from ahajournals.org
Transcript
from ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.113.001811 Drug-Eluting Balloon in peripherAl inTErvention for Below the Knee Angioplasty Evaluation (DEBATE-BTK): A Randomized Trial in Diabetic Patients with Critical Limb Ischemia Running title: Liistro et al.; Drug-eluting balloon in BTK angioplasty Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 Francesco Liistro, MD1; Italo Porto, MD PhD1; Paolo Angioli, MD1; Simone Grotti, MD1,2; Lucia Ricci, MD3; Kenneth Ducci, MD1; Giovanni Falsini, MD1; Giorgio Vent Ventoruzzo, nttorruz uzzo zo o, MD1; Filippo Turini, MD1; Guido Bellandi, MD1; Leonardo Bolognese, MD1 1 Cardiovascular Ca ardiovascul ular ar aand nd dN Neurological euro eu rolo ro lo ogi gica caal De Dept Dept; ptt; 3Di Diabetes D ab es abete es Unit, Unnit, nit, San San n Donato Don o at ato to Hospital, Hosppittal Ho al,, Arezzo; Arez Ar e zo ez zo; 2De Dept ptt of Ca Cardiovascular ard rdiova vascuular Diseases, va Disseaase ses, U University nivversiity of Siena, Siena, a, L Lee Sc Scotte cottte H Hospital, osppittal, tal,, Siena, Sie iena,, Italy; Ittal alyy; Addr Ad Address dres esss for for Correspondence: C rr Co rres espo pond nden ence ce:: Francesco Liistro, MD Cardiovascular and Neurological Diseases Department San Donato Hospital via Pietro Nenni 20 52100, Arezzo Italy Tel: +39 0575 255617 Fax: +39 0575 255617 E-mail: [email protected] Journal Subject Codes: Treatment:[123] Restenosis, Hypertension:[17] Peripheral vascular disease 1 DOI: 10.1161/CIRCULATIONAHA.113.001811 Abstract: Background—One-year restenosis rate after balloon angioplasty of long lesions in below-theknee (BTK) arteries may be as high as 70%. Our aim was to investigate the efficacy of a paclitaxel drug-eluting balloon (DEB) vs. conventional percutaneous transluminal angioplasty (PTA) for the reduction of restenosis in diabetic patients with critical limb ischemia (CLI) undergoing endovascular intervention of BTK arteries. Methods and Results—The Drug Eluting Balloon in peripherAl inTErvention (DEBATE)-BTK is a randomized, open label, single-center study comparing DEB vs. PTA. Inclusion criteria Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 were: diabetes, critical limb ischemia (Rutherford 4), significant stenosis or occlusion > 40mm of at least one BTK vessel with distal run-off, and life expectancy > 1 year. Binary in-segment estenosis at 1-year angiographic or ultrasonographic follow-up was the primary endpoint. end ndpo poin po int. t. restenosis Clinically-driven target lesion revascularization (TLR), major amputation and target taarg rget et vessel ves esse sell se occlusion were the secondary endpoints. One hundred and thirty two patients with 158 nfrrap apop opli op lite li teal te al ath th her eroosclerotic lesions were enrolle leed. d. Mean length of th he tr treated segments was infrapopliteal atherosclerotic enrolled. the 12 29± ±83 83mm iin n th thee DE DEB B vs s. 13 131± 1±79 79mm 79 mm iin n th thee PT PTA A ggroup rouup (p (p=0.7 .77). B inar in arry re est sten enos en o is os is,, as asse sess se sssed bby y 129±83mm vs. 131±79mm (p=0.7). Binary restenosis, assessed ang an ngiography in >90% >90% off patients, pattie iennts, occurred occ ccuurr urred in in 20/74 74 (27%) (27 27%) 27 %) lesions leesions ns inn the thhe he DEB DEB group grooup vs. vs. 55/74 55/ 5/74 74 angiography 74% 4%)) lesions lesi le sion onss in the on thhe he PTA PTA A group gro oup (p<0.001); (p< p<0. 0 00 001) 1);; TLR 1) TL LR in in 12(18%) 12( 2(18 2( 18% 18 %) vs. vs. 29(43%) 29( 9(43 4 %)) (p=0.002); 43 (p= p=0. 0 00 0. 02) 2);; and and target tarrgeet ta et (74%) vess ve ssel ss el oocclusion cclu cc lusi lu sion si on iin n 12 ((17%) 17%) 17 %) vvs. s. 441 1 (5 (55% 5%)) (p 5% (p<0 <0.001 001 01)). O nlyy 1 ma nl majo jorr am jo ampu puta pu tati ta tion ti on ooccurred, ccur cc urre ur redd, iin re n th thee vessel (55%) (p<0.001). Only major amputation PTA gr grou oupp (p (p=0 =0 9) PTA group (p=0.9). Conclusions—DEB, as compared to PTA, strikingly reduce 1-year restenosis, target lesion revascularization, and target vessel occlusion in the treatment of BTK lesions in diabetic patients with CLI. Clinical Trial Registration Information—http://ClinicalTrials.gov; Identifier: NCT01558505. Key words: percutaneous procedure, peripheral artery disease, restenosis, drug-eluting balloon 2 DOI: 10.1161/CIRCULATIONAHA.113.001811 Introduction Critical limb ischemia (CLI), characterized by ischemic rest pain and/or tissue loss, represents the most advanced state of peripheral artery disease, burdened by high morbidity and mortality1,2. CLI generally occurs in diabetics with extensive atherosclerotic disease of belowthe-knee (BTK) vessels1. The optimal strategy for treating CLI patients, however, has not been clearly defined yet: the outcome of medical therapy is unsatisfactory3, and early, aggressive percutaneous Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 revascularization with the aim to obtain direct flow to the foot is increasingly considered as firstline strategy 4,5. Indeed, although vessel patency alone cannot match patient-centered clinical endpoints6, and any endovascular program has to be integrated in a network-based network-base seed system s stem sy stem m ooff ca ccare re involving nvolving different professional figures7,8, an increased cutaneous oxygen pressure due to ucccesssf sful ul rrevascularization ev vasscu cula larization promotes infection cclearance leaarance and ulc le cer e gr gran anuulation at a crucial timean successful ulcer granulation poin point nt 9 . Thee ef Th eefficacy ffi ficcacy cy ooff conv cconventional onven e ti en tion onal on al ppercutaneous e cu er cuta taneeou ta o s ttransluminal r nslu ra lum lu mina nall angi na aangioplasty ngi giop opplaast styy (P (PTA (PTA) TA)) uusing TA sin in ng conventionall bballoons, a