Methods Study Design. Patient Population. Study Device. Stent Procedure and Follow-up. 312 Journal of Endovascular Therapy 24(3)

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2 312 Journal of Endovascular Therapy 24(3) Table 1. Inclusion and Exclusion Criteria. Inclusion Criteria Stenotic ( 50%) or occlusive de novo lesion or restenosis after PTA in the infrapopliteal arteries Lesion length <50 mm Reference vessel diameter 3.0 to 4.5 mm Symptomatic CLI (Rutherford category 4 or 5) Willingness to comply with specified follow-up evaluations at the specified times Greater than 18 years old Written informed consent provided Life expectancy >12 months Exclusion Criteria Untreated flow-limiting inflow lesions. Currently breast-feeding or pregnant or plans to become pregnant Previous bypass graft in target limb Major distal amputation in any limb Severe calcification in target lesion In-stent restenosis of the target lesion RVD unsuitable for available stent design Contraindication, allergy, or hypersensitivity to medication, contrast medium, or device material Currently enrolled in another investigational device or drug trial Abbreviations: CLI, critical limb ischemia; PTA, percutaneous transluminal angioplasty; RVD, reference vessel diameter. Methods Study Design The prospective, single-arm, multicenter PES-BTK-70 trial evaluated the safety and efficacy of the Stentys Stent System (Stentys SA, Paris, France) in the treatment of a single stenotic or occlusive lesion 50 mm long in the tibioperoneal arteries of patients with CLI (Rutherford categories 4 or 5). The study was conducted in 5 clinical centers in Belgium according to the Declaration of Helsinki and Good Clinical Practice, with oversight by the Flanders Medical Research Program. The protocol was approved by the ethics committees of each clinical institution, and all patients provided written informed consent. The main inclusion and exclusion criteria are given in Table 1. Eligible patients were enrolled after a guidewire was successfully delivered across the target lesion. Treatment of inflow lesions during the same procedure was allowed. Imaging studies were reviewed by an independent core laboratory (Genae Associates, Antwerp, Belgium). The trial was registered on the National Institutes of Health website (ClinicalTrials.gov identifier NCT ). Study Device The Stentys system is a self-expanding, paclitaxel-eluting, nitinol stent on a rapid exchange delivery system. The Stentys system is Conformité Européenne (CE) marked for treatment of de novo lesions in native coronary vessels involving a bifurcation or with diameter variations (eg, tapered, ectatic) and in coronary bypass grafts. The stent is coated with a stable polymer, polysulfone, containing paclitaxel, which acts by interfering with normal microtubule function thereby inhibiting cellular activities such as mitosis, migration, endocytosis, and secretion. These actions can inhibit smooth muscle cell migration, proliferation, and extracellular matrix secretion known to occur during the restenotic process in arteries. At the time of the study, the stents were available for vessel diameters from 3.0 to 4.5 mm and lengths from 22 and 27 mm. Patient Population Between January 2012 and May 2013, 70 patients (mean age 74.6±9.4 years; 45 men) with CLI [Rutherford category 4 (37, 52.9%) or 5 (33, 47.1%)] were enrolled. Risk factors and comorbidities were typical of a CLI population (Table 2) with the exception of smoking; a history of tobacco use was noted in only 20 (28.6%) patients. Calcification was found at the target lesion in 43 (61.4%) patients and ulceration in 4 (5.7%). The majority of lesions (60, 85.7%) were stenoses, with only 10 (14.3%) occlusions. The mean lesion length was 17.2 mm ( ). Stent Procedure and Follow-up Daily aspirin therapy was initiated and clopidogrel (75 mg/d) was given for at least 4 days before the procedure. 1 Department of Vascular Surgery, AZ Sint-Blasius, Dendermonde, Belgium 2 Department of Vascular Surgery, Heilig Hart Hospital, Tienen, Belgium 3 Department of Cardiovascular and Thoracic Surgery, University Hospital of Antwerp, Edegem, Belgium 4 Department of Cardiovascular and Thoracic Surgery, Imelda Hospital, Bonheiden, Belgium 5 Department of Cardiovascular and Thoracic Surgery, OLV Hospital, Aalst, Belgium Corresponding Author: Marc Bosiers, Department of Vascular Surgery, AZ Sint-Blasius, Dendermonde, Belgium. office@fmrp.be

