J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 1 1 , N O . 1 0 , 2 0 1 8

ª 2 0 1 8 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N

P U B L I S H E D B Y E L S E V I E R

1-Year All-Comers Analysis ofthe Eluvia Drug-Eluting Stent forLong Femoropopliteal LesionsAfter Suboptimal Angioplasty

Theodosios Bisdas, MD, Efthymios Beropoulis, MD, Angeliki Argyriou, MD, Giovanni Torsello, MD,Konstantinos Stavroulakis, MD

ABSTRACT

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OBJECTIVES The aim of this study was to assess the performance of the fluoropolymer-based paclitaxel-eluting stent

(PES) in long femoropopliteal lesions.

BACKGROUND The new-generation fluoropolymer-based PES showed promising outcomes in short femoropopliteal

lesions. The main feature of the stent is its controlled and sustained paclitaxel release over 12 months. However, the

safety and efficacy of this technology in longer femoropopliteal lesions remain unclear.

METHODS Between March 2016 and March 2017, 62 patients were included in this analysis. Indications for

fluoropolymer-based PES deployment were insufficient luminal gain or flow-limiting dissection after plain old balloon

angioplasty in a femoropopliteal lesion. Primary patency, freedom from target lesion revascularization, amputation-free

survival, and paclitaxel-related adverse events were retrospectively analyzed for up to 1 year of follow-up.

RESULTS Lesions were de novo in 84% of patients. Mean lesion length was 20 � 12 cm, and 79% of the lesions

(n ¼ 49) were chronic total occlusions. Moderate or severe calcification was present in 42% of the lesions (n ¼ 26).

Stent implantation involved the distal superficial femoral artery and the proximal popliteal artery in 76% (n ¼ 47)

and 44% (n ¼ 27) of patients, respectively. The Kaplan-Meier estimate of primary patency and freedom from target

lesion revascularization was 87%. Amputation-free survival was 100% for patients with claudication (n ¼ 32 [52%])

and 87% in patients with critical limb ischemia (n ¼ 30 [48%]) (hazard ratio: 6.3; 95% confidence interval: 1.25 to 31.54;

p ¼ 0.052). Five aneurysm formations of the treated segments (8%) were thought to be attributable to paclitaxel.

CONCLUSIONS The fluoropolymer-based PES showed promising 1-year clinical and angiographic outcomes in

real-world long femoropopliteal lesions. The long-term impact of aneurysm formation remains to be further investigated.

(J Am Coll Cardiol Intv 2018;11:957–66) © 2018 by the American College of Cardiology Foundation.

T he technical success and durability of theendovascular therapy in patients withatherosclerotic arterial disease are depen-

dent on acute luminal gain and freedom from reste-nosis in the long run, respectively. The use of bare-metal stents as permanent scaffolds leads to excellentacute luminal gain, but it is associated with a highrate of restenosis (1,2). Although the use of drug-coated balloons (DCBs) has been suggested as an

N 1936-8798/$36.00

m the Clinic for Vascular Surgery, St. Franziskus Hospital and University C

sultant for Boston Scientific, Medtronic, Bard, and Cook Medical. Dr. Stav

ston Scientific. All other authors have reported that they have no relationsh

nuscript received February 5, 2018; revised manuscript received March 2

attractive alternative for short lesions (3), the highbailout stenting rate observed in the all-comersDCB registries and the inferior results of DCBs inlong and calcified lesions limit the performance of“leave nothing behind” strategies (4–6). Vessel prep-aration prior to paclitaxel delivery in the vessel wallmight improve the outcomes of paclitaxel-based an-gioplasty, but the lack of reimbursement, theincreased need for repeated angiography and

https://doi.org/10.1016/j.jcin.2018.03.046

linic of Muenster, Muenster, Germany. Dr. Bisdas is a

roulakis has received honoraria from Medtronic and

ips relevant to the contents of this paper to disclose.

1, 2018, accepted March 27, 2018.

