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Drug-eluting balloons for femoropopliteal lesions show better performance in de novo stenosis or occlusion than in restenosis
From the Society for Vascular Surgery
Drug-eluting balloons for femoropopliteal lesions show better performance in de novo stenosis or occlusion than in restenosis Monika Herten, PhD,a Giovanni B. Torsello, PhD,a,b Eva Schönefeld, MD,a,b Britta Imm,a Nani Osada, PhD,a and Stefan Stahlhoff, MD,a Münster, Germany Objective: Although drug-eluting balloons (DEBs) have shown promising results treating de novo (DN) atherosclerotic lesions and appear to have been widely adopted in Europe, their long-term efficacy in the broad spectrum of femoropopliteal restenosis (RE) remains to be proven. The purpose of the study was to assess the efficacy of paclitaxel-DEBs in restenotic (stented and nonstented) vs DN stenotic femoropopliteal arteries. Methods: The study prospectively enrolled 100 patients undergoing femoropopliteal endovascular intervention by DEB for RE or DN stenosis. Patients who received additive atherectomy were excluded. The primary end point was the primary patency (PP) rate at 12 months. Secondary end points were sustained clinical improvement and clinically driven target lesion revascularization. Results: DEBs were used to treat 105 limbs for intermittent claudication (82 [78%]) or critical limb ischemia (23 [22%]) in 100 patients. Of these, 111 lesions were DN stenosis (46 [41%]) or RE (65 [59%]). The overall PP was 86% at 6 months and 74% at 12 months. PP of DN stenosis was higher at 6 months (93% vs 81%) and was significantly (P [ .021) better than RE at 12 months (85% vs 68%). Sustained clinical improvement based on Rutherford classification was significant in both groups (P < .001). Target lesion revascularization was significantly lower in DN stenosis compared with RE at 12 months (15% vs 32%; P [ .021). Conclusions: DEB angioplasty is an effective therapy for DN femoropopliteal lesions. The results of DEB angioplasty for RE are inferior compared with DN stenosis after 12 months. Nevertheless, results of DEB angioplasty for RE seem comparable with technically more demanding literature-derived strategies. (J Vasc Surg 2014;-:1-6.)
The role of the drug-eluting balloon (DEB) in the therapy for atherosclerotic lesions is well established. Recent randomized clinical trials (RCTs) showed paclitaxel (PTX)-DEB angioplasty was superior compared with standard uncoated percutaneous transluminal angioplasty (PTA). Results demonstrated effectiveness in above-theknee lesions,1-5 whereas contradictory outcomes in safety and efficacy have been reported for below-the-knee lesions.6,7 The target lesion revascularization (TLR) rate after PTA of the femoropopliteal region ranges between 22% and 37% at 6 months and between 28% and 48% at 12 months. DEB angioplasty significantly reduced the TLR to 4% to 13% at 6 months and to 7% to 18% at 12 months.1-5 However, most lesions treated within the published studies and registries have been de novo (DN)
From the Department of Vascular and Endovascular Surgery, University of Münstera; and the Department of Vascular Surgery, St. FranziskusHospital Münster.b Author conflict of interest: none. Presented as an oral presentation at the 2014 Vascular Annual Meeting of the Society for Vascular Surgery, Boston, Mass, June 4-7, 2014. Reprint requests: Monika Herten, PhD, Department of Vascular and Endovascular Surgery, University of Münster, University Hospital, Albert-Schweitzer-Campus 1, W30, 48149 Münster, Germany (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2014 by the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvs.2014.08.005
stenosis, ranging from 63% to 100% in above-the-knee13,5,8,9 and from 65% to 100% in below-the-knee studies.6,7,10 For femoropopliteal in-stent restenosis (RE), some data indicate a promising role of DEBs, with a TLR rate at 1 year of 7.9%,11 9.8%,12 and 13.6%.13 DEBs in combination with directed atherectomy achieved TLR rates of 10%14 and 15.3%.15 However, long-term patency rates are still missing. The purpose of the study was to assess the efficacy of PTX-DEB in RE (stented and nonstented) vs DN stenotic femoropopliteal arteries. METHODS This study was conducted in agreement with the International Conference on Harmonization Guidelines, Good Clinical Practice, Declaration of Helsinki, and Ethics Committee requirements. Study population. Between October 2009 and February 2013, 111 lesions in 100 consecutive patients with intermittent claudication (78%) or critical limb ischemia (22%) underwent femoropopliteal endovascular intervention with intention to treat by DEB angioplasty in two centers. Clinical data were collected prospectively (Table I). All patients provided written informed consent before the intervention. Patients and lesions. Lesions were categorized according to their etiology as RE (n ¼ 65), in-stent or not in-stent, or DN (n ¼ 46; Fig 1). Plaque excision with and without DEBs was performed only in short lesions. No other procedures were performed for RE during the study 1
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Table I. Baseline demographic and clinical data Variablea
RE
DN
Patients (n ¼ 100) 61 (61) 39 (39) Limbs (n ¼ 105) 63 (60) 42 (40) Age, years 69.9 6 11.0 66.3 6 10.8 Male 35 (57) 23 (59) Arterial hypertension 50 (82) 33 (85) Diabetes mellitus 23 (38) 10 (26) History of smoking 15 (25) 22 (56) Hyperlipidemia 35 (57) 23 (59) Obesity 15 (25) 15 (38) Dialysis 1 (2) 0 (0) Limbs Intermittent claudication 45 (71) 37 (88) Critical limb ischemia 18 (29) 5 (12) Preinterventional Rutherford classification 3 (1, 5) 3 (2, 5) ABI 0.57 6 0.29 0.68 6 0.25
P value
.104 .875 .731 .211 .001 .875 .140 1.000 .055 .055 .179 .048
ABI, Ankle-brachial index; DN, de novo (the DN stenosis group included only native stenotic vessels); RE, restenosis (the RE group included stented and nonstented restenotic arteries). a Continuous data are shown as mean 6 standard deviation or as median (minimum, maximum) and categoric data as number (%).