lo al oon ons, s, hhowever, ow wev everr, is i llimited imit im ited it ed bby y th thee hi hhigh g 112-month gh 2 mo 2mont nthh restenosis nt reest s en enos osis os iss and and ttarget arge ar gett lesion ge revascularization (TLR) rates10. Loss of vessel patency affects the healing process resulting in no healing, decrease-increase behavior of the lesion or appearance of new foot lesions11. While drug-eluting stents (DES) may offer a therapeutic alternative to PTA in the BTK district12,13, widespread use in CLI patients is limited by the complex pattern of BTK atherosclerosis, characterized by long, calcific stenoses/occlusions. Local delivery of paclitaxel via drug eluting balloons (DEB) has recently shown promising results in the treatment of femoropopliteal disease14, and, in the BTK district, a reduction of 3-month binary restenosis has been observed in comparison with historical controls 3 DOI: 10.1161/CIRCULATIONAHA.113.001811 treated with standard PTA 15. Historical data, however, may not represent an adequate comparator due to changes in technology and clinical practice over time16, and the efficacy of DEB in diabetic patients with CLI has not been validated in a randomized fashion. We designed a prospective, randomized trial designed to compare the performance of a novel DEB (Amphirion In.Pact, Medtronic, Santa Rosa, CA) with conventional PTA in diabetics with de-novo, long atherosclerotic lesions of the BTK district, using 1-year binary restenosis rate as primary endpoint. Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 Methods Study design The Drug Eluting Balloon in peripherAl inTErvention for Below The Knee angioplasty ev val alua uati ua tion ti onn (DEBATE-BTK) (DE D BA BATE T -BTK) is a single-center, pa para allel-group, pr ros o peect ctiv ive, iv e randomized, openevaluation parallel-group, prospective, abeel involvin ng th tthee bl lin i de dedd ev eva aluaati alua t on on off endd ppoints oin ntss (PR PROB PR OB BE) E) ttrial rial17 evaluating evalu valuat atin at ingg the in th he efficacy effi ef f caacy of fi of a label involving blinded evaluation (PROBE) 0. 0.014” .01 014” 4” guidewire-compatible gui uide dewi de wire ree-ccom mpaati tibl blee DEB DEB (Amphirion (Amp (Amp mphi hirrion hi on In.Pact, In n.P Pacct, Medtronic) Medtr edtr tron onnicc) vs. vs. standard stan stan nda dard r P rd PTA TA TA (Amphirion Amphirion Deep, Dee eep, p, Medtronic) Med e tr t onnicc) inn reducing redu d ci cing ng 12-month 122 mo mont nthh restenosis nt rest re sten st enos en o is rate os rat a e in n diabetic dia iabe beti be t c patients pati pa tien ti ents en t with CLII undergoing endovascular BTK revascularization. It was approved by the local ethics committee and was carried out in accordance with the Helsinki declaration. All patients provided written informed consent. The study was registered with ClinicalTrials.gov (unique identifier NCT01558505). The study was performed without any industry financial support. Study Patients From November 2010 through October 2011, all consecutive diabetic patients with CLI undergoing angioplasty of at least one BTK vessel at our center were screened for enrollment. 4 DOI: 10.1161/CIRCULATIONAHA.113.001811 Inclusion criteria were: presence of diabetes, CLI (Rutherford class4), stenosis or occlusion 40mm of at least one tibial vessel with distal run off to the foot, and agreement to 12-month angiographic evaluation. Exclusion criteria were: life expectancy < 1 year, allergy to paclitaxel, contraindication to combined antiplatelet treatment and planned major amputation before angiography. Lesions were randomly assigned to one of the two study arms after successful passage of the guidewire. Randomization was performed in blocks of ten with the use of computerDownloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 generated random digits, and the assignments were placed in sealed envelopes. Study Procedures Interventions nterventions were performed mainly by antegrade approach and with the use off 66-French -F Freenc nchh sheaths. heaths. In case of failure to recanalize, a retrograde approach was attempted. In DEB group, pre-dilatation balloon(s) always performed pr ree-di dila di lattati la tati tion on off th thee target lesion with standard ba ball loon(s) was alw wayss pe perf r ormed before dilatation The DEB has previously ddila i ata tation withh DE DEB. B. T he D EB uused sedd in se n tthis his sstudy tu udy ha as bbeen een pr prev eviiously ly ddescribed escrrib ibed ed15. Th Thee DEB/vessel DE EB/ B/ve v ss ve ssel el diameter dia iame mete me terr ratio rati ra t o was ti waas pl plan planned anne an nedd to bbee 1:1. 1:1.. D DEB EB B aavailable vail va i ab able lee dduring uriing tthe ur hee sstudy tudy tu dy pperiod erio io od ha hadd a diameter of 2. 2.5 .5 to 44.0 . m .0 mm m an andd a le leng length ngth ng h ooff 40 tto o 12 1200 mm mm.. Ra Radi Radiopaque diop di opaq op aq que rrulers uler ul erss we er were re uused seed to ensure that the zone treated with DEB consistently exceeded of at least 10mm at the proximal and distal edges the area predilated with standard balloons, in order to avoid geographic miss. If more than 1 balloon was used per lesion, the overlap zone was at least 5 mm. Inflation time was at least 2 minutes for both DEB and PTA arms. In case of flow-limiting dissection or residual stenosis of more than 30%, a prolonged dilation of up to 3 min was performed. Drug eluting coronary stents (Xience V, Abbott, CA, USA) were used as a bailout. Technical success was defined as restoration of direct flow in the target vessel with run-off to the foot and a residual stenosis of less than 30%. Clinical success was defined as technical success without clinical events during 5 DOI: 10.1161/CIRCULATIONAHA.113.001811 hospitalization. Inflow lesions located in the femoropopliteal segment were treated by standard techniques