3 Bosiers et al 313 Table 2. Characteristics of the 70 Patients Enrolled in the Study. a Age, y 74.6±9.4 (45 92) Men 45 (64.3) Nicotine abuse 20 (28.6) Hypertension 46 (65.7) Diabetes mellitus 28 (40.0) Renal insufficiency 7 (10.0) Hypercholesterolemia 30 (42.9) Obesity 11 (15.7) History of PAD 34 (48.6) History of CAD 23 (32.9) Rutherford category 4 37 (52.9) 5 33 (47.1) Lesion length, mm 17.2±8.5 ( ) Stenosis 60 (85.7) Occlusion 10 (14.3) Abbreviations: CAD, coronary artery disease; PAD, peripheral vascular disease. a Continuous data are presented as the means ± standard deviation (range); categorical data are given as the counts (percentage). Figure 1. (A) Angiographic image of a high-grade tibial artery stenosis. (B) Artery after Stentys implantation and (C) at 12-month follow-up. Alternatively, a 300-mg loading dose of clopidogrel was administered the day before the procedure). Heparin (150-U/kg bolus) was given after sheath insertion. Standard vascular access (typically contralateral for BTK lesions) and stent implantation procedures were followed at each participating site. Predilation was used at the discretion of the operator. The postprocedure antithrombotic regimen was lifelong aspirin (80 mg/d), 0.6-mL fraxiparine daily for 3 weeks, and clopidogrel (75 mg/d) for a minimum of 12 months. Patients had a duplex ultrasound scan before discharge. Follow-up visits were scheduled at 1, 6, and 12 months postoperatively. At each visit, physical examination, anklebrachial index (ABI) measurement, Rutherford category assessment, and duplex ultrasound imaging were performed. The 1-year examination also included angiography. The 6-month duplex scans were reviewed by the core laboratory. Outcomes and Definitions The primary outcome measures of the study were (1) primary patency at 6 months, defined by a peak systolic velocity ratio 2.4 at the target lesion with no clinically driven reintervention within the treated segment verified by the independent core laboratory; and (2) primary patency at 12 months, defined as absence of restenosis ( 50% stenosis) or occlusion within the target lesion based on angiography, also verified by the core laboratory. Secondary outcomes included freedom from target lesion revascularization (TLR) and limb salvage. The independent angiographic core laboratory analyzed all available 12-month follow-up data for potential crush injuries to the stent. Technical success was satisfactory implantation of the study stent. Procedure success was the ability to achieve <30% residual stenosis by visual estimation without inhospital clinically-driven target vessel revascularization, major unplanned amputation of the treated limb, or allcause mortality. Statistical Analysis Continuous data are presented as the means ± standard deviation (range); categorical data are given as the counts (percentage). Time-to-event analysis using the Kaplan-Meier method was applied to the entire patient group; estimates are given with the 95% confidence intervals (CI). All calculations were performed using IBM SPSS statistical software (version 20.0; IBM Corporation, Somers, NY, USA). Results Contralateral access was performed in the majority of cases (55, 78.6%). Inflow lesions were treated in 29 (41.4%) limbs, and further BTK procedures were performed in 12 (17.1%) cases. The mean operating time was 50±28 minutes (range ), during which a mean 102±30 ml (range ) contrast dosage was injected for fluoroscopy that averaged 15±10 minutes (range 1 65). The mean reference vessel diameter as adjudicated by the core laboratory was 2.6±0.5 mm (range ). Technical and procedure success (Figure 1) was achieved in 68 (97.1%) of 70

4 314 Journal of Endovascular Therapy 24(3) Figure 2. Kaplan-Meier graphs of 12-month cumulative (A) survival, (B) primary patency, (C) freedom from target lesion revascularization (TLR), and (D) limb salvage. Standard error did not exceed 10% at 12 months in any analysis. cases. Two patients had complications during stent deployment; both resolved uneventfully. Kaplan-Meier estimates showed a 1-year survival rate of 89.4% (95% CI 85.6 to 93.2; Figure 2A). Seven patients died; cause of death was unknown in 3 and no autopsy was performed. The other 4 died of kidney failure, stroke, a hypoglycemia coma at home, and worsening general condition. Primary patency was 87.6% (95% CI 83.5% to 91.7%) at 6 months and 72.6% (95% CI 66.9% to 78.3%; Figure 2B) at 1 year. Freedom from TLR was 79.1% at 1 year (95% CI 73.9% to 84.3%; Figure 2C) and limb salvage was 98.5% (95% CI 97% to 100%; Figure 2D). No stent fractures were found by the core laboratory review of all follow-up data available up to 12 months. In terms of clinical improvement, 40 (59.7%) of 70 patients did not have any claudication complaints at the 1-month visit; only 1 patient had a negative shift in Rutherford category. At the 6-month visit, clinical improvement was reported in 49 (80.3%) of 61 cases compared to baseline values. Only 12 of 61 patients had nonhealing wounds. At the 12-month follow-up, 43 (79.6%) of 54 patients had a 1-level improvement in their Rutherford category (Figure 3), and the mean ABI had improved 0.33 compared with baseline. Discussion As is generally known, there are some shortcomings of the balloon-expandable DES platforms because they are crushable, not flexible, and prone to fracture. In addition, balloon-expandable stents are difficult to size in arteries with tapering or ectatic diameters. 