Drug-Coated Balloon Versus Standard Balloon for ... · Therefore, we initiated the randomized controlled Femoral Artery In-Stent Restenosis (FAIR) trial to assess the mid-term efficacy

DOI: 10.1161/CIRCULATIONAHA.115.017364

1

Drug-Coated Balloon Versus Standard Balloon for

Superficial Femoral Artery In-Stent Restenosis:

The Randomized Femoral Artery In-Stent Restenosis (FAIR) Trial

Running title: Krankenberg et al.; DCBA versus POBA for SFA in-stent restenosis

Hans Krankenberg, MD1*; Thilo Tübler, MD2*; Maja Ingwersen, DVM1; Michael Schlüter, PhD3;

Dierk Scheinert, MD4; Erwin Blessing, MD5; Sebastian Sixt, MD6; Arne Kieback, MD7;

Thomas Zeller, MD8

1Dept of Angiology, Cardiovascular Center (HGZ) Bad Bevensen, Bad Bevensen, Germany;

2Medtronic, Meerbusch, Germany; 3Asklepios proresearch, Hamburg, Germany; 4University of

Leipzig Heart Center, Leipzig, Germany; 5Dept of Internal Medicine, SHR Clinic Karlsbad-

Langensteinbach, Karlsbad-Langensteinbach, Germany; 6Hamburg University Cardiovascular

Center, Hamburg, Germany; 7Dept of Angiology, University Medical Center Hamburg-

Eppendorf, Hamburg, Germany; 8Dept of Angiology, Heart Center Bad Krozingen, Bad

Krozingen, Germany

*shared first authorship

Address for Correspondence:

Hans Krankenberg, MD

Department of Angiology, Cardiovascular Center (HGZ) Bad Bevensen

Römstedter Str. 25

29549 Bad Bevensen, Germany

Tel: +49 5821 82 1157

Fax: +49 5821 82 3816

E-mail: [email protected]

Journal Subject Terms: Peripheral Vascular Disease; Restenosis

1Dept of Angiology, Cardiovascular Center (HGZ) Bad Bevensen, Bad Bevensenenen, GeGeGermrmrmananany;y;y; 2Medtronic, Meerbusch, Germany; 3Asklepios proresearch, Hamburg, Germany; 4University of

LeLeLeipipipziziziggg HeHeHeart tt CCCenter, Leipzig, Germany; 5Deeeptptpt ooof Internal Meddicine,e,e, SSSHR Clinic Karlsbad-

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Abstract

Background—Drug-coated balloon angioplasty (DCBA) was shown to be superior to standard

balloon angioplasty (POBA) with regard to restenosis prevention for de-novo superficial femoral

artery (SFA) disease. For in-stent restenosis (ISR), the benefit of DCBA over POBA remains

uncertain.

Methods and Results—One-hundred-nineteen patients with SFA ISR and chronic limb ischemia

were recruited over 34 months at 5 German clinical sites and prospectively randomized to either

DCBA (n = 62) or POBA (n = 57). Mean lesion length was 82.2 ± 68.4 mm. Thirty four (28.6%)

lesions were totally occluded, 30 (25.2%) were moderately or heavily calcified. Clinical and

duplex ultrasound follow-up was conducted at 6 and 12 months. The primary endpoint of

recurrent ISR assessed by ultrasound at 6 months was 15.4% (8/52) in the DCBA and 44.7%

(21/47) in the POBA group (P = 0.002). Freedom from target lesion revascularization (TLR) was

96.4 % vs. 81.0% (P = 0.0117) at 6 months and 90.8% vs. 52.6% (P < 0.0001) at 12 months,

respectively. At 12 months, clinical improvement by 1 Rutherford category without the need of

TLR was observed in 35/45 DCBA patients (77.8%) and 23/44 POBA patients (52.3%, P =

0.015). No major amputation was needed. Two patients in the DCBA and 3 patients in the POBA

group died. No death was procedure-related.

Conclusions—DCBA for SFA ISR is associated with less recurrent restenosis and a better

clinical outcome than POBA, without an apparent difference in safety.

Clinical Trial Registration Information—www.clinicaltrials.gov. Identifier: NCT01305070.

Key words: in-stent restenosis; angioplasty; drug-eluting balloon; peripheral artery disease; randomized controlled trial; superficial femoral artery

esions were totally occluded, 30 (25.2%) were moderately or heavily calcified. ClClClinininicicicalalal aaandndnd

duplex ultrasound follow-up was conducted at 6 and 12 months. The primary endpoint of

ecuuurrrrrrenenent tt ISISISR RR assesesessss ed by ultrasound at 6 monthhhsss waww s 15.4% (8/52) in thththeee DCBA and 44.7%

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3

Introduction

In the majority of patients with peripheral arterial disease the femoropopliteal segment is

involved. Due to guideline recommendations mainly encouraging an endovascular first-line

approach1, 2 and due to the development of new generation nitinol stents, stenting of

femoropopliteal lesions has become mainstream in recent years. However, mid- and long-term

primary patency rates are suboptimal, with 1-year primary patency of 65-81%3-6 for slotted tube

nitinol stents, 83-86% for interwoven-wire nitinol stents7, 8, and 83%9 for drug-eluting stents.

Five-year primary patency after endovascular therapy is reported to be 50% for Trans Atlantic

Inter-Society Consensus (TASC) A-C and 34% for TASC D lesions10. As a result, the treatment

of in-stent restenosis (ISR) has become increasingly important.

Randomized trials have shown that drug-coated balloon angioplasty (DCBA) for

femoropopliteal de-novo disease is associated with less restenosis and target lesion

revascularization than standard (“plain old”) balloon angioplasty (POBA)11. However, for

superficial femoral artery (SFA) ISR currently available data are poor. In a small prospective

registry of DCBA for SFA ISR12, 13, recurrent restenosis rates were 7.9% (4/39) and 29.7%

(11/37) at 12 and 24 months, respectively. For diabetic patients, Liistro et al.14 reported

significantly lower recurrent ISR rates at 12 months after DCBA as compared to a historical

POBA group (19.5% [8/41] vs.71.8% [28/39], P<0.001).