ABBR EV I A T I ON S

AND ACRONYMS

CLTI = critical limb-threatening

ischemia

DCB = drug-coated balloon

PES = paclitaxel-eluting

stent(s)

POBA = plain old balloon

angioplasty

SFA = superficial femoral

artery

TLR = target lesion

revascularization

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consequently contrast medium, the higherradiation exposure, and the lack of random-ized controlled trials proving a clear benefitstill limit its applicability (7–9).

In contrast, paclitaxel-eluting stents (PES)combine the acute luminal gain of thepermanent scaffolding and the antirestenoticeffect of the antiproliferative agent. The firstgeneration of polymer-free PES showedexcellent and durable (up to 5 years) efficacyin short superficial femoral artery (SFA)lesions compared with plain old balloon an-gioplasty (POBA) and bare-metal stents (10).

However, the outcomes of polymer-free PES in longerfemoropopliteal lesions did not always confirm theinitial enthusiasm (11–13). Toward the concept ofa polymer-free stent coating, a new generation offluoropolymer-based PES (Eluvia, Boston Scientific,Marlborough, Massachusetts) was developed to pre-clude the biology of in-stent restenosis in the SFA byallowing the sustained and controlled release ofpaclitaxel over the first 12 months after stentimplantation (14).

SEE PAGE 967

At present, the performance of the Eluvia drug-eluting stent is not well investigated. Only 1 pro-spective, core laboratory–adjudicated single-armstudy including 57 patients assessed the safety andefficacy of the new stent platform in short lesions(71 � 28 mm) (15). Although freedom from targetlesion revascularization (TLR) was high, the patencyrate in this small study cohort amounted to 91%and 82% at 1 and 2 years, respectively (15). Severalprospective ongoing randomized controlled trials arenow assessing the effectiveness of the device indifferent scenarios but still in short lesions. TheREGAL (Real World Evaluation of the Eluvia Stent inSubjects With Lesions Located in the FemoropoplitealArteries) registry will assess the performance ofthe device in all comers and more complexfemoropopliteal lesions, but the results will not beavailable until 2020. Therefore, the aim of ourstudy was to assess for the first time the safety andefficacy of fluoropolymer-based PES in a real-worldstudy cohort of patients with long and complexfemoropopliteal lesions after suboptimal POBA.

METHODS

This was a single-center, retrospective analysis ofprospectively collected data, performed in line withthe requirements of the local ethics committee andadhering to the Declaration of Helsinki. All patients

provided informed consent prior to the intervention.The study was performed without financial supportfrom industry.

Between March 2016 (when the stent becamecommercially available) and March 2017, the clinicalrecords of all patients who underwent endovasculartreatment of a femoropopliteal lesion with the Eluviadrug-eluting stent were included in this study.The main criterion for stent implantation wasany recoil or flow-limiting dissection after POBA.Patients with in-stent restenosis, concomitant com-mon femoral artery stenosis, or stenosis of a bypassanastomosis were not treated with PES. Patients withadditional interventions due to iliac or infrapoplitealocclusive disease were not excluded from ouranalysis. In case of recoil after DCB angioplasty, PESdeployment was principally not performed.

All patients underwent a thorough clinicalexamination at baseline. Patient demographics andcomorbidities as well as imaging and clinical datawere prospectively collected and retrospectivelyanalyzed. Follow-up examinations were scheduled at6 and 12 months after the initial procedure. Thepatency of the treated vessels was assessed usingduplex ultrasound at each follow-up visit. In casesof clinical worsening, angiography was performed.At 6 months, radiographic control of stent integritywas performed.

Dual-antiplatelet therapy with aspirin (100 mg/day)and clopidogrel (75 mg/day) was routinely prescribedfor 3 months, followed by lifelong aspirin or clopi-dogrel monotherapy. Patients previously taking war-farin or oral anticoagulant agents were maintained onthe anticoagulant agents with additional clopidogreltherapy for 3 months after the procedure. Patient withaspirin allergy received lifelong clopidogrel.