during the same session. In patients with bilateral CLI, an additional procedure for the revascularization of the contralateral limb was planned in a different session to limit the risk of x-rays exposition and contrast-induced nephropathy, maintaining the same randomization arm. All patients were taking aspirin 100 mg daily. After sheath insertion, 70 IU/Kg heparin was administered. Post-intervention dual antiplatelet therapy with aspirin 100 mg and clopidogrel 75 mg once daily was given at least for 4 weeks and 100 mg aspirin was given daily Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 thereafter. Follow-up Once discharged, patients were followed in a multidisciplinary, dedicated foot cclinic liini nicc to o ffacilitate acil ac ilit il itaate healing process and recovery of the ambulatory function 7. Office visits were scheduled 2 daays ys/w /wee /w eekk fo forr th he fi first 2 months, once a week fo or th he third monthh an aand d th the en every two weeks. days/week the for the then Minor Minnor no amputa amputations atiionss wh whic which ch we wer were re pplanned re lannne la nned ed bef before for ore th the he iinterventions nteerv ven ntiion onss were were pperformed erfo fo orm med 22-4 -4 w weeks eeeks ks af after fter revascularization eva vasc sccul u ar ariz izat iz atio ionn and and in incl included: c ud cl udeed: ffinger inge in gerr am amputations, mpu putaati tion on ns,, m metatarsal etaata et tarrsal al aamputation mput mp u attio ut on du duee to necrosis/infection necrosis/infec eccti t on of of tissues tiisssuees an aand d bo bbones n s wi ne with th ppreservation rese re seervvat a io ionn off hhealthy ealt ea lthy lt hyy ssurrounding urro ur roun ro undi un d ng ttissue. issu is sue. su e All patients were scheduled to be re-admitted for control peripheral angiography at 12 months. Before angiography, duplex ultrasound (DUS) of the target vessel was consistently performed. In case of clinical CLI recurrence, angiography and repeat revascularization were performed within one week from diagnosis. In patients undergoing clinically-driven repeat angiography of the target limb between 9 months and 12 months and who did not show evidence of restenosis of the target lesion, scheduled angiography at 12 months was not performed if DUS evaluation was clearly diagnostic for vessel patency with no restenosis. Study Endpoints and Definitions 6 DOI: 10.1161/CIRCULATIONAHA.113.001811 Before, immediately after the intervention, and at follow-up, angiography of the target vessel was performed in identical projections (2 orthogonal planes for each treated lesion). The target lesion was identified by an image of the vascular anatomy and specific landmarks (collaterals, bone landmarks), with a second image showing the inflated balloon(s). These images were compared with follow-up angiograms. The primary endpoint of the study was the comparison of 12-month binary restenosis rates between the DEB and PTA groups. Restenosis was defined by angiography as a reduction Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 in the luminal diameter >50% according to the worst angiographic view within the treated lesion plus the 10-mm segments proximal and distal to it or, in the few patients who did not undergo 12-month angiography, as a peak systolic velocity ratio (PSVR) 2.5 by DUS. Pre-specified secondary endpoints of the study were: 1. Clinically-driven target lesion revascularization percutaneous intervention evaasccul ular arriz izat a ionn (TLR), at (T defined as repeat percut utan ut an neous intervent nttio i n or ssurgical u gical by-pass graft ur angiographic due tto due o the ang gio ioggrap graphi h c evidence hi evid evid iden ence en ce of of restenosis rest re steenossiss at level levvell of le of the the he treated tre reaateed lesion l si le s on on ±10 ±10 10 mm, mm, in in presence pres pr esen ence en off at at least leas le astt one one off the thhe he following fol ollo l wi lo wing ng criteria: cri rite teri te riaa: a: a) a) recurrence recu re urr r enc ence ce of of pain paiin pa in in in the the foot f ot at fo at rest reestt which whic hich ch increased inc ncre reas assed d in the foot he supine position; possit itio i n; b) io b) recurrence r cu re urr rren e ce of en of fo oot o llesion essio on or o eevidence v deenc vi ncee during duri du ring ri ng follow-up fol ollo lo oww up u of of fo foot ot llesion esion size decrease-increase behavior; c) appearance of new foot lesion. 2. Major amputation, defined as unplanned amputation of the target limb where prosthesis was required for standing or walking. 3. Target vessel occlusion (either by angiography or DUS). Acquired angiograms and DUS scans were reviewed by two blinded investigators who did not actively participate in recruitment (I.P. and G.V.) and who had no knowledge of clinical status and randomization group. Post-hoc analyses was performed for the cumulative 12-month prevalence of major adverse events (MAE: death, major amputation, TLR, and Rutherford class 4) in the two groups, 7 DOI: 10.1161/CIRCULATIONAHA.113.001811 as well as for other clinical endpoints such as rate of complete index ulcer healing, time to complete index ulcer healing and change in ankle-brachial index between baseline and follow-up. Further post-hoc exploratory comparisons were performed between long (>100 mm) vs. shorter lesions, total occlusions vs. stenosis, and true lumen vs. subintimal recanalization technique. Statistical Analysis Values are reported as numbers with relative percentage or standard deviation. Nominal variables were compared by Fisher’s exact test; continuous variables were compared with t-test. Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 Twelve-month binary restenosis rate, the primary endpoint of the study, was compared with Fisher’s exact test. Kaplan-Meier estimates and log-rank test survival methods were used to assess freedom from TLR, a secondary endpoint. Cohen’s k statistics was used too compare com ompa pare pa re angiography and DUS for detection of restenosis. All statistical computations were performed using IL). us sin ng SPSS SPSS version versi siion 17 (SPSS Inc., Chicago, IL) ). Assuming group, reported with Assumi minng a rrestenosis esteeno nosi siis ra rate tee ooff 660% 0% inn tthe he PT PTA gr grou oup, p, aass re epo port rted ed ffor orr ppatients atie at ieent ntss wi w th h extensive infrapopliteal ex xte tens nsiv ns i e in iv nfr frap apop opli op lite teaal ddisease iseaase10, we is we hypothesized hyp ypot othhesi ot hesi size zeed th that a D at DEB EB w would ould ha ould halve alv ve th the he re rrestenosis stten enossis rrate atee to at o 30% on the basis bas a is i of of the th he extremely extr ex trem tr emel em elyy positive el posiiti po tive ve result res esul u t reported ul reepo portted for for DEB DEB in in the th he superficial supe su peerffic icia iaal femoral f moral fe artery.18,19 A minimum of 63 evaluable lesions per group were considered necessary to have an 90% power (2-sided 5% significance level) to detect a 50% relative risk reduction (RRR) in the DEB group. The number of lesions per group was further increased to 70 in order to maximize study power. Assuming a rate of eligible lesions/patient=1.3, a minimum of 110 patients had to be enrolled in the study. The number of patients was increased to 130 considering a drop-out rate of 20% due to the expected high morbidity and mortality in CLI patients. 8 DOI: 10.1161/CIRCULATIONAHA.113.001811 Results Patients and Lesions During the study period, 156 patients were screened for study enrolment and 132 met the inclusion criteria and were randomized, 65 patients (80 lesions in 71 limbs) to DEB and 67 (78 lesions in 72 limbs) to PTA (Figure 1). Baseline clinical characteristics were similar between study groups (Table 1). Ten per cent of the patients in each study arm were on chronic dialysis and the majority of patients had 0-1 patent tibial arteries at baseline. Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 Procedural and angiographic characteristics are reported in Table 2. The most frequently treated vessel was the anterior tibial artery (ATA). Treated lesions had a high degree of more complexity in both study arms, as 80% of the lesions were total occlusions and m orre th than an n 220% 0% 0% were heavily calcified. Subintimal recanalization was performed in one fifth of the lesions. About underwent lesion treatment. Ab Abou outt 50 ou 50% % of o patients pat atiient ien s in both study arms under rwent inflow lesio on trea eaatm tment. Technical and clinical was cl lin nic ical success ss w as obtained obt btai aine ai nedd in ne in aall l ppatients. ll atieents.. Follow-up Fo Foll llow ll ow-u ow -up p an aand d cclinical liinic iniccal ooutcome u co ut come me No major adverse adv dvver erse se event eve v nt occurred occ ccur cc urreed in-hospital. ur in n-h -hos ospi os pita pi tal. ta l Eight l. Eig ght patients pat atie ient ie ntss died nt died during dur urin ur ingg follow-up: in foll fo llow ll ow w-uup: causes cau a ses of death included sudden death (n=3), respiratory failure (n=1), stroke (n=1), heart failure (n=1), and sepsis (n=1). Percentages of cardiac vs. noncardiac death in the two groups were not significantly different. Of the 124 patients alive at 12 months (60 patients with 74 lesions in DEB group vs. 64 patients with 74 lesions in PTA group), angiographic follow-up could not be obtained in 13 patients (5 patients for worsening of pre-existing renal failure, 2 for major stroke, 2 for congestive heart failure and 4 patients refused the examination), who underwent DUS. In the 135 lesions with both angiographic and DUS follow-up assessment, agreement for restenosis 9 DOI: 10.1161/CIRCULATIONAHA.113.001811 detection (see Methods for definitions) was good, with a k value of 0.88. Among the 73 lesions with angiographic restenosis, DUS revealed Doppler restenosis in 67 (91.7%). All cases of DUSdefined restenosis were confirmed by angiography. Among those patients who could not undergo 12-month angiography, only 2 lesions in 2 patients (1 in each group) were found to have restenosis, which was of the occlusive pattern in both. Angiograms were thus available for 67 of 74 (91%) and 68 of 74 (92%) eligible lesions in the DEB and PTA arms, respectively. No patient was lost to follow-up. Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 Clinical and angiographic data of 12-month follow-up are presented in Table 3. The primary endpoint, 12-month binary restenosis, occurred in 20(27%) and 55(75%) lesions in the DEB and PTA groups (p<0.001), respectively. Freedom from TLR was significa significantly antly ntly y hhigher ighe ig herr in he in the he DEB group (Figure 2). Thirty six (mainly planned) minor amputations were performed, 19 in the occurred, in the he PTA PTA and and 17 in in the th DEB arm, respectively (p=0.8). (p p=0.8). Only 1 major maajo j r amputation am mputation pu PTA (p=0.9). Target vessel 13(17%) DEB-treated vs. 41(55%) PTA A group (p p=0 0.99). T arge ar gett ve ge ves ssell oocclusion ssel c lu cc lussionn ooccurred ccu urr rreed iin n 13 13(1 (17% 7% %) DE DEBB treaate tedd vs s. 41 41(5 (55% (5 5%)) 5% PTA-treated vessels (p<0.001). Twelve-month MAE less DEB PT TAA-tr trea tr eate teed ve ves ssels (p (p< <0.001 <0.0 011). T welve elvee-m mon onth hM AE ooccurred cccur urre redd le esss ffrequently r quen re quentl tlyy in tl i tthe he D EB ((31%) 31% %) %) than (51%) group (p=0.02), mainly TLR han in PTA (5 51% 1%)) gr grou oupp (p ou (p=0 = .002) 2 , ma main inly in ly ddriven riv ven by by a reduction redu re duct du ctio ct ionn in io nT LR aand n bbetter nd ette et terr ul te uulcer cer healing. Rate of complete healing of the index ulcer was higher and time to index ulcer healing was shorter in the DEB group (Table 3). Subanalyses for lesion length, baseline vessel status (stenosis or occlusion) and revascularization technique (intraluminal vs. subintimal) yielded similar comparative results (Figure 3). Three vessels treated with DEB showed an increase 30% in reference vessel diameter at follow-up: interestingly, no angiographically evident flaps were visible during the initial procedure in these 3 cases. Examples of DEB-treated lesions are shown in Figures 4 and 5. 