A direct comparison of DCBA and POBA for the treatment of SFA ISR has not been

performed to date. Therefore, we initiated the randomized controlled Femoral Artery In-Stent

Restenosis (FAIR) trial to assess the mid-term efficacy and safety of DCBA compared to POBA

for SFA ISR.

of in-stent restenosis (ISR) has become increasingly important.

Randomized trials have shown that drug-coated balloon angioplasty (DCBA) for

femomoorororopopopoplplplitititeae l dedede-novo disease is associated wwwititithhh less restenosis and tatatarrrget lesiond

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4

Methods

Study design

The FAIR trial had a prospective, multicenter, block-randomized, non-blinded design and was

conducted at 5 experienced vascular centers in Germany. Patients with SFA ISR were allocated

1:1 to either DCBA or POBA treatment.

Patients

Patients were eligible for enrollment if they had a SFA ISR of up to 20 cm in length. Diameter

stenosis had to be at least 70% by duplex ultrasound. At baseline the popliteal artery as well as

one of the infrapopliteal (below-the-knee) vessels had to be patent ( 50% stenosis) for sustained

distal run-off. Clinically, the patients had to suffer from chronic limb ischemia of Rutherford

category15 2 to 4. Major exclusion criteria were an untreated ipsilateral iliac artery stenosis;

ongoing dialysis treatment; and treatment with oral anticoagulants other than antiplatelet agents.

The FAIR trial was approved by the Freiburg Ethics Commission International (FEKI). All

patients provided written informed consent.

Interventions

Patients were premedicated with acetylsalicylic acid (100 mg/d) and clopidogrel (75 mg/d) for at

least 10 days. Patients not on this regimen were given an intravenous bolus of 500 mg of aspirin

before the intervention and a loading dose of 600 mg clopidogrel orally before or immediately

after the intervention. Following the procedure, patients received aspirin 100 mg/d indefinitely

plus clopidogrel 75mg/d for at least 6 months.

Access to the SFA ISR was achieved at the investigator’s discretion either by way of a

retrograde approach from the contralateral femoral artery using a dedicated 6F “cross-over”

sheath or via an ipsilateral approach with a standard 6F sheath. After sheath placement, a body

distal run-off. Clinically, the patients had to suffer from chronic limb ischemia offf RRRutututheheherfrfrfororord d d

category15 2 to 4. Major exclusion criteria were an untreated ipsilateral iliac artery stenosis;

ongogogoinining g g dididialalalysyy isss tttrrreatment; and treatment with ooorararalll anticoagulants othererer ttthan antiplatelet agents.

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5

weight-adjusted intravenous bolus of 5,000 to 10,000 units of heparin was administered to

achieve an activated clotting (ACT) time of >250 seconds.

Digital subtraction angiography (DSA) was subsequently performed to assess the

following variables: the type of lesion (restenosis or reocclusion), its location, pattern, length

(determined by means of a radiopaque ruler placed under the patient’s upper thigh), and degree

of calcification (by visual estimate). Furthermore, the patency status of the ipsilateral iliac

arteries, the popliteal artery, and the infrapopliteal arteries was documented. Protocol-mandated

angioplasty of a significant ipsilateral iliac-artery stenosis was performed, if needed, prior to

treatment of the SFA ISR.

Following successful passage of the target lesion with a hydrophilic 0.018-in. or 0.035-in.

guide wire, patients were randomly assigned either to POBA or to DCBA.

POBA

In patients randomized to POBA, an over-the-wire PTA balloon (Admiral Xtreme™, Medtronic,

Minneapolis, MN) was advanced into the lesion. Its nominal diameter had to be about the same

as the reference vessel diameter (RVD) and its length had to match the lesion length, with a

maximum balloon overhang of 10 mm at both edges. The balloon was gradually inflated until the

lesion diameter appeared to be visually identical to the RVD. Angioplasty was continued for at

least 60 seconds.

DCBA

In patients randomized to DCBA, predilation of the target lesion with a standard balloon was

mandatory to ensure that the DCB coating remains intact during lesion passage. The nominal

diameter of the predilation balloon had to be at least 1 mm less than the RVD. The drug-coated

balloon (IN.PACT™ Admiral paclitaxel-eluting balloon, Medtronic, Minneapolis, MN) is

Following successful passage of the target lesion with a hydrophilic 0.018-8-8-ininin. ororor 000.0.00353535-i- n

guide wire, patients were randomly assigned either to POBA or to DCBA.

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6

mounted on an over-the-wire catheter and coated with a mixture consisting of urea and paclitaxel

(FreePac™ coating, paclitaxel dose 3.5 μg/mm2). It was available in nominal diameters of 4, 5,

6, and 7 mm and nominal lengths of 40, 60, 80, and 120 mm at study inception. The duration of

dilatation had to be at least 60 seconds. The nominal balloon diameter had to match the RVD.

The DCBA-treated segment should at least have covered the lesion to avoid geographic miss but

not exceeded it by more than 10 mm.

Both treatment groups

In lesions with >50% diameter residual stenosis, balloon inflation was repeated once for at least

3 minutes with the balloon already used. In case of a flow-limiting dissection or residual

stenosis, “bailout” nitinol stent implantation was allowed.

Outcome assessment

Clinical evaluation

The patient’s clinical status was evaluated before the intervention as well as during outpatient

hospital visits at 6 and 12 months. The evaluations included assessment of the Rutherford

category, the ankle-brachial pressure index (ABI) at rest, and a treadmill test at 2 mph on a 12%

incline to determine the patient’s relative and absolute claudication distance.

Ultrasound evaluation

Color duplex ultrasound (DUS) examination of the target SFA was performed within 1 week

before the intervention and at 6- and 12-month follow-up. Each examination comprised

measurements of the maximum peak systolic velocity 2 cm proximal to the culprit lesion

(“prestenotic”), within the lesion (“intrastenotic”), and up to 4 cm distal to the lesion

(“poststenotic”). In order to examine the correct lesion segments at DUS follow-up, the distance

from the groin and the tibia plateau was noted in the patient chart with the help of a ruler placed

tenosis, “bailout” nitinol stent implantation was allowed.