INSTITUTIONAL PROTOCOL. Vessel preparationwas performed using a standard uncoated ballooncatheter inflated to a diameter of 1 mm less thanthe reference vessel diameter. The inflation time isstandardized at our institution (60 s). In cases of aflow-limiting dissection or residual stenosis >50%,repeated prolonged (>2 min) balloon inflation with anuncoated balloon was applied. In case of persistentsuboptimal angiographic outcomes, adjunctive im-plantation of the Eluvia stent was performed fromhealthy to healthy vessel. The maximum overlapbetween 2 stents was 1 cm. The stent was dilatedafter deployment using a standard uncoated ballooncatheter to achieve its reference diameter. In casefurther interventions for other lesions were neces-sary, these were treated upon the discretion of thetreating physician.

TABLE 1 Patient Demographics and Characteristics

Total number 62 (100)

Age, yrs 71 � 8

Men 39 (63)

Comorbidities

Arterial hypertension 57 (92)

Diabetes mellitus 23 (37)

Myocardial infarction >6 months 5 (8)

Congestive heart disease 25 (40)

Chronic obstructive pulmonary disease 12 (19)

Cerebrovascular disease 17 (27)

Chronic kidney disease 11 (18)

Dialysis 3 (5)

Current smoker 14 (23)

History of claudication 15 (24)

Previous interventions at the index limb

Peripheral bypass 2 (3)

Peripheral intervention 10 (16)

Values are n (%) or mean � SD.

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DEVICE DESCRIPTION. The Eluvia drug-elutingstent uses a dual-layer coating, which consists of aprimer n-butyl methacrylate layer, which promotesadhesion to the stent of an active layer comprisinga combination of paclitaxel and polyvinylidenefluoride-hexafluoropropylene. The polymer enablessustained and controlled release of the drug over thefirst 12 months after stent implantation. The stent isbased on the Innova bare-metal stent platform (Bos-ton Scientific), which consists of a 6-F self-expandingnitinol stent, delivered through a triaxial deliverysystem. The stent architecture combines a closed-celldesign at each end of the stent for more predictabledeployment and an open-cell design along thestent body for optimal flexibility, strength, andfracture resistance. The paclitaxel concentration is0.167 mg/mm2 stent surface area.

ENDPOINTS. The primary measure outcome of thisstudy was primary patency, defined as freedom fromsignificant restenosis or occlusion without any rein-tervention. Secondary outcomes were technicalsuccess rate, secondary patency rate, and freedomfrom clinically driven TLR. Amputation-free survivalwas also analyzed. Finally, any adverse eventconcerning the arterial wall during follow-up wasrecorded to assess the safety of prolonged paclitaxelrelease.

DEFINITIONS. Technical success was defined asresidual stenosis <30% after stent implantation.Significant restenosis was indicated by a peak systolicvelocity ratio >2.0, calculated as peak systolic flowvelocity in the lesion divided by peak systolic velocity1 cm proximal to the lesion. Secondary patency wasdefined as restored flow in the treated segment afterocclusion or restenosis. Amputation-free survival wasdefined as the time until a major amputation of theindex limb and/or death of any cause, whicheveroccurred first. A major amputation was defined as anyabove-ankle amputation. The degree of calcificationwas graded on the basis of arterial wall calciumdeposits observed during fluoroscopy. Mild calcifica-tion was defined as the presence of calcifications at1 side of the lumen with length <1 cm, whereasmoderate calcification was defined as the presence ofcalcifications at both sides of the lumen withlength <1 cm. Severe calcification was defined as thepresence of radiopacities on both sides of the arterialwall with length more than 1 cm.