19 The Stentys self-expanding DES has been shown to have optimal wall apposition in the coronary arteries. Amoroso et al 26 found that the Stentys Figure 3. Rutherford category evolution. MFU, months of follow-up. had expanded to the same extent as the epicardial vasodilation and appeared completely apposed to the vessel wall 3 days after the procedure. van Geuns et al 27 demonstrated similar satisfactory apposition using optical coherence tomography in the APPOSITION II study. The PES-BTK-70 study evaluated if these coronary results can be replicated in the BTK vessels in a typical CLI cohort with 40% diabetics and nearly identical rates of rest pain and nonhealing ulcers. Lesions treated with the Stentys Stent System averaged 17 mm long with a large proportion of (61.4%) of calcified lesions. In the past 5 years, several randomized trials were performed to compare limus-eluting balloon-expandable stents (coronary type) with balloon angioplasty (BA) or bare metal stents (BMS) in focal BTK lesions The Achilles trial 18 demonstrated that sirolimus-eluting balloon-expandable stents may offer a promising therapeutic alternative to BA

5 Bosiers et al 315 for the treatment of infrapopliteal arterial disease. This study in 200 patients (mean lesion length 27±21 mm) observed lower restenosis rates (22.4% vs 41.9%; p=0.019) and greater vessel patency (75.0% vs 57.1%; p=0.025) after 12 months in favor of the DES. DESTINY-I (mean lesion length 15.9 mm in the DES group) found a significant (p<0.001) benefit for an everolimus-eluting balloon-expandable stent over BMS for the treatment of infrapopliteal occlusive disease. At 12 months, the primary patency rate was 85.2% in the DES group and 54.4% in the BMS group. 19 In the YUKON trial, Rastan et al 20 investigated the midterm effects of sirolimus-eluting stents vs BMS in 161 lesions with a mean length of 31±9 mm. The authors demonstrated that the event-free survival, amputation rates, and changes in Rutherford category after treatment of focal infrapopliteal lesions were significantly improved with the DES in comparison with BMS. There was a significant difference (p=0.02) in the event-free survival rate from 65.8% in the DES group and 44.6% in the BMS group. Differences were also found in the amputation rates (2.6% and 12.2%; p=0.03) and target vessel revascularization (9.2% and 20% respectively; p=0.06). In the Destiny II study, Bosiers et al 21 investigated the results of DES for longer infrapopliteal lesions, with a mean lesion length of 47.4 mm, and also found promising results in favor of the DES approach (12- month primary patency 75.4%). The 72.6% primary patency and 98.5% limb salvage at 12 months with the Stentys selfexpanding DES in the current study are not inferior to the results from these randomized trials of balloon-expandable DES. Moreover, no fractures were identified in the Stentys stent by the independent core laboratory, and 80% of patients had clinical improvement at the 6- and 12-month follow-up evaluations. A sirolimus-eluting version of the Stentys stent is now also CE-marked for coronary indications. Given that sirolimus has shown greater efficacy than paclitaxel to prevent neointimal proliferation in multiple studies, it could be of interest to evaluate the Stentys sirolimus-eluting stent in longer BTK lesions. Limitations The PES-BTK-70 study began when the Stentys Stent System was available in a diameter range between 3.0 to 4.5 mm. The core laboratory analyses indicated, however, that the vessel diameter mean was 2.6 mm (77% of patients had a vessel diameter <3 mm). This is one of the limitations of the study results, and it could be of interest to investigate the effect of the smaller radial force from the smaller diameter STENTYS stent ( mm), which is now available. Other limitations of this study are the low number of enrolled patients and the nonrandomized design of the study. Conclusion In this study, a self-expanding, nitinol, paclitaxel-eluting coronary stent was found to be safe and effective in the BTK region, with results similar to the most recent limuseluting stent trials. The flexible and noncrushable design of the Stentys stent, combined with excellent wall apposition as proven in the coronary arteries, are extra benefits of this stent system. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) received no financial support for the research, authorship, and/or publication of this article. References 1. Jaff MR, Biamino G. An overview of critical limb ischemia: today s therapeutic advances are changing the way we evaluate and treat this common and often fatal disorder. Endovascular Today. 2004;3: Adam DJ, Beard JD, Cleveland T, et al; BASIL trial participants. 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