Outcome assessment

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7

under the patient’s leg at the time of intervention. The ratio of the maximum intrastenotic and the

maximum prestenotic peak systolic velocity (PVR) determined the degree of percent diameter

stenosis (DS) by means of a validated reference table16 (PVR 2.4 corresponds to DS 50%).

End points

The primary study end point was the cumulative incidence of binary recurrent in-stent restenosis

at 6 months. Restenosis was assessed by duplex ultrasound (PVR 2.4) at the study sites and

confirmed by an independent and blinded core laboratory (coreLAB Bad Krozingen, Germany).

Secondary procedural end points were primary angiographic success (successful access

and deployment of the device with 50% diameter residual stenosis without bailout procedures),

cumulative incidence of binary recurrent restenosis at 12 months, and Kaplan-Meier estimate of

freedom from TLR on grounds of recurrent restenosis 50%/reocclusion and based on clinical

signs through 6- and 12-month follow-up (not including procedural bailout). Secondary

hemodynamic end points were ABI at 6 and 12 months as well as immediate and sustained

hemodynamic success (ABI improvement of 0.15 from baseline to discharge and to 6 and 12

months without the need for TLR). Secondary clinical end points were sustained clinical

improvement by 1 Rutherford category, relative and absolute claudication distance at 6 and 12

months, and major adverse vascular events (MAVE), defined as all-cause death, myocardial

infarction, major amputation, major bleeding, and thrombosis or surgical intervention related to

the target limb.

Statistics

Based on an expected 6-month binary recurrent restenosis rate of 60% after POBA17 and

postulating a reduction of the recurrent restenosis rate by half to 30% after DCBA, we calculated

a sample size of 59 patients per group to give 80% power to detect a significant difference with a

cumulative incidence of binary recurrent restenosis at 12 months, and Kaplan-Meeeieieier r r esese tititimamamatetete ooof

freedom from TLR on grounds of recurrent restenosis 50%/reocclusion and based on clinical

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8

two-sided error of 5%. An anticipated dropout rate of 20% was taken into account.

Following a parallel-group, block randomization with a block size of 10 and an allocation

ratio of 1:1, patients were assigned either DCBA or POBA. Allocation sequence was concealed

from the investigators by sequentially numbered, opaque, and sealed envelopes.

Continuous variables are presented by means ± standard deviations, categorical variables

by percent and counts. Differences between continuous variables were assessed using Student’s t

test or Kolmogorov-Smirnov’s test. Differences between categorical variables were assessed

using Fisher’s exact test, chi-square test and Kruskal-Wallis’ test. Kaplan-Meier analysis was

performed to estimate freedom from TLR. The Mantel-Cox log-rank test was run to test whether

the survival functions differ. A P-value < 0.05 indicated statistical significance. Statistical

analyses were performed using SPSS 16.0.

Results

Between January 2010 and November 2012, 119 patients were enrolled at 5 German centers and

randomized to undergo either DCBA or POBA for SFA ISR (Figure 1).

Patient cohorts were well matched with respect to risk factors and lesion characteristics.

The majority of patients presented with hypertension or hyperlipidemia and more than a third

had diabetes. The difference in diabetes prevalence between both groups was not significant (p =

0.085). Most patients (92.4%) had moderate (Rutherford 2) or severe (Rutherford 3) claudication

(Table 1). Treated ISR lesion lengths in the DCBA and POBA group were 82.3 ± 70.9 mm and

81.1 ± 66.2 mm, respectively (median lesion length 60 [IQR 20-133] mm). Almost one third of

the lesions were totally occluded and one fourth were moderately or heavily calcified (Table 2).

Primary end point outcome

The primary end point of binary recurrent restenosis assessed by DUS and adjudicated by core

he survival functions differ. A P-value < 0.05 indicated statistical significance. SSStatatatititistststicicicalalal

analyses were performed using SPSS 16.0.

RReRessusults

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9

laboratory was 15.4% (8/52) in the DCBA group and 44.7% (21/47) in the POBA group (P =

0.002; Figure 2). The DUS-dropout at 6 months for DCBA and POBA was 16.1% and 17.5%,

respectively (Figure 1). Therefore, it was within the anticipated rate of 20% for sample size

calculation.

Secondary procedural, clinical, and hemodynamical outcomes

Primary angiographic success was achieved in 95.1% (58/61) of patients in the DCBA group and

in 78.9% (45/57) of patients in the POBA group (P = 0.102). However, due to repeated and

prolonged inflations or provisional/bailout stenting (Table 2), there was no difference in the

residual stenosis rate between both groups (median 0% [IQR 0-30%] versus 0% [IQR 0-20%] P

= 0.630).

At 12 months, incidences of recurrent restenosis assessed by DUS were 29.5% (13/44

patients) in the DCBA and 62.5% (25/40 patients) in the POBA group (P = 0.004). Accordingly,

freedom from TLR was significantly higher in the DCBA than the POBA group (96.4 % vs.

81.0% at 6 months, P = 0.0117; 90.8% vs. 52.6% at 12 months, P < 0.0001, Figure 3).

From baseline to discharge, ABI increased from 0.63 ± 0.27 to 0.94 ± 0.30 in the DCBA

group and from 0.64 ±0.25 to 0.81 ± 0.22 in the POBA group. Rutherford category 0 or 1 was

achieved in 64.7% (33/51) of DCBA and 53.2% (25/47) of POBA patients at 6 months (P =

0.413) and in 66.7% (30/45) of DCBA and 70.5% (31/44) of POBA patients at 12 months (P =

0.820). At 12 months, clinical improvement by 1 Rutherford category without the need of TLR

was observed in 35/45 DCBA patients (77.8%) and 23/44) POBA patients (52.3%, P= 0.015,

Table 3, Figure 4).