10 DOI: 10.1161/CIRCULATIONAHA.113.001811 Discussion The DEBATE-BTK is the first randomized study evaluating the efficacy, in terms of 12-month restenosis and TLR, of DEB vs. standard PTA in diabetic patients with CLI undergoing revascularization of BTK arteries. DEB significantly reduce 12-month restenosis, with a relative risk reduction (RRR) of 64%. This advantage was irrespective of lesion length, revascularization technique and baseline vessel conditions. When DEB failed to match 12-month vessel patency, the length of reocclusion was significantly shorter compared to that observed after standard PTA, Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 facilitating re-intervention. Our findings confirm, in a randomized fashion, those previously reported in a single center registry15, which evaluated 3-month binary restenosis in unselected CLI patients treated with the same DEB platform as in our study. Our data show w tthe hee ppersistence ersi er sist si sten st e ce en c of the results at 12 months and add important clinical endpoints. Moreover, the high frequency oof angiographic an ngi giog ogrraph og raph phic ic fol follow-up llo low w-up and the very low rate off ba bbail-out il-out treatment n wit nt with itth ddrug-eluting rug-eluting stents ensure en nsuure r the reliability relia iabi b liity bi y ooff ou ourr res rresults. esult sults. s s. Thee ad conferred DEB restenosis Th aadvantage dva vaanttag agee co onf n errre redd by D EB oon n re est s en enoosiis rresulted esuulte es teed in i a significant sig gnifi fica cant ca nt ddecrease ecrreas ec asse in clinically-driven value clinically-dri ive venn TLR, TLR, a secondary sec econ ec o da on dary r endpoint ry end dpo poin intt of tthe in he sstudy. t dy tu dy.. TL TLR R ha hhass an iimportant mpor mp o taant pprognostic or rogn ro g ostic valu gn ue in CLI patients, as early failure of endovascular recanalization was found to predict limb loss and poor prognosis20, and repeat interventions with multiple contrast exposures are harmful in these very sick patients with frequent life-threatening comorbidities. Besides major amputation, our study did not have pre-planned endpoints of minor amputation and healing due to the fact that vessel patency alone is considered necessary but not sufficient to guarantee amputation-free survival.2,8,21 However, post hoc analysis revealed that DEB are likely to provide significant improvement in the rate of complete index ulcer healing at 12 months. The possibility that treatment with DEB might result in significant clinical benefit is further compounded by the 11 DOI: 10.1161/CIRCULATIONAHA.113.001811 more favorable distribution of Rutherford classes at follow-up and faster index ulcer healing in the DEB group. Treatment with DEB, however, did not translate to a significantly higher rate of limb salvage due to the very low rate of major amputations (1 limb out of 143). This low rate of limb loss may depend on several factors: 1) patients were enrolled in the study only after successful wiring of the target vessel and, therefore, the rate of major amputation observed cannot be compared to that derived from studies designed on an intention-to-treat basis; 2) we established a Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 dedicated multidisciplinary team providing wound care and continuous surveillance regimen of the foot lesion and vessel patency, including fast-track angiography and re-intervention when clinically needed8,21. We previously showed the long-term benefit of this integra integrated ated t ed multidisciplinary framework in this high-risk subset of patients7. Th saafeety ooff DEB, moreover, was similar simillar tto o conventiona al ball llloo oons n , as no acute Thee safety conventional balloons, thrombosis hro omb m osis occ occurred ccuurreed oon n1m month onth on th ddual ual an ua antiplatelet ntipllat ateelet th therapy herap apyy in ap n bboth othh aarms. ot rms ms. IIn n ffew ew ccases, assess, DE DEB B we were r associated as sso soci ciat ci a ed with at with ith a llimited imi mittedd in incr increase crrea ease se iin n re reference efeere rennce nce vessel v sse ve ssel diameter diaame meteer att follow-up. fol ollo l wlo w-up up. Longer Long Lo nger ng err follow-up foollo ol oww-uup up will clarify iff th this is pphenomenon h no he nomeeno non is ooff cl clin clinical inic in iccal rrelevance. elev el ev van ance c . ce Study Limitations Like many device trials in interventional cardiology, this is not a blinded study. In addition, patients were enrolled only in a single, high-volume center that might have a unique patient referral pattern and interventional technique. In addition, this study had no financial support and no external angiography or DUS core laboratory was available for adjudication of the endpoints. However, the size of the observed effect and the additional evidence in favor of DEB in the femoropopliteal district14 leaves few chances for these results to be controverted in a multicenter randomized study. We used everolimus drug-eluting stents as a bailout, which could have 12 DOI: 10.1161/CIRCULATIONAHA.113.001811 potentially affected the study results and interacted with DEB leading to excessive neointimal inhibition. However, only two DES were implanted (one in each study group) and we did not observe any sign of positive remodelling in