STATISTICAL ANALYSIS. For the statistical analysisand graphics, MedCalc version 12.4.0.0 (MedCalcSoftware, Ostend, Belgium) was used. Continuousvariables are presented as mean � SD or as median

(interquartile range), while categorical data areexpressed as counts. Continuous numeric variableswere compared using the Student’s t-test for pairedsamples or the Wilcoxon test according to theirdistribution (D’Agostino-Pearson test). Cumulativeprimary and secondary patency, as well as freedomfrom TLR and amputation-free survival, were esti-mated using the Kaplan-Meier method and comparedusing the log-rank test between the group of patientswith claudication and those with critical limb-threatening ischemia (CLTI). The Kaplan-Meiercurves were truncated when the standard errorexceeded 10%. A logistic regression analysis wasperformed to identify risk factors for patency loss.The risk factors included were severe or moderatecalcium versus mild or no calcium, P1 versus no P1involvement, lesion length $150 mm versus lesionlength <150 mm, and occlusion versus stenosis. Thethreshold of statistical significance was p # 0.05.

RESULTS

BASELINE CHARACTERISTICS. Sixty-two patientswere included into this study. Table 1 summarizes thebaseline characteristics of the study cohort. Inthe clinical setting, 32 patients (52%) presented withlife-style-limiting claudication (Rutherford class 3)and 30 patients (48%) with CLTI (Rutherford class 4,n ¼ 14 [23%]; class 5, n ¼ 10 [16%]; class 6, n ¼ 6[10%]). The median pre-operative ankle-brachialindex was 0.5 (interquartile range: 0.39 to 0.70).Table 2 provides an overview of the lesions’

TABLE 2 Lesion Characteristics

Minimum luminal diameter, mm 0.06 � 0.17

Occlusion 49 (79)

Moderate/severe Ca2þ 26 (42)

Location

Proximal SFA 33 (53)

Middle SFA 43 (69)

Distal SFA 47 (76)

P1 segment 27 (44)

P2 segment 2 (3)

Runoff status

0 vessel 1 (2)

1 vessel 11 (18)

$2 vessels 50 (80)

Values are mean � SD or n (%).

SFA ¼ superficial femoral artery.

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characteristics. The majority of lesions (84%) were denovo. Mean lesion length was 20 � 12 cm, and 79% ofthe lesions were chronic total occlusions. The mediannumber of implanted stents was 1.5 stent per limb(interquartile range: 1 to 3). A concomitant endovas-cular intervention was performed in 27 patients (44%)(Table 3).

EARLY OUTCOMES. The technical success rateamounted to 98% (n ¼ 61). In 1 patient, a residualstenosis of 50% remained because of the severecalcification at the origin of the SFA. No other adverseevents during stent implantation were observed.Access site–related complications included 2 hema-tomas without evidence of false aneurysm formation.In 7 patients with CLTI (11%), minor amputation wasperformed. The post-operative ankle-brachial indexwas 1.00 (interquartile range: 0.91 to 1.10;p < 0.0001). Fourteen patients (23%) received oralanticoagulation plus clopidogrel at discharge.

TABLE 3 Additional Intraoperative Non-Device-Related

Procedures

DCB angioplasty at P1/P2 segment 8 (13)

Bare-metal stenting at the common iliac artery 4 (6)

DCB angioplasty, proximal SFA 5 (8)

DCB angioplasty, distal SFA 1 (2)

Balloon angioplasty, peroneal artery 1 (2)

Directional atherectomy and DCB angioplasty, P2 segment 1 (2)

DCB, external iliac artery 1 (2)

Balloon angioplasty, anterior tibial artery 2 (3)

Cutting balloon angioplasty of the SFA 2 (3)

Rotational thrombectomy and DCB 1 (2)

Stent graft in the SFA because of severe iatrogenicarteriovenous fistula

1 (2)

Values are n (%).

DCB ¼ drug-coated balloon; SFA ¼ superficial femoral artery.