Safety outcomes

Two patients from the DCBA group (3.2%) and 3 patients from the POBA group (5.3%, P =

= 0.630).

At 12 months, incidences of recurrent restenosis assessed by DUS were 29.5% (13/44

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10

0.67) died within 12 months. None of these deaths was procedure-related. Procedure-related

complications were one late stent thrombosis in a DCBA group patient and one subacute stent

thrombosis after TLR with DCB in a POBA group patient. In another POBA group patient the

tibioperoneal trunk occluded at 294 days. In two DCBA group patients a transient cerebral

ischemic attack not related to the procedure occurred. Two distal embolizations in DCBA group

patients were resolved without the need for intervention. Neither myocardial infarction nor major

bleeding occurred and no major amputation was necessary (Table 3).

Discussion

This study represents the first randomized comparison of DCBA vs. POBA for SFA ISR. The

treatment groups did not differ significantly with respect to patient or lesion characteristics.

There were four main findings in this trial: DCBA reduced the 6-month recurrent

restenosis rate by two thirds as compared to POBA, thus demonstrating superiority. TLR was

needed significantly less frequent with DCBA than with POBA. There was a positive and

sustained clinical impact for patients treated with DCBA in terms of Rutherford category

improvement. DCBA treatment of ISR was safe.

After stent implantation in the SFA, ISR is known to be associated with a high risk of

recurrence in the mid-term. This applies in particular to femoropopliteal lesions, possibly due to

a continued restenosis process and neointimal hyperplasia.

The majority of previously assessed data on SFA ISR treatment have not been

convincing. Results derived from single-arm observations (DCBA12, 13), historical comparisons

(DCBA vs. POBA14), subgroup analyses (drug-eluting stent18), studies on specific lesions

(chronic total occluded ISR19), and initial experiments (cutting balloon vs. POBA17). In some

This study represents the first randomized comparison of DCBA vs. POBA for SFFFA A A ISISISR.R.R. TTThehehe

reatment groups did not differ significantly with respect to patient or lesion characteristics.

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11

cases, high rates of bailout stenting (10%13, 15.9%14) or additional laser mediated debulking

(10%13) weaken the significance of findings.

Two prospective, randomized, controlled studies showed promising results for long SFA

ISR lesions. The trial on covered stents20 (mean lesion length 173 mm) showed a significantly

higher 12-month primary patency than POBA. However, duration and dosage of dual antiplatelet

therapy with covered stents need further evaluation. Even the long-term benefit of a “stent-

sandwich” remains to be proven. The trial on excimer laser atherectomy with adjunctive POBA21

(mean lesion length 196 mm) showed superiority to stand alone POBA alone with respect to 6-

month freedom from TLR and 30-day major adverse events. The comparably higher rate of 6-

month freedom from TLR after DCBA in FAIR may be attributable to shorter lesions. Therefore,

efficacy and safety of the less invasive treatment of DCBA for long ISR lesions is worth to be

assessed.

After all, the question of whether DCBA is working in ISR as opposed to de novo SFA

lesions can now be answered: based on the clinical results of the present study, paclitaxel-coated

balloons are as effective in restenotic lesions as in native vessels.

Limitations

This study was designed to assess the safety and efficacy of DCBA in comparison to POBA for

SFA ISR treatment. At this stage, we did not focus on the assessment of predictive risk factors

(e.g. subgroup analysis) for restenosis recurrence. The DUS-dropout rate for DCBA and POBA

at 12 months was 29.0% and 29.8%, respectively (Figure 1). Therefore, the significance of the

secondary outcome of 12-month restenosis rate is of minor weight.

Implications for future research

The recent results should be verified for longer follow-up periods. In addition, with a larger

month freedom from TLR after DCBA in FAIR may be attributable to shorter lesssioioionsnsns.. ThThTherererefefeforoo e

efficacy and safety of the less invasive treatment of DCBA for long ISR lesions is worth to be

asseessssssededed..

After allll,l,l thhe qqqueueuestststioioion n n ofofof wwwhehehethththerr DDDCBCBCBA iss wwworrrkikikingngg iiin nn ISISISR R R asas oooppppp osededed tttoo dedede novovovo SFSFSFA A A

eesiss ononons can nononow bebebe annsswwew reddd: bbbaseeed d d onnn tttheh cccliiinin caal resssulltlts oofof theheh pppreresess nnnt stuuudydydy,,, paccclitititaxeel--coaaateed

bababalllllloooooonsnsns aaarerere aaasss efefeffefefectctctiviiveee ininin rrresesestetetenononottticicic lllesesesioioionsnsns aaasss ininin nnnatatativiiveee veevesssssselelelsss.




12

number of patients, a multivariable analysis could provide information on predictive risk factors,

such as lesion length and complexity (TOSACA classification22), vessel morphology,

comorbidities and gender. Moreover, the mode of stenting (intraluminal vs. subintimal) or the

type of stent may be associated with the success of ISR treatment. Furthermore, it would be

valuable to directly compare the efficacy of DCBA and DES implantation. In the next step, the

treatment of recurrent ISR could be investigated.

Conclusions

This multicenter, randomized controlled study demonstrates for the first time that the treatment

of SFA ISR of medium length with DCBA is associated with lower recurrent restenosis rates and

TLRs at 6 and 12 months than POBA. Clinical improvement of 1 Rutherford category at 12

months without the need of TLR was more frequent after DCBA in comparison to POBA. Safety

profiles were equivalent between both treatment groups. Therefore, from the FAIR trial, a clear

treatment recommendation can be made for DCBA in SFA ISR lesions up to 150 mm in length.

Funding Sources: The investigator initiated study was secondarily funded by an unrestricted

grant from Medtronic (Minneapolis, MN). The decision on manuscript content was exclusively

retained by the authors.

Conflict of Interest Disclosures: T. Tübler served as a consultant for Medtronic in 2012. The

other authors report no conflicts of interest.