the single patient that was eventually treated with DEB+DES. Finally, clinical results achieved by an integrated multidisciplinary approach to CLI may not reproduced with DEB in other centers with different organization. Conclusions Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 DEB angioplasty of tibial vessel in diabetic patients with CLI is associated with a significant reduction in binary restenosis, TLR and vessel occlusion at 12 months. The higher vessel patency single-center provided by DEB translated into some clinical advantage, although our single-cen en nteer tria ttrial ria iall do does es not have the power to evaluate more patient-centered outcomes. Large multicenter randomized trials ria ials ls will wil illl be needed neeede dedd to assess whether the increased increaase s d patency of limb lim im mb arteries arrte terries afforded by DEB promotes survival. prom motes clear ar iimprovement mpro mp rovveme ment me nt iin n li limb mb ssalvage alvvagee aand al nd su urviivaal. l Conflict None. Conf Co nfli nf lict li ct of of Interest Inte In tere te rest re st Disclosures: Dis iscl clos cl osur os ures ur es:: N es onee. on References: 1. Clair D, Shah S, Weber J. Current state of diagnosis and management of critical limb ischemia. Curr Cardiol Rep. 2012;14:160-170. 2. Faglia E, Clerici G, Clerissi J, Gabrielli L, Losa S, Mantero M, Caminiti M, Curci V, Quarantiello A, Lupattelli T, Morabito A. Long-term prognosis of diabetic patients with critical limb ischemia: A population-based cohort study. Diabetes Care. 2009;32:822-827. 3. Adam DJ, Bradbury AW. Tasc ii document on the management of peripheral arterial disease. Eur J Vasc Endovasc Surg. 2007;33:1-2. 4. Verzini F, De Rango P, Isernia G, Simonte G, Farchioni L, Cao P. Results of the "endovascular treatment first" policy for infrapopliteal disease. J Cardiovasc Surg (Torino). 2012;53:179-188. 13 DOI: 10.1161/CIRCULATIONAHA.113.001811 5. Bosiers M, Hart JP, Deloose K, Verbist J, Peeters P. Endovascular therapy as the primary approach for limb salvage in patients with critical limb ischemia: Experience with 443 infrapopliteal procedures. Vascular. 2006;14:63-69. 6. Jeffcoate WJ, Price P, Harding KG. Wound healing and treatments for people with diabetic foot ulcers. Diabetes Metab Res Rev. 2004;20 Suppl 1:S78-89. 7. Liistro F, Angioli P, Grotti S, Brandini R, Porto I, Ricci L, Tacconi D, Ducci K, Falsini G, Bellandi G, Bolognese L. Impact of critical limb ischemia on long term cardiac mortality in diabetic patients undergoing percutaneous coronary revascularization. Diabetes Care. 2013;36:1495-1500. Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 8. Alexandrescu V, Hubermont G, Coessens V, Philips Y, Guillaumie B, Ngongang C, Vincent G, Azdad K, Ledent G, De Marre C, Macoir C. Why a multidisciplinary team may represent a key factor for lowering the inferior limb loss rate in diabetic neuro-ischaemic wounds: Application in a departmental institution. Acta Chir Belg. 2009;109:694-700. Ricke 9. Redlich U, Xiong YY, Pech M, Tautenhahn J, Halloul Z, Lobmann R, Adolf D, R i ke JJ,, ic predicting Dudeck O. Superiority of transcutaneous oxygen tension measurements in predi ictin ct ng li limb mb salvage alvage after below-the-knee angioplasty: A prospective trial in diabetic patientss wi with th ccritical riti ri tica ti call ca limb imb ischemia. Cardiovasc Intervent Radiol. 2011;34:271-279. 10. 10 0. Schmidt Schm Sc hmid hm idtt A, id A, Ulrich Ulr lric i h M, Winkler B, Klaefflingg C, C, Bausback Y, Braunlich Braun un nli lich c S, Botsios S, Kruse RL, Kum S,, Sc Scheinert Angiographic patency and after HJ, Varcoe HJ Va R L,, K u S um Sche hein in ner ert rt D. A ngio ng iogr g ap gr aphhicc pate teenc ncyy an nd cclinical lini li nica caal ooutcome utc tcom omee af om afte terr ba bballoonllloo oonn angioplasty for infrapopliteal disease. Catheter an ngiop o lasty fo or eextensive xttens nssiv ivee in infr fraapop fr apop pliite t al aarterial rterriaal di iseeasee. e. Ca Cath thet eter err Cardiovasc Car ardi d ovassc Interv. Inte In terv r . rv 2010;76:1047-1054. 20 010 0;76:1047 47-10054. 05 11. Ro Rocha-Singh MR, Crabtree Bloch Ansel Performance chaha-Si S ng nghh KJ KJ,, Ja JJaff ff M R C R, rabt ra b ree TR TR, B loc och DA DA, An Anse sell G.. P erfo er form man ance ce goals goalss and and d endpoint assessments asssesssm men ents t for ts for o clinical cli lini n caal trials ni tria tr ialss of ia of femoropopliteal femo fe moro mo ropo ro poopl plittea eall bare baree nitinol nit i in nol stents sten ents t in ts in patients pati pa tien ti ents with en symptomatic Catheter Cardiovasc Interv. 2007;69:910-919. ymp mpto toma mati ticc peripheral peri pe riph pher eral al arterial art rter eria iall disease. dise di seas asee Ca Cath thet eter er C ardi ar diov ovas ascc In Inte terv rv 20 2007 07;6 ;69: 9:91 9100-91 9199 12. Scheinert D, Katsanos K, Zeller T, Koppensteiner R, Commeau P, Bosiers M, Krankenberg H, Baumgartner I, Siablis D, Lammer J, Van Ransbeeck M, Qureshi AC, Stoll HP. A prospective randomized multicenter comparison of balloon angioplasty and infrapopliteal stenting with the sirolimus-eluting stent in patients with ischemic peripheral arterial disease: 1-year results from the achilles trial. J Am Coll Cardiol. 2012;60:2290-2295. 13. Rastan A, Brechtel K, Krankenberg H, Zahorsky R, Tepe G, Noory E, Schwarzwalder U, Macharzina R, Schwarz T, Burgelin K, Sixt S, Tubler T, Neumann FJ, Zeller T. Sirolimuseluting stents for treatment of infrapopliteal arteries reduce clinical event rate compared to baremetal stents: Long-term results from a randomized trial. J Am Coll Cardiol. 2012;60:587-591. 14. 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;5:582-589. 14 DOI: 10.1161/CIRCULATIONAHA.113.001811 15. Schmidt A, Piorkowski M, Werner M, Ulrich M, Bausback Y, Braunlich S, Ick H, Schuster J, Botsios S, Kruse HJ, Varcoe RL, Scheinert D. First experience with drug-eluting balloons in infrapopliteal arteries: Restenosis rate and clinical outcome. J Am Coll Cardiol. 