period. The evaluation excluded patients who received additional atherectomy. Lesions characteristics are reported in Table II. Because the RE group comprised patients with lower baseline ankle-brachial indices (ABIs) and with longer lesions, those lesions were at higher risk. Procedure and devices. Vascular access was accomplished by a contralateral or ipsilateral transfemoral approach. Heparin (5000 units) was given after vascular access was performed. Predilatation PTA was systematically performed before treatment with IN.PACT Admiral (Medtronic GmbH, Meerbusch, Germany) or Freeway (Eurocor GmbH, Bonn, Germany) PTX-DEB systems. Both DEBs contained PTX at a concentration of 3 mg/mm.2 The procedural details are listed in Table II. In case of persistent flow-limiting dissections or recoil after balloon dilatation, additional self-expanding nitinol stents were implanted as provisional stenting. End points and definitions. Primary end point was the primary patency (PP), defined as freedom from RE >50% of the target lesion by duplex ultrasound imaging based on a peak systolic velocity ratio >2.4 m/s at the lesion site. Hemodynamic parameters by duplex ultrasound imaging were combined with, at minimum, one clinically driven parameter: decrease of Rutherford class $1 or ABI decrease >20%. In a subanalysis, we analyzed PP with or without provisional stenting. Secondary end points were secondary sustained clinical improvement and symptom-driven TLR at 12 months. Secondary sustained clinical improvement was defined as an improvement shift of the Rutherford classification of $1 category for claudicant patients and rest pain resolution for patients with critical limb ischemia. Clinically driven TLR expresses the need for repeated procedures (surgical or endovascular) at the site of the previously treated lesion.
Fig 1. Study flow. ABI, Ankle-brachial index; DEB, drug-eluting balloon; FU, follow-up; ISR, in-stent restenosis.
Statistical analysis. Statistical analysis was performed using SPSS 22.0 software (IBM Corp, Armonk, NY). Continuous variables are presented as mean 6 standard deviation and categoric variables as frequency and percentage. Ordinal parameters (Rutherford classification) are expressed as median with the minimum and maximum or with the interquartile range (25th percentile-75th percentile). Analysis of normal distribution of each continuous variable was performed by the Kolmogorov-Smirnov test before further statistical testing. The Mann-Whitney U test was used for comparison of nonparametric values between two study groups. Paired continuous nonparametric data were compared by the Wilcoxon test; proportions were compared by c2 test and by Fisher exact test, as appropriate. Survival and patency rates were determined with the Kaplan-Meier estimate in a time-to-event model. The logrank test was used for estimating the effect of variables on the clinical outcome. Differences were considered significant at P < .05. RESULTS Baseline characteristics of patients and lesions. The RE and DN groups did not differ significantly except for a significantly higher rate of smokers in the DN group. Preinterventional Rutherford classes were comparable between the groups. Baseline ABIs were significantly lower in the RE than in the DN group (P ¼ .048). Lesion and procedural characteristics are listed in Table II. There was no significant difference in parameters apart from the longer lesion length in the RE group (P ¼ .05). IN.PACT and Freeway were overall used in 95 and 16 cases, respectively,
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Table II. Lesion characteristics and procedural detail Variablea Lesions (n ¼ 111) In-stent RE Superficial femoral artery Popliteal artery involved Lesion length, mm Degree of stenosis, % Total occlusion DEB lesions, No. Length of PTX-DEB, mm PTX-DEB diameter, mm Inflation pressure, bar Inflation time, seconds
RE
DN
65 (59) 46 (71) 49 (75) 16 (24) 99 6 76 82 6 16 16 (25) 1.2 6 0.6 129 6 71 4.9 6 0.5 13 6 7 148 6 80
46 (41) 29 (64) 17 (37) 77 6 68 81 6 18 12 (27) 1.3 6 0.7 122 6 78 4.9 6 0.6 12 6 6 159 6 52
P value
.161 .161 .050 .900 .935 .191 .289 .553 .507 .223
DEB, Drug-eluting balloon; DN, de novo (the DN stenosis group included only native stenotic vessels); PXT, paclitaxel; RE, restenosis (the RE group included stented and nonstented restenotic arteries. a Continuous variables are presented as mean 6 standard deviation and categoric variables as number (%).