References: 1. Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clement D, Collet JP, Cremonesi A, De Carlo M, Erbel R, Fowkes FG, Heras M, Kownator S, Minar E, Ostergren J, Poldermans D, Riambau V, Roffi M, Rother J, Sievert H, van Sambeek M, Zeller T. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the

of SFA ISR of medium length with DCBA is associated with lower recurrent restetetenononosisisisss rararatetetesss aaandh

TLRs at 6 and 12 months than POBA. Clinical improvement of 1 Rutherford category at 12

montntnthshshs wwwititithohohout ttthehehe need of TLR was more frequeueuentntnt after DCBA in commmppparison to POBA. Safety

ppprofffiles were eqqquuuivvaalelelenttt bbbetetetweweweeenen boboboththth trreatttmemement ggrooouppps.s.s. TTThehehererr fofoforeee, frfrfromomom theee FFFAIAIAIR R R trtt iaiaall,l, aaa cccleleleararar

reeaeatmtmtment reeecococommmmene ddaattit on cccananan bbe mamm ddde forrr DDDCBAA in SFSFFA A ISSSR RR lllesssionono s upupp ttooo 11150 mmmmmm inn lllenggthtth.




13

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3. Bosiers M, Deloose K, Callaert J, Moreels N, Keirse K, Verbist J, Peeters P. Results of the Protege EverFlex 200-mm-long nitinol stent (ev3) in TASC C and D femoropopliteal lesions. JVasc Surg. 2011;54:1042-50. 4. Iida O, Soga Y, Hirano K, Suzuki K, Yokoi H, Nobuyoshi M, Muramatsu T, Inoue N, Nanto S, Uematsu M. Long-term outcomes and risk stratification of patency following nitinol stenting in the femoropopliteal segment: retrospective multicenter analysis. J Endovasc Ther. 2011;18:753-61. 5. Laird JR, Katzen BT, Scheinert D, Lammer J, Carpenter J, Buchbinder M, Dave R, Ansel G, Lansky A, Cristea E, Collins TJ, Goldstein J, Jaff MR. Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery: twelve-month results from the RESILIENT randomized trial. Circ Cardiovasc Interv. 2010;3:267-76. 6. Krankenberg H, Tubler T, Sixt S, Fischer M, Schmiedel R, Schulte KL, Balzer JO, Kieback A, Fiehn E, Wittenberg G, Ali T, Tiefenbacher C, Jahnke T, Steinkamp HJ, Wegscheider K, Treszl A, Ingwersen M, Zeller T. German multicenter real-world registry of stenting for superficial femoral artery disease: clinical results and predictive factors for revascularization. J Endovasc Ther. 2014;21:463-71. 7. Garcia L, Jaff MR, Metzger C, Sedillo G, Pershad A, Zidar F, Patlola R, Wilkins RG, Espinoza A, Iskander A, Khammar GS, Khatib Y, Beasley R, Makam S, Kovach R, Kamat S, Leon LR, Jr., Eaves WB, Popma JJ, Mauri L, Donohoe D, Base CC, Rosenfield K. Wire-Interwoven Nitinol Stent Outcome in the Superficial Femoral and Proximal Popliteal Arteries: Twelve-Month Results of the SUPERB Trial. Circ Cardiovasc Interv. 2015;8. 8. Werner M, Paetzold A, Banning-Eichenseer U, Scheinert S, Piorkowski M, Ulrich M, Bausback Y, Braunlich S, Schmidt A, Scheinert D. Treatment of complex atherosclerotic femoropopliteal artery disease with a self-expanding interwoven nitinol stent: midterm results from the Leipzig SUPERA 500 registry. EuroIntervention. 2014;10:861-8. 9. Dake MD, Ansel GM, Jaff MR, Ohki T, Saxon RR, Smouse HB, Zeller T, Roubin GS, Burket MW, Khatib Y, Snyder SA, Ragheb AO, White JK, Machan LS. Paclitaxel-eluting stents show superiority to balloon angioplasty and bare metal stents in femoropopliteal disease: twelve-month Zilver PTX randomized study results. Circ Cardiovasc Interv. 2011;4:495-504. 10. Iida O, Takahara M, Soga Y, Suzuki K, Hirano K, Kawasaki D, Shintani Y, Suematsu N, Yamaoka T, Nanto S, Uematsu M. Shared and differential factors influencing restenosis following endovascular therapy between TASC (Trans-Atlantic Inter-Society Consensus) II class

Lansky A, Cristea E, Collins TJ, Goldstein J, Jaff MR. Nitinol stent implantation versrsus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artttererery:y:y: tttwewewelvlvlve-e-e-month results from the RESILIENT randomized trial. Circ Cardiovasc Interv. 200101010;3;3;3:2:22676767-7-7-76.6.6.

6. Krankenberg H, Tubler T, Sixt S, Fischer M, Schmiedel R, Schulte KL, Balzer JO, Kieback AFiehhhnn n E,E,E, WWWititittett nbbbererrg G, Ali T, Tiefenbacher C, JaJaJahnhnhnke T, Steinkamp HJHJJ, Wegscheider K, Treszl A,A,A, IInnngwersenenen M, Zeller T. German multicenter reall-world registryryry of stenting for superficial tfefefemmom ral artery dddiiiseeasesese: clclclinininicicicalalal rresesesululultsts annd ppprereeddicttivvve fafafactctctorrrs fofof rr reree avavascscscuuulaarizzzatatatioioion.n.n. J J J EnEnEndododovavavascss ThTT eeer. 2014;21:466633-71.