OUTCOMES DURING FOLLOW-UP. The medianfollow-up duration was 13.3 months (interquartilerange: 12.0 to 16.5). Primary patency at 12 months was87% (Figure 1). Only 1 patient had a Tosaka class IIin-stent restenosis, whereas all other cases developedTosaka class III in-stent occlusions. An acute(<4 weeks) stent thrombosis was observed in a singlepatient. All patients with patency loss were symp-tomatic and underwent TLR, thus freedom from TLRwas 87% as well. The endovascular reinterventionsperformed consisted of rotational thrombectomy(Rotarex, Straub Medical, Dusseldorf, Germany)combined with DCB angioplasty in 3 patients,rotational thrombectomy and stent graft deployment(Viabahn, Gore, Flagstaff, Arizona) in 2 subjects, anddirectional atherectomy (Hawk One, Medtronic,Minneapolis, Minnesota) with antirestenotic therapyin the case of Tosaka class II in-stent restenosis(n ¼ 1). A femoropopliteal bypass below the knee wasindicated in 2 additional patients. Secondary patencywas 96% at 12 months. The logistic regression analysisdid not reveal any statistically significant risk factorfor patency loss. No stent fractures were observed at6 months in 48 patients who underwent radiography.

Amputation-free survival was 100% in patientswith claudication and 87% in those with critical limbischemia (hazard ratio: 6.3; 95% confidence interval:1.25 to 31.54; p ¼ 0.052). Two patients underwentmajor amputations (at 2 and 6 months) during thefirst 12 months, and 3 patients died during the first 12months (septic shock at 8 months and acute coronarysyndrome at 30 days and 8 months). Figure 2 presentsthe clinical improvement of the study cohort on thebasis of the Rutherford category during follow-up(Rutherford stage 1 or 2, n ¼ 56 [90.3%]; Rutherfordstage 3, n ¼ 2 [3.3%]; Rutherford stage 5, n ¼ 2 [3.3%]).

Duplex ultrasound revealed aneurysmal degener-ation of the arterial wall (mean diameter 14 mm) in5 patients (8%), which was thought to be attributableto stent deployment (Figure 3). All but 1 patient wereasymptomatic and received dual-antiplatelet therapyfor 6 months and re-evaluation with duplex ultra-sound every 6 months. No peripheral embolization oraneurysm rupture was observed. Of note, all caseswere de novo chronic total occlusions without anyprevious treatment with paclitaxel-eluting technolo-gies. Two of the cases were treated subintimally,while 3 cases were crossed intraluminally. None ofthe lesions were treated using atherectomy prior tostent implantation. In 1 patient (20%), an acute stentthrombosis was observed (Figure 4). In this patient,magnetic resonance angiography of the stent wasperformed before the occlusion to assess the possibleinflammation of the wall (Figures 4A to 4C). At that

FIGURE 2 Clinical Improvement in Rutherford Class Between Baseline and

Last Follow-Up

FIGURE 1 Primary Patency at 12 Months

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time the patient was asymptomatic. Two weeks later,the patient presented with clinical worsening (Ruth-erford class 4). The stent was occluded (Figure 4D),and a femoropopliteal bypass was performed.Immunohistological analysis of the arterial wallrevealed an overexpression of CD3þ, CD56þ T cells(Figure 5).

DISCUSSION

The new-generation fluoropolymer-based PES led to aprimary patency rate of 87% in long and complex SFAlesions after suboptimal angioplasty. Freedom fromTLR was also 87% (i.e., all cases of in-stent stenosis orocclusion were symptomatic). Because of the limitednumber of adverse events, no clear association ofpatency loss or TLR with any of the well-known riskfactors could be observed. Finally, the continuouselution of paclitaxel over 12 months did not seemto negatively affect patients with CLTI comparedwith those with intermittent claudication (p ¼ 0.052).In summary, the overall performance of the devicecould justify its use in long SFA and proximalpopliteal atherosclerotic lesions.