2011;58:11051109. 16. Kumar A, Brooks SS, Cavanaugh K, Zuckerman B. Fda perspective on objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg. 2009;50:1474-1476. 17. Hansson L, Hedner T, Dahlof B. Prospective randomized open blinded end-point (probe) study. A novel design for intervention trials. Prospective randomized open blinded end-point. Blood Pressure. 1992;1:113-119. Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 18. Tepe G, Zeller T, Albrecht T, Heller S, Schwarzwalder U, Beregi JP, Claussen CD, Oldenburg A, Scheller B, Speck U. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med. 2008;358:689-699. Hosten Hamm 19. Werk M, Langner S, Reinkensmeier B, Boettcher HF, Tepe G, Dietz U, Hoste en N, N H amm am m B, Paclitaxel-coated versus Speck U, Ricke J. Inhibition of restenosis in femoropopliteal arteries: Paclitaxel l-ccoaate tedd ve vers rsus rs u us uncoated balloon: Femoral paclitaxel randomized pilot trial. Circulation. 2008;118:1358-1365. 2008;1 1188:1 :135 3588-13 35 8-13 1365 65. 65 WP, 20. Robinson W P,, 3rd, Nguyen LL, Bafford R, Belkin M. Results of second-time angioplasty and stenting disease affecting an nd st sten enti en ting ti ng ffor or ffemoropopliteal emoropopliteal occlusive diseas em asee aand as nd factors af ffe fectin ng ooutcomes. utcomes. J Vasc Surg. 2011;53:651-657. 20 011 1;5 53:65 51--65 57.. Larsson Apelqvist Agardh CD, Stenstrom A.. De Decreasing major 221. 1. L arsson J,, Ape pelqvvistt J, Ag pe Agar a dh d C D, S tennsttrom mA Dec creas cre easingg iincidence nciddennce nce ooff m ajjorr aamputation mputaatiion mp inn diabetic patients: consequence multidisciplinary care approach? Diabet Med. diaabe b ti ticc pa pati tien en ntss: A co ons nseq queenc ncee off a m ul idi ulti disc sccip pli l nary ry ffoot oo ot ca aree tteam eaam ap appr p oa pr o ch h? Di iabbet M ed ed. 1995;12:770-776. 1995 95;1 ;122:77 7700 77 776. 15 DOI: 10.1161/CIRCULATIONAHA.113.001811 Table 1. Patients baseline characteristics Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 Number of patients Age — yr Male gender — no. (%) Diabetes — no. (%) Hypertension — no. (%) Smoking — no. (%) Hypercholesterolemia — no. (%) Dialysis — no. (%) Serum creatinine — mg/dl eGFR— ml/min/1.73m2 Coronary artery disease — no. (%) Cerebrovascular disease — no. (%) Number of limbs Patent tibial vessels — no. (%): 0 1 2 ABII AB Inflow nfl floow ow lesio lesion ionn tr treatment reaatm t en nt — no no.. (% (%)) M Mean ean an Rutherf Rutherford for ordd Class Classs Clas Rutherford R utherfo ord Class Claass 4 — no. no. (%) (%) % Ruth Ru Rutherford ther th erfo er ford fo rd C Class laass 5 — nno. o.. ((%) %) Ruth Ru Rutherford ther th erfo er ford fo rd C Class lass la ss 6 — nno. o. ((%) %) Plus–minus val values allue uess ar aree me m means anss ±S an ±SD. SD. ABI kl b hi l i d ABI: A Ankle-brachial-index 16 DEB 65 74±9.4 54 (83.1) 65 (100) 46 (70.8) 13 (20.0) 23 (35.4) 7 (10.8) 1.2±0.4 51±27 12 (18.5) 5 (7.7) 71 PTA 67 75±9.6 52 (77.6) 67 (100) 52 (77.6) 7 (10.4) 16 (23.9) 7 (10.4) 1.2±0.5 54±23 10 (14.9) 7 (10.4) 72 23 (35.4) 30 (46.2) 12 (18.5) 0.31±0.2 32 32(49.2) 2(4 (499.2) 9.2) 5.15±0.4 5 15± 5. 15±0.4 .4 2 (2.8) (2.8)) (2. 56 ((78.9) 78.9 78 .99) 13 (18.3) (18.3) 3) 19 (28.4)) 37 (55.2) 11 (16.4) 0. 0.29±0.3 335 5 (5 (52.2) 52. 2.2) 2) 55.09±0.4 .0 09± 9±0. 0.44 3 (4.2) (4.2) (4.2 59(8 59 59(81.9) (81. 1 9) 1. 10 (13.9) (13.9) 9) P value 0.7 0.5 1 0.4 0.1 0.1 1 0.9 0.8 0.6 0.7 0.5 0.6 00.8 .88 00.4 .44 0.7 7 DOI: 10.1161/CIRCULATIONAHA.113.001811 Table 2. Procedural and angiographic characteristics Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 Number of lesions Vessel location — no. (%): ATA PTA PA TPT Complete vessel occlusion — no. (%) Lesion length — mm Severe calcification — no. (%) RVD — mm MLD — mm DS — % Predilatation — no. ((%)) Subintimal recanalization — no. (%) Antegrade recanalization — no. (%) Retrograde recanalization — no. (%) Balloon inflation time — sec Ball Ba Balloon lloo ll oonn di oo diam diameter ameter am err — mm Ball Ba loon leng ngtth — m m Balloon length mm B ail illou o t stenting ng — nno. o. ((%) %) Bailout Te Technical ech hni n cal su success ucc c esss — no no. (% (%) %) Proc Pr occed edur ural ur al ssuccess ucce uc cess ce sss — no. no. o. (%) %) Procedural DEB 80 PTA 78 37 (46.3) 13 (16.3) 14 (17.5) 16 (20.0) 62 (77.5) 129±83 20 (25.0) 2.91±0.27 0.06±0.14 97.2±7.7 ( ) 80 (100.0) 17 (21.3) 78 (97.5) 2 (2.5) 142±38 2.90±0.39 14 48± 8±83 8 148±83 1 (1 (1. .3)) (1.3) 80 ((100) 1000) 65(1 65 (100 (1 00)) 00 65(100) 32 (41.0) 18 (23.1) 21 (26.9) 7 (9.0) 64 (82.1) 131±79 22 (28.2) 2.87±0.29 0.05±0.14 97.1±8.0 17 (21.8 (21.8) 8) 75 (96.2) (96.2 2) 3 (3.8) 140±50 22.85±0.36 2.85 .8 ±0.36 1140±79 400±7 ±799 1 (1.3 ((1.3) 1.3)) 778 8 (1 (100 (100) 00) 6 (1 67 100 00)) 67(100) P value 0.5 0.5 0.9 0.5 0.7 0.6 0.9 00.8 0. 8 0.7 07 0. 0.7 0.5 0.4 0.5 0. 5 00.9 0. 