7. GGGarararciciciaaa LLL, Jaffff ff MRMRMR, MeMeMetzt ger r CCC, SSSedillllololo GGG, PePePersrsshhahaddd A,AA ZZZidididararar F, PaPaPatttlolololaa RRR, WWWilililkikikinnsns RG,GG EsEsEspipipinononozaaza AAA, IsIsIskakakandndndererer AAA, KhKhKhamamammamamarrr GSGSGS, KhKhKhatatatibibib YYY, BBBeaeaeaslslsleyeey RRR, MaMaMakakakammm SSS, KKKovoovacacachhh RRR, KKKamamamatatat SSS,




14

A to C and D lesions in the femoropopliteal artery. JACC Cardiovasc Interv. 2014;7:792-8. 11. Cassese S, Byrne RA, Ott I, Ndrepepa G, Nerad M, Kastrati A, Fusaro M. Paclitaxel-coated versus uncoated balloon angioplasty reduces target lesion revascularization in patients with femoropopliteal arterial disease: a meta-analysis of randomized trials. Circ Cardiovasc Interv. 2012;5:582-9. 12. Virga V, Stabile E, Biamino G, Salemme L, Cioppa A, Giugliano G, Tesorio T, Cota L, Popusoi G, Pucciarelli A, Esposito G, Trimarco B, Rubino P. Drug-eluting balloons for the treatment of the superficial femoral artery in-stent restenosis: 2-year follow-up. JACCCardiovasc Interv. 2014;7:411-5. 13. Stabile E, Virga V, Salemme L, Cioppa A, Ambrosini V, Sorropago G, Tesorio T, Cota L, Popusoi G, Pucciarelli A, Biamino G, Rubino P. Drug-eluting balloon for treatment of superficial femoral artery in-stent restenosis. J Am Coll Cardiol. 2012;60:1739-42. 14. Liistro F, Angioli P, Porto I, Ricci L, Ducci K, Grotti S, Falsini G, Ventoruzzo G, Turini F, Bellandi G, Bolognese L. Paclitaxel-eluting balloon vs. standard angioplasty to reduce recurrent restenosis in diabetic patients with in-stent restenosis of the superficial femoral and proximal popliteal arteries: the DEBATE-ISR study. J Endovasc Ther. 2014;21:1-8. 15. Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, Jones DN. Recommended standards for reports dealing with lower extremity ischemia: revised version. JVasc Surg. 1997;26:517-38. 16. Ranke C, Creutzig A, Alexander K. Duplex scanning of the peripheral arteries: correlation of the peak velocity ratio with angiographic diameter reduction. Ultrasound Med Biol. 1992;18:433-40. 17. Dick P, Sabeti S, Mlekusch W, Schlager O, Amighi J, Haumer M, Cejna M, Minar E, Schillinger M. Conventional balloon angioplasty versus peripheral cutting balloon angioplasty for treatment of femoropopliteal artery in-stent restenosis: initial experience. Radiology. 2008;248:297-302. 18. Zeller T, Dake MD, Tepe G, Brechtel K, Noory E, Beschorner U, Kultgen PL, Rastan A. Treatment of femoropopliteal in-stent restenosis with paclitaxel-eluting stents. JACC Cardiovasc Interv. 2013;6:274-81. 19. Gandini R, Del Giudice C, Merolla S, Morosetti D, Pampana E, Simonetti G. Treatment of chronic SFA in-stent occlusion with combined laser atherectomy and drug-eluting balloon angioplasty in patients with critical limb ischemia: a single-center, prospective, randomized study. J Endovasc Ther. 2013;20:805-14. 20. Bosiers M, Deloose K, Callaert J, Verbist J, Hendriks J, Lauwers P, Schroe H, Lansink W, Scheinert D, Schmidt A, Zeller T, Beschorner U, Noory E, Torsello G, Austermann M, Peeters P. Superiority of stent-grafts for in-stent restenosis in the superficial femoral artery: twelve-

Bellandi G, Bolognese L. Paclitaxel eluting balloon vs. standard angioplasty to reduccce recurrent estenosis in diabetic patients with in-stent restenosis of the superficial femoral annnd d d prprproxoxoximimimalalal

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15. Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, Jones DN. Recocoommmmmmenenendededed stststananandards for reports dealing witth h h lololower extremity ischemememia: revised version. JVaVaVasccc Surg. 19191997;26:517-38.

1611 . Ranke C, Creeeuutziggg AA, Alllexxxander KKK. DDupppleeex sccannnninnng g g ofofof thhhe pppeeeripheeeraal aaarteeeries:: cooorreelaationnn ofhhhee e pepepeak velllocococityy y rrar tiooo wwiw th aaangigigiogogograraraphhhiccc diaiaiammmeter rrredududuccctiooonn.n. UlUlU tttraasasouoo ndnnd MMMededed Biolll.

199222;1;1;18:8:8:4343433-3 4000.




15

month results from a multicenter randomized trial. J Endovasc Ther. 2015;22:1-10. 21. Dippel EJ, Makam P, Kovach R, George JC, Patlola R, Metzger DC, Mena-Hurtado C, Beasley R, Soukas P, Colon-Hernandez PJ, Stark MA, Walker C. Randomized controlled study of excimer laser atherectomy for treatment of femoropopliteal in-stent restenosis: initial results from the EXCITE ISR trial (EXCImer Laser Randomized Controlled Study for Treatment of FemoropopliTEal In-Stent Restenosis). JACC Cardiovasc Interv. 2015;8:92-101. 22. Tosaka A, Soga Y, Iida O, Ishihara T, Hirano K, Suzuki K, Yokoi H, Nanto S, Nobuyoshi M. Classification and clinical impact of restenosis after femoropopliteal stenting. J Am Coll Cardiol. 2012;59:16-23.