Generally, the updated guidelines of the EuropeanSociety of Cardiology and Vascular Surgery recom-mend a bypass-first approach in long ($25 cm)femoropopliteal lesions, if the patient is not athigh risk, an autologous vein is available, and lifeexpectancy is >2 years (16). This recommendationconsiders the need for preservation of the landingzones for potential bypass grafts after endovasculartreatment and is based on the results of the BASIL(Bypass Versus Angioplasty in Severe Ischaemia ofthe Leg) trial (17). However, the BASIL trial includedonly balloon angioplasty in the treatment group (17).Because a relevant number of patients do not meetthe aforementioned criteria for bypass surgery andbecause of the lack of a head-to-head comparisonbetween novel endovascular modalities and bypasssurgery, a further assessment of alternative mini-mally invasive approaches is warrantable (18). In thiscontext, the CRITISCH (First-Line Treatment Strate-gies in Patients With Critical Limb Ischemia) registryshowed statistically noninferior performance of theendovascular therapy in comparison with bypasssurgery in the interim analysis of matched CLTIcohorts (19).

In any case, the currently available endovasculartreatment options for patients with long SFA lesionscan be classified as nonantiproliferative and anti-proliferative strategies. In the first group, bare-metalstents have shown a high rate of technical success(i.e., acute luminal gain) but a high restenosis rate in

the long run. For instance, the Durability-200 study,which assessed the performance of the ProtégéEverflex 200-mm nitinol stent in Trans-AtlanticInter-Society Consensus Document C and D lesionsrevealed a 12-month primary patency rate of 65% withstent fracture of 6% (2). Similarly, the low-profilePulsar-18 nitinol stent showed a primary patencyrate of 77% in the SFA Trans-Atlantic Inter-SocietyConsensus Document D registry at 1 year (20).Of note, the study cohort was small (n ¼ 22), and aspot-stenting strategy was undertaken. Morecurrently, the RAPID trial showed a 12-month primarypatency rate of 62% in intermediate and long

FIGURE 4 Additional Imaging in a Patient With Aneurysmatic Degeneration of the Arterial Wall 1 Year After Implantation of a

Polymer-Based PES

(A to C) Double inversion recovery (DIR) fat-suppressed T1 and T2 magnetic resonance sequences without pre- and post-contrast (gadolinium)

in a patient with aneurysmal degeneration of the superficial femoral artery after fluoropolymer-based paclitaxel-eluting stent implantation.

(D) Computed tomographic angiography to confirm occlusion of the stent in the same patient.

FIGURE 3 Aneurysmal Degeneration of the Arterial Wall in the Superficial Femoral Artery After Eluvia Stent Implantation in 5 Patients

No blood flow was identified outside the stent.

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FIGURE 5 Macroscopic Image and Immunohistological Analysis Arterial Wall Degeneration 1 Year After Implantation of a

Polymer-Based PES

(A) Macroscopic image and (B to D) immunohistological analysis of the arterial wall in the patient with the occluded stent and aneurysmal

degeneration of the arterial wall: (B) thin infiltration with CD20þ B cells, (C) overexpression of CD3þ T cells, and (D) increased expression

of CD56þ T cells.

TABLE 4 Overview of the Trials and Registries Reporting on the Patency of the

Zilver PTX Stent in Long Superficial Femoral Artery Lesions

Study Name/First Author (Ref. #) n

Mean LesionLength, mm

ChronicTotal

OcclusionCalcification(Severe)

PrimaryPatency

FreedomFrom TLR

Zilver PTX single-arm study(11)

135 226.1 77.6% 85.4%

STELLA PTXregistry (12)

45 252 NR NR 56.3% 63.6%

Zeller et al. (23) 97 195 63% 79% (9%) NR w80%*

ZEPHYR trial (13) 690 170 45% 65% (NR) NR† NR

Zilver PTX Post MarketRegistry in Japan (24)

907 147 42% NR 86% 91%

*Approximately calculated by Kaplan-Meier curve. †The 1-year restenosis rate was 37%.

NR ¼ not reported; TLR ¼ target lesion revascularization.

