherectomy specimens was performed to identify adventitial injury. Clinical follow-up included physical examination and duplex ultrasound scans at 3, 6, and 12 months in all patients. The primary endpoint was the duplex-documented 1-year rate of restenosis, which was determined by a peak systolic velocity ratio <2.4. Patients were dichotomized by the presence or absence of adventitial or medial cuts as evaluated by histopathology., Results: Adventitial injury were identified in 62 (53%) of patients. There were no differences in baseline demographic and clinical features (p>0.05), lesion length (58.7±12.8 vs 56.2±13.6 mm, p=0.40), or vessel runoff (1.9±0.6 vs 2.0±0.6, p=0.37) between patients with and without adventitial injury, respectively. The overall 1-year incidence of restenosis was 57%, but the rate was significantly higher (p<0.0001) in patients with adventitial or medial injury (97%, 60/62) as compared with those without (11%, 6/54)., Conclusion: Lack of adventitial injury after atherectomy for femoropopliteal stenosis is strongly related to patency at 1 year., (© The Author(s) 2015.)

Background: The treatment of peripheral artery disease with percutaneous transluminal angioplasty is limited by the occurrence of vessel recoil and restenosis. Drug-coated angioplasty balloons deliver antiproliferative agents directly to the artery, potentially improving vessel patency by reducing restenosis., Methods: In this single-blind, randomized trial conducted at 54 sites, we assigned, in a 2:1 ratio, 476 patients with symptomatic intermittent claudication or ischemic pain while at rest and angiographically significant atherosclerotic lesions to angioplasty with a paclitaxel-coated balloon or to standard angioplasty. The primary efficacy end point was primary patency of the target lesion at 12 months (defined as freedom from binary restenosis or from the need for target-lesion revascularization). The primary safety end point was a composite of freedom from perioperative death from any cause and freedom at 12 months from limb-related death (i.e., death from a medical complication related to a limb), amputation, and reintervention., Results: The two groups were well matched at baseline; 42.9% of the patients had diabetes, and 34.7% were current smokers. At 12 months, the rate of primary patency among patients who had undergone angioplasty with the drug-coated balloon was superior to that among patients who had undergone conventional angioplasty (65.2% vs. 52.6%, P=0.02). The proportion of patients free from primary safety events was 83.9% with the drug-coated balloon and 79.0% with standard angioplasty (P=0.005 for noninferiority). There were no significant between-group differences in functional outcomes or in the rates of death, amputation, thrombosis, or reintervention., Conclusions: Among patients with symptomatic femoropopliteal peripheral artery disease, percutaneous transluminal angioplasty with a paclitaxel-coated balloon resulted in a rate of primary patency at 12 months that was higher than the rate with angioplasty with a standard balloon. The drug-coated balloon was noninferior to the standard balloon with respect to safety. (Funded by Lutonix-Bard; LEVANT 2 ClinicalTrials.gov number, NCT01412541.).

Background: Drug-coated balloons (DCBs) have shown promise in improving the outcomes for patients with peripheral artery disease. We compared a paclitaxel-coated balloon with percutaneous transluminal angioplasty (PTA) for the treatment of symptomatic superficial femoral and popliteal artery disease., Methods and Results: The IN.PACT SFA Trial is a prospective, multicenter, single-blinded, randomized trial in which 331 patients with intermittent claudication or ischemic rest pain attributable to superficial femoral and popliteal peripheral artery disease were randomly assigned in a 2:1 ratio to treatment with DCB or PTA. The primary efficacy end point was primary patency, defined as freedom from restenosis or clinically driven target lesion revascularization at 12 months. Baseline characteristics were similar between the 2 groups. Mean lesion length and the percentage of total occlusions for the DCB and PTA arms were 8.94 ± 4.89 and 8.81 ± 5.12 cm (P=0.82) and 25.8% and 19.5% (P=0.22), respectively. DCB resulted in higher primary patency versus PTA (82.2% versus 52.4%; P<0.001). The rate of clinically driven target lesion revascularization was 2.4% in the DCB arm in comparison with 20.6% in the PTA arm (P<0.001). There was a low rate of vessel thrombosis in both arms (1.4% after DCB and 3.7% after PTA [P=0.10]). There were no device- or procedure-related deaths and no major amputations., Conclusions: In this prospective, multicenter, randomized trial, DCB was superior to PTA and had a favorable safety profile for the treatment of patients with symptomatic femoropopliteal peripheral artery disease., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique Identifiers: NCT01175850 and NCT01566461., (© 2014 The Authors.)

Objectives: The purpose of the DEFINITIVE Ca(++) study was to evaluate the safety and effectiveness of directional atherectomy and distal embolic protection, used together to treat moderate to severely calcified femoropopliteal lesions., Background: Despite advances in endovascular treatment modalities, treatment of calcified lesions remains a challenge., Methods: A total of 133 subjects with 168 moderate to severely calcified lesions were enrolled. Lesions were treated with directional atherectomy devices, coupled with distal embolic protection., Results: The 30-day freedom from MAE rate was 93.1%. Per angiographic core laboratory assessment, the primary effectiveness endpoint (≤50% residual diameter stenosis) was achieved in 92.0% (lower confidence bound of 87.6%) of lesions. By core lab analysis, these results did not achieve the success criteria (90%) for the primary effectiveness objective. Per site assessment, the objective was met with the endpoint being achieved in 97.0% (lower confidence bound 93.8%). A mean residual diameter stenosis of 33.3% was achieved with the directional atherectomy device. This was further decreased to 24.1% with the use of adjunctive therapy. The proportion of asymptomatic subjects [Rutherford Clinical Category (RCC) = 0] increased from 0% at baseline to 52.3% at the 30-day follow-up visit. In total, 88.5% of subjects experienced an improvement of one or more Rutherford categories., Conclusions: The results of the DEFINITIVE Ca++ study demonstrate that the SilverHawk and TurboHawk atherectomy devices are safe and effective in the endovascular treatment of moderate to severely calcified lesions in the superficial femoral and/or popliteal arteries when used with the SpiderFX distal embolic protection device., (© 2014 The Authors. Catheterization and Cardiovascular Interventions. Published by Wiley Periodicals, Inc.)