16

Clinical Perspective

Due to an increasing tendency to stent superficial femoral artery (SFA) lesions, which is,

however, associated with not entirely satisfying primary patency rates, the treatment of SFA in-

stent restenosis (ISR) has become increasingly important. Drug-coated balloon angioplasty

(DCBA), when compared with standard balloon angioplasty (POBA), had shown superior

efficacy for de-novo lesions. Therefore, DCBA seemed to be the obvious approach to minimally

invasive treatment of SFA ISR. However, available data were poor and did not allow for

therapeutic decisions. The multicenter, randomized controlled FAIR trial demonstrates for the

first time that the treatment of SFA ISR with DCBA is associated with lower recurrent restenosis

rates and target lesion revascularizations (TLRs) than POBA at 6 and 12 months. Moreover,

clinical improvement of 1 Rutherford category at 12 months without the need of TLR was

observed more often after DCBA. Safety profiles were equivalent between both treatment

groups. Therefore, the question of whether DCBA is working in an SFA ISR as opposed to de-

novo SFA lesions can now be answered: Based on the clinical results of the FAIR trial,

paclitaxel-coated balloons are as effective in restenotic lesions as in native vessels. A clear

treatment recommendation can be made for DCBA in SFA ISR up to 150 mm in length.

first time that the treatment of SFA ISR with DCBA is associated with lower recuuurrrrrrenenent tt rererestststenenenooosis

ates and target lesion revascularizations (TLRs) than POBA at 6 and 12 months. Moreover,

clinicicicalalal iiimpmpmprororovememement of 1 Rutherford category y y atatat 112 months without ttthehehe need of TLR was

obobobsseserved more oofofteen nn aafafteteterr r DCDCDCBABABA... SaSaSafefefetyy prororofffiiles wwwere e e eqeqequiuiuivavavaleentnn bbbetetetwwweeen bbbototothhh trtrtreaeaeatmmmenee t t t ffff

grrrouououpspsp . Therererefee orrre,,, theee qqquesttiioi n n n of wwwheeethhher DDDCCCBAA iiis wwwooorkiingngng iiin n annn SSSFAAA ISRRR aaas oppppopoposedd ttto deee-

nononovoovo SSSFAFAFA lllesesesioioionsnsns cccananan nnnowoow bbbeee anananswsswerererededed::: BaBaBaseseseddd ononon thththeee clclclinininicicicalalal rrresesesullultststs ooofff thththeee FAFAFAIRIRIR tttriririalalal,




17

Table 1. Baseline Patient Characteristics. DCBA (n = 62) POBA (n = 57) PAge, years 69 ± 8 67 ± 9 0.296 Male 53.2% (33) 70.2% (49) 0.058 Obesity (BMI 30) 19.4% (12) 21.1% (12) 0.316 Diabetes mellitus 45.2% (28) 29.8% (17) 0.085

Insulin-dependent 42.9% (12/28) 35.3% (12/17) 0.616 Hypertension 83.9% (52) 93.0% (53) 0.123 Hyperlipidemia 77.4% (48) 78.9% (45) 0.840 Renal insufficiency 12.9% (8) 17.5% (10) 0.480

Dialysis 0.0% (0/8) 10.0% (1/10) 1.000 Smoking 0.635

Active 29.0% (18) 35.1% (20) Previous 41.9% (26) 45.6% (26)

Coronary artery disease 41.9% (26) 38.6% (22) 0.681 Carotid vascular disease 22.6% (14) 17.5% (10) 0.791 Infrapopliteal vascular disease 25.8% (16) 21.1% (12) 0.495 Ankle-brachial index 0.63 ± 0.27 0.64 ± 0.25 0.872 Relative claudication distance, m 79.2 ± 52.0 102.9 ± 70.9 0.527 Absolute claudication distance, m 131.4 ± 87.1 145.9 ± 93.7 0.849 Leg treated 0.582

Left Right

50.0% (31) 50.0% (31)

56.1% (32) 43.9% (25)

Rutherford category 0.927 0 – asymptomatic 0.0% (0) 0.0% (0) 1 – mild claudication 0.0% (0) 0.0% (0) 2 – moderate claudication 43.5% (27) 47.4% (27) 3 – severe claudication 51.6% (32) 42.1% (24) 4 – ischemic pain at rest 1.6% (1) 10.5% (6) 5 – minor tissue damage 3.2% (2) 0.0% (0) 6 – major tissue damage 0.0% (0) 0.0% (0)

Data are means ± SD or percent (number).

Carotid vascular disease 22.6% (14) 17.5% (10) ) ) 0.0.0.797979111nfrapopliteal vascular disease 25.8% (16) 21.1% (1222) )) 0.0.0 494949555

Ankle-brachial index 0.63 ± 0.27 0.64 ± 0.25 0.872Relative claudication distance, m 79.2 ± 52.0 102.9 ± 70.9 0.527 Absosoolululutetete ccclalalauduu icccatatation distance, m 131.4 ± 87.1 1114544 .9 ± 93.7 0.849 LeLeeg g g tttreated d 0.582

Left Right

5000.000%%% (3(3(31)1)) 5000.0.0.0%%% (3331)

56.1% % % ((3(32)2)2) 43.999%%% (25)))

RuRuuthththerererfof rddd cccaaategggorrry y 00.9272727 00 – asymptomatic 0.0% (0) 0.0% (00) 1 – mild claudication 0 0% (0) 0 0% (0)




18

Table 2. Baseline Lesion and Procedural Characteristics. DCBA (n = 62) POBA (n = 57) PTarget lesion 0.184

Proximal SFA 48.8% (30) 43.9% (25) Mid SFA 38.7% (24) 45.6% (26) Distal SFA 38.7% (24) 29.8% (17) Adjacent to 1th segm. popliteal artery 11.3% (7) 8.8% (5)

Reference vessel diameter, mm 5.1 ± 0.9 5.4 ± 0.5 0.062 Lesion length, mm 82.3 ± 70.9 81.1 ± 66.2 0.991 Diameter stenosis, % 89.0 ± 8.9 89.9 ± 9.6 0.627 Total occlusions 24.2% (15) 33.3% (19) 0.313 Ulceration 6.2% (2) 1.8% (1) >0.999 Thrombus 4.8% (4) 5.3% (3) >0.999 Calcification 0.327

Mild 17.7% (11) 14.0% (8) Moderate 21.0% (13) 10.5% (6) Heavy 9.7% (6) 8.8% (5)

ISR pattern 0.952 Focal 25.8% (16) 28.1% (16) Diffuse 51.6% (32) 52.6% (30) Multifocal 22.6% (14) 19.3% (11)

Patency of distal run-off vessels 0.854 All vessels patent 54.8% (34) 57.9% (33)