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femoropopliteal lesions (mean lesion length 15.8 cm)treated using the Supera stent alone (21). Finally, theViabahn-25cm trialists observed a 67% primarypatency rate at 1 year (22).

In the group of antiproliferative treatment strate-gies, the SFA-Long study showed a primary patencyrate of 83% for a mean lesion length of 25.1 cm with an11% bailout stenting rate (6). Zeller et al. (23) reportedoutcomes from a retrospective registry comparingpolymer-free PES with DCBs in long SFA lesions(mean lesion length 19 cm); no statistically significantdifference regarding 12-month freedom from TLRor event-free survival between the groups wasobserved. However, stratification of TLR and event-free survival to DCB only, DCB with provisionalstenting (18%), and PES showed a trend toward betteroutcomes for the DCB plus provisional stent cohort.In fact, the polymer-free PES has been investigatedcomprehensively with very controversial results(Table 4). The Zilver PTX Global registry showed a12-month primary patency rate of 78% with a 2.1%stent fracture rate (mean lesion length 22.6 cm), and

the Zilver PTX Post-Market Study in Japan founda primary patency rate of 86% (mean lesion length14.7 cm) (11). In contrast, the STELLA PTX registryshowed a primary patency rate of 53% at 12 monthswith a stent fracture rate of 9% (mean lesion length25 cm), whereas the ZEPHYR (Zilver PTX for the

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Femoral Artery and Proximal Popliteal Artery - Pro-spective Multicenter Registry) investigators observed37% restenosis rate at 1 year (12,13). In the latterstudy, lesion length $16 cm was an independentpredictor of restenosis of the PES (13).

Taking into consideration the aforementionedresults of the endovascular treatment of long SFAlesions, the results of our study justify the use ofthe Eluvia stent as a primary treatment strategy.At present, the device has been investigated only inthe framework of the prospective MAJESTIC (Stentingof the Superficial Femoral and/or Proximal PoplitealArtery Project) trial (15). Although the study cohortwas small and the study had a single arm, the lesioncharacteristics were challenging: involvement ofdistal SFA in 77% and of the P1 segment in 8% of thecohort, severe calcification in 65%, and chronic totalocclusions in 46%. Our study included longer andmore complex lesions with 48% patients with CLTI,P1 involvement in 44%, and chronic total occlusionsin 79% of the patients. Moreover, in our trial themedian number of implanted stents was 1.5 comparedwith only 1 stent in the MAJESTIC trial. Of note, noaneurysm formation was reported during the follow-up period by the MAJESTIC trialists.

Indeed, the aneurysm formation was an unex-pected finding of our study considering the low doseof paclitaxel on the stent platform (0.167 mg/mm2

stent surface area). The precise pathophysiology ofthis phenomenon remains unknown. Data from thecoronary arteries suggest that the combination ofvessel injury induced during stent implantation andof paclitaxel-associated impaired vascular healingcontribute jointly to vessel wall degeneration (25–28).Farb et al. (26) reported a dose-dependent increasein fibrin deposition and medial necrosis after PESimplantation in the rabbit iliac artery. The immuno-histological analysis of the arterial wall in our patientrevealed excessive CD3þ and CD56þ T-cell infiltrationof the arterial wall (Figure 5). Excessive positiveremodeling, hypersensitivity reactions triggered fromthe stent platform or the drug carrier (polymer), andbacterial arteritis have additionally been related to anincreased risk for aneurysmal degeneration(25,27,28). Furthermore, the development of coronaryaneurysms after PES implantation was higher amongpatients who presented initially with chronic totalocclusions and longer lesions as well as in cases ofpost-DCB dissections and overlapping stents(25,27,28). Although the development of coronaryartery aneurysms remains a rare event, it is relatedto considerable thrombotic complications, majoradverse events, and morbidity (25,27,28). In our

cohort, the rate of aneurysmal degeneration amoun-ted to 8% and a 20% occlusion rate.