9 1 1 Plus–minus Plus Pl us–m us min inus us vvalues alue al uess ar ue aree me mean means anss ±S an ±SD. SD. D. ATA: anteriorr ti ttibial bial bi al artery, art rter ery, er y, PTA: PTA A: posterior postter po erio i r tibial io t biial artery, ti art r er e y, PA: PA: peroneal pero pe r neeal ro a artery, art rter ery, er y, T TPT: PT T: tibioperoneal tibi ti biop bi oper op eron er onea eall trunk, ea trrun unk, k, RVD: reference minimal lumen efe fere renc ncee vessel vess ve ssel el diameter, dia iame mete terr MLD: MLD LD:: mi mini nima mall lu lume menn diameter, diam di amet eter er %D %DS: S: ppercentage erce er cent ntag agee diameter diam di amet eter er sstenosis teno te nosi siss 17 DOI: 10.1161/CIRCULATIONAHA.113.001811 Table 3. Clinical and angiographic outcome at 12 months Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 DEB 5(7.7) 0(0.0) 2 (3.1) 3 (4.6) 20 (31) 66 0.78±0.22 0.90±1.8 57 (86.3) 0 (0) 8 (12.2) 1 (1.5) 56/65 ((86)) 4.4±1.5 74 20(27.0) 13(17.6) 87±88 Death — no. (%) Major Amputation — no. (%) CVA — no. (%) AMI — no. (%) MAE — no. (%) Limbs available for 12-month follow-up ABI Mean Rutherford class category Rutherford Class 0-3 — no. (%) Rutherford Class 4 — no. (%) Rutherford Class 5 — no. (%) Rutherford Class 6 — no. (%) p g*— no. ((%)) Complete index ulcer healing Time to index ulcer healing*— months Lesions available for 12-month follow-up Binary Restenosis (>50%) — no. (%)† Vessel el Occlusion Occlu lusi s onn — no. (%)† Occlusion Occcl cluusio on le leng length gth — mm† PTA 3(4.5) 1 (1.5) 3 (4.5) 3 (4.5) 34 (51) 67 0.47±0.28 2.0±2.3 44 (65.7) 2 (3) 19 (28.3) 2 (3) 43/64 ((67)) 5.2±1.6 6 74 55(74.3) 441(55.4) 1(55.4) 1128±75 12 8±75 P value 0.4 0.9 0.9 0.9 0.05 <0.001 0.004 0.06 0.01 00.01 .0 01 <0.001 <0.001 <0.001 Pllus– Plus–minus –m –minus val values alue uess ar aree me mean means anss ±S ±SD. D D. CVA: C VA A: cerebrovascular A: cerebrovascuularr accident, acc cciideent, AMI: AMI: acute acu cutte cu te myocardial myocard diaal infarction, inffar farctioon, n, M MAE: AE: ma AE major ajo or ad adverse dversse ev eve events. ents ts. * Refers R efe fers to limb fe limbs mbss ava available aillablee fo for or 12 12-month 2-month on h fol follow-up olllo low w-up with w-u withh Rutherford Rutther therfo ford rd cclass lasss 5-6 att basel la baseline linne †P †Per Per llesion esio es ion analysis anal an alys al ysis is Figure Legends: Figure 1. Study Flow. Figure 2. Kaplan-Meyer analysis for survival free from target lesion revascularization (TLR) in both study groups. Figure 3. Post-hoc analysis of restenosis (%) in different subgroups of the 2 study groups. 18 DOI: 10.1161/CIRCULATIONAHA.113.001811 Figure 4. Right limb below the knee (BTK) vessels in a 76-year old male with critical limb ischemia. Panel A: stenosis in the proximal segment of the peroneal artery (PA); long diseased segment of the posterior tibial artery (PTA, black arrows). Panel B: patent plantar arteries. Panel C: Dilatation of the proximal segment of the tibioperoneal trunk and PTA with a 3.0x120mm drug-eluting balloon (DEB, Amphirion In.Pact, Medtronic, Santa Rosa, CA). Panel D: Dilatation of the mid-distal segment of the PTA with a 3.0x120mm DEB (Amphirion In.Pact, Medtronic, Santa Rosa, CA) overlapping for 10mm with the segment previously treated with the other DEB. Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 Panel E: immediate angiographic result with good patency of the PTA without residual stenosis. The PA lesion could not be enrolled in the study (length <40 mm) and was dilated with conventional, non-eluting balloon (not shown). Panel D: Twelve-month follow-u follow-up up aangiography up nggio iogr grap gr aphy ap hy showing howing optimal patency of the PTA without restenosis. Figure knee male limb Figu gure u 5. Right Rig ght llimb im mb be bbelow low lo w th thee kn nee ((BTK) BTK)) vvessels BT esseelss inn a 778-year 8-yyear yearr oold ld m alle wi with th ccritical riti ri tiica c l li imb ischemia: artery (upper sch chem em mia ia:: Panel Pane Pa nell A: proximal pro oxima xim l occlusion occl oc clus cl usiion us ion of the the anterior anteeriior o ttibial ib bia iall ar arte t ry te ry ((ATA) ATA TA)) (u upp pper e bblack er lack la k aarrow) rrow rrow w) with filling of of the the dorsalis dors do rssal alis pedis ped ediss artery a teery (lower ar (lo owe werr black b ac bl a k arrow) a roow) by ar by the the peroneal pero pe rone ro neal ne al artery artter eryy (PA), (PA) (P A , which shows significant stenosis in the proximal segment (white arrows); occlusion of the posterior tibial artery (PTA) with collateral filling of the plantar arteries by the PA. Panel B: Immediate results after drug-eluting balloon (DEB, Amphirion In.Pact, Medtronic, Santa Rosa, CA) dilation of both ATA (3.5x120mm+3x120mm+3x80mm) and PA (3,5x120mm). Panel B: immediate angiographic result with no residual stenosis of both ATA and PA. Panel C: Twelve-month follow-up angiography showing good patency of both ATA and PA arteries. Black arrow indicates focal ectasia of the ATA in the segment previously treated with DEB. 19 Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 156 diabetic patients with CLI (Rutherford class4) with at least one 50% stenosis of tibial vessels vessels 40mm in length with distal run-off 24 excluded 16 did not meet angiographic inclusion criteria 2 need for major amp amputation utat tatio ion n 4 lack of consent 2 life expectancy < 1 year yea 132 patients with 158 lesions in 143 limbs e enrolled n olled nr 1:1 1: 1 1 Randomization R nd Ra n omiz i attio ion 12-month FUP Figure 1 DEB DEB 65 patients, 80 lesions in 71 limbs PTA PTA 67 patients, 78 lesions in 72 limbs Death = 5 Death = 3 67 lesions Angio FUP1 7 lesions DUS FUP2 68 lesions Angio FUP1 6 lesions DUS FUP2 1 Angio FUP performed at 12 months or at the time of TLR 2 DUS=Doppler Ultrasoud imaging Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 Figure 2 Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 Figure 3 Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 Figure 4 Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 Figure 5 Drug-Eluting Balloon in peripherAl inTErvention for Below the Knee Angioplasty Evaluation (DEBATE-BTK): A Randomized Trial in Diabetic Patients with Critical Limb Ischemia Francesco Liistro, Italo Porto, Paolo Angioli, Simone Grotti, Lucia Ricci, Kenneth Ducci, Giovanni Falsini, Giorgio Ventoruzzo, Filippo Turini, Guido Bellandi and Leonardo Bolognese Downloaded from http://circ.ahajournals.org/ by guest on September 29, 2016 Circulation. published online June 24, 2013; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/early/2013/06/24/CIRCULATIONAHA.113.001811 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/