1 vessel occluded 43.5% (27) 42.1% (24) Predilation 90.3% (56) 12.3% (7) < 0.001 Inflation time, sec 131.1 ± 46 153 ± 63 0.021 Postdilation 9.7% (6) 22.8% (13) 0.113 Stenting 1.6% (1)* 7.0% (4)† 0.199 SFA = superficial femoral artery *Stenting for persistent stenosis; †Stenting for persistent stenosis (3.5%), occlusive complication (1.8%), or dissection (1.8%)

Moderate 21.0% (13) 10.5% (6) Heavy 9.7% (6) 8.8% (5)

ISR pattern 0.952 Focal 25.8% (16) 28.1% (16) DiDiDiffffffusususeee 515151.6% (32) 52.6%6%6% (30) Multifififooocal 2222.6% (1( 4) 19.3% (11)

PPPateeency of distaaal ll ruun-nn ofofoff f f vevevesssssselelels 00.888545454 All vesselss ppatentnnt 5444.8% % % (3(3(34)44 57.9%99% (333333) )

1 vevevesssss el ooocccccludededed dd 4333.5% % % (2(2(2777) 4442.22 1%1%1% ((242424) ) ) Predilatiion 90.3% (5(( 6))) 12.3% (((7))) < 0.001 nflation time sec 131 1 ± 46 153 ± 63 0 021




19

Table 3. Hemodynamic, Clinical and Safety Outcomes.

At 6 months At 12 months DCBA POBA P DCBA POBA P

Hemodynamic outcome* Hemodynamic improvement† 67.5% (27/40) 58.3% (21/36) 0.408 61.1% (22/36) 50.0% (18/36) 0.343 Ankle-brachial index 0.90 ± 0.25 0.84 ± 0.33 0.379 0.86 ± 0.30 0.90 ± 0.17 0.502

Clinical outcome* Clinical improvement‡ 70.6% (36/51) 57.4% (27/47) 0.209 77.8% (35/45) 52.3% (23/44) 0.015 Relative claudication distance, m 115 ± 63 153 ± 107 0.118 126 ± 89 105 ± 82 0.431 Absolute claudication distance, m 200 ± 128 216±128 0.610 218 ± 187 216 ± 136 0.968

Safety outcome (cumulative incidence) All cause death§ 0% 2.1% (1/47) 0.124 4.3% (2/47) 6.8% (3/44) 0.591 Myocardial infarction 0% 0% - 0% 0% - Major bleeding 0% 0% - 0% 0% - Major amputation 0% 0% - 0% 0% - Thrombosis** 1.8 (1/55) 2.1% (1/47) 0.910 2.1%(1/47) 4.5% (2/44) 0.519 Surgical intervention†† 0% 0% - 2.1% (1/47) 0% 0.331

* Without the need for TLR † ABI improvement of 0.15 ‡ Clinical improvement of 1 Rutherford category §No procedure related death **DCBA group: one patient with target lesion occlusion at 199 days; POBA group: one patient with subacute stent-thrombosis following TLR with DCB at 84 days and one patient with occlusion of tibioperoneal trunk at 294 days ††Femoropopliteal bypass at target limb

p ( ) ( ) ( ) %% ( )Relative claudication distance, m 115 ± 63 153 ± 107 0.118 126 ± 89 1010105 55 ±±± 828282 0.Absolute claudication distance, m 200 ± 128 216±128 0.610 218 ± 187 2122 6 6 6 ±±± 1313136 6 6 0.0y outcome (cumulative incidence)

All cause death§ 0% 2.1% (1/47) 0.124 4.3% (2/47) 6.8% (3/44) 0.Myocardial infarction 0% 0% - 0% 0%Majooorr r blblbleeeeeedididingngng 0% 000% %% - %%0% 0% MaMaajojojor rr amputa iitiononon 0% 000% %% - 0% 0% ThThTh oorombosis** 1.1.1.888 (1(1(1/5/5/55)5)5) 2.1% %% 1( /47)7)7) 000.9.. 0100 222.1.1.1%(%(%(1/47) ) ) 4.4.4.5%5%% (((2/2/2 444444))) 0.SuSuS ggrgical intervention†††† 000% 0%0%0% - 2. %%1% (1(( /4447)77 0%%% 0.hhouoo t ththt e need for TLRLR

mmimprpp ovovovement of 0.0.0 15 ical iiimpmpmprorovevevememementntnt of 111 RuRuRuthththerererfofofordrdrd cccatatatege ory §N§N§No prprprocoo edureee rerr lalalateteted d d dededeatatath hhBA group: one patient with target lesion occlusion at 199 days; POBA group: one patient with subacute stent-thrombosis following TLR with DCB a

ddnd one p tatiiie tnt wititithhh oc llclusiiion ffof ttibibibiiioperone llal ttru kknk att 292929444 dddays moropopliteal bypass at target limb




20

Figure Legends:

Figure 1. Patient flow chart. DCBA = drug-coated balloon angioplasty; POBA = standard

balloon angioplasty.

Figure 2. Primary endpoint of binary recurrent in-stent restenosis at 6 months.

Figure 3. Cumulative freedom from, and Kaplan-Meier estimates of, target lesion

revascularization (TLR) according to treatment modality. SE = standard error.

Figure 4. Change in Rutherford category at 6 and 12 months according to treatment modality.

Negative changes denote clinical improvement. TLR = target lesion revascularization.

evascularization (TLR) according to treatment modality. SE standard error.

Figure 4. Change in Rutherford category at 6 and 12 months according to treatment modality.

NeNeNegagagative chahahanngn es denote clinical improvement. TTTLRRR = targget lessioioion revascularization.



Figure 1 at Cleveland Clinic Foundation on December 6, 2015http://circ.ahajournals.org/Downloaded from








Blessing, Sebastian Sixt, Arne Kieback and Thomas ZellerHans Krankenberg, Thilo Tübler, Maja Ingwersen, Michael Schlüter, Dierk Scheinert, Erwin

Restenosis: The Randomized Femoral Artery In-Stent Restenosis (FAIR) TrialDrug-Coated Balloon Versus Standard Balloon for Superficial Femoral Artery In-Stent

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