Although late incomplete stent apposition hasbeen reported after polymer-free PES deployment(27), the combination of prolonged paclitaxel releaseand of the drug carrier might together lead to higherrates of aneurysm formation. Additionally, thecomplexity of the included lesions might furthercontribute to the high observed degeneration rates.Up to now, little is known regarding the naturalhistory of paclitaxel-associated aneurysms in the pe-ripheral vasculature. Given the high rates of throm-botic events observed in the coronary arteries,prolonged dual-antiplatelet therapy and close post-procedural surveillance seem reasonable and wererecommended to our patients. The recommendedduration according to the MAJESTIC trial is 60 days,but there is not sufficient evidence to support this.Probably prolonged dual-antiplatelet treatment up to12 months should be reevaluated, considering alsoprevious angioscopic studies, which showedenlargement of the extrastent lumen from 6 to 12months after polymer-free PES implantation (29) anddifferent vascular healing responses between PES andbare-metal stents (30).

STUDY LIMITATIONS. The retrospective nature ofthis study, the lack of a control group, and theabsence of core laboratory adjudication were signifi-cant limitations of this analysis. The limited numberof events and the small number of patients includedin this study allowed no meaningful analysis con-cerning specific subgroups. The additional proced-ures and the mixed population of both patients withclaudication and those with CLTI were also limita-tions of the study, although our primary focus was onthe angiographic result after POBA regardless type ofclinical symptomatology. Finally, the vast majority ofpatients received the 6 � 150 cm Eluvia drug-elutingstent, which was removed from the market becauseof malfunction of the triaxial system during implan-tation. Such an adverse event was not observed in ourstudy cohort.

CONCLUSIONS

Despite the continuous development of endovascularmodalities, the treatment of long femoropopliteallesions remains a challenge. In this study, the use of apolymer-based PES platform led to encouraging out-comes at 12 months. Nonetheless, aneurysmaldegeneration of the treated vessels might compro-mise the performance of this treatment modality.Larger multicenter prospective trials are needed to

PERSPECTIVES

WHAT IS KNOWN? The performance of polymer-free

paclitaxel-coated stents in long lesions of the SFA remains

undetermined. The new polymer-based PES could be a viable

treatment option because of its prolonged drug elution, but no

data on its safety and efficacy in such lesions have been reported.

WHAT IS NEW? This study demonstrates for the first time

encouraging performance of polymer-based PES in long and

complex SFA lesions. However, the aneurysm formation rate at

1 year raises concerns about the safety of polymer-based

prolonged paclitaxel elution.

WHAT IS NEXT? Safety analysis regarding prolonged paclitaxel

elution and the effects of drug carrier in the ongoing prospective

trials is mandatory to validate our observations.

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 1 1 , N O . 1 0 , 2 0 1 8 Bisdas et al.M A Y 2 8 , 2 0 1 8 : 9 5 7 – 6 6 Eluvia Stent for Long Femoropopliteal Lesions

965

confirm the theoretical advantages of this approach,especially in comparison with a combined treatmentstrategy with DCBs and bare-metal stents or vesselpreparation techniques and antirestenotic therapy.Moreover, an evidence-based reassessment of thecurrent recommendations regarding the duration ofdual-antiplatelet treatment after PES implantationremains mandatory.

ACKNOWLEDGMENT The authors thank Dr. TilmannSpieker from the Institute of Pathology in St. Fran-ziskus Hospital Muenster for the immunohistologicalanalysis of the vessel specimens.

ADDRESS FOR CORRESPONDENCE: Dr. TheodosiosBisdas, Clinic for Vascular Surgery, St. FranziskusHospital and University Clinic of Muenster,Hohenzollernring 72, 48147 Muenster, Germany.E-mail: th.bisdas@gmail.com.

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KEY WORDS drug-eluting stent(s), Eluvia,long femoropopliteal lesions, paclitaxel,paclitaxel-eluting stent(s), peripheralarterial disease