and their distribution was not significantly different across the RE (80% and 20%) vs DN groups (93% and 7%; P ¼ .057). Additional stenting was performed in 20 lesions (18%) and was necessary significantly more often in DN (12 lesions [28%]) than in RE (eight lesions [7%]; P ¼ .007). Primary end point. Overall PP was 86% and 74% at 6 and 12 months after DEB application. PP of DN was better than of RE at 6 months (93% vs 81%, P ¼ .093) and was significantly better at 12 months (85% vs 68%; P ¼ .021; Fig 2 and Table III). Subanalysis of PP without provisional stenting revealed superior rates for DN at 6 months (97% vs 80%; P ¼ .028) and at 12 months (89% vs 67%; P ¼ .007; Table III). Secondary end point. The ABI significantly improved, from 0.61 at preintervention to 0.87 at 12 months (P ¼ .037). Within the groups, ABI increased significantly in RE, from 0.57 6 0.29 at preintervention to 0.85 6 0.20 at 12 months (P < .001) and in DN from 0.68 6 0.25 to 0.90 6 0.12, respectively (P < .001; Table IV). In both groups, secondary sustained clinical improvement was demonstrated by the shift of at least one category of the Rutherford classification at 12 months (P < .001) without difference between the two groups (RE, 78%; DN, 83%; P ¼ .568; Table V). TLR after treatment of DN was lower, at 7% and 15% at 6 and 12 months, respectively, compared with 19% and 32% for RE (Table VI). Subanalysis of TLR without provisional stenting revealed superior rates for DN at 6 (3% vs 20%, P ¼ .028) and 12 months (10% vs 32%; P ¼ .007). No amputation was necessary at 12 months of follow-up. No major adverse cardiac or cerebrovascular events occurred during the hospital stay. Seven patients died for reasons not related to the intervention, five from the RE group and two from the DN group. Fig 3 shows that the cumulative survival rates by KaplanMeier method of both groups did not differ significantly (P ¼ .965).
Fig 2. Primary patency (PP) rate by Kaplan-Meier method after drug-eluting balloon (DEB) intervention of restenotic (RE) or de novo (DN) stenotic femoropopliteal arteries. Standard errors were #3.7% for RE and #6.4% for DN.
Table III. Primary patency (PP) at 6 and 12 months, including or excluding provisional stenting in restenotic (RE) or de novo (DN) stenotic femoropopliteal arteriesa Including bailout stenting PP Patients, No. 6 months, % 12 months, %
Excluding bailout stenting
Both P value P value groups RE DN RE vs DN RE DN RE vs DN 100 86 74
61 81 68
39 93 85
.093 .021
53 80 67
27 97 89
.028 .007
a The DN stenosis group included only native stenotic vessels and the RE group included stented and nonstented restenotic arteries.
DISCUSSION The present study shows that PTX-DEBs are safe and effective in treating femoropopliteal lesions. However, the results are significantly better after treatment of DN than after RE lesions. Treatment of femoropopliteal restenotic lesions, particularly after stenting, is associated with inferior outcomes and a higher rate of RE recurrence vs DN lesions. In our study, the results of the DN group are in line with RCTs comparing DEB angioplasty with uncoated-balloon PTA in the superficial femoral artery (Femoral Paclitaxel Randomized Pilot Trial [FemPac Trial], Local Taxan with Short Time Contact for Reduction of Restenosis in Distal Arteries
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Table IV. Comparative ankle-brachial index (ABI) values, before and and at 12 months’ follow-up after drug-eluting balloon (DEB) intervention, of restenotic (RE) or de novo (DN) stenotic femoropopliteal arteries ABI valuea Baseline At 12 months Difference 12 months e baseline Improved outcome at 12 months P value baseline vs 12 months
RE
DN
P value
0.57 6 0.29 0.85 6 0.20 0.25 6 0.25
0.68 6 0.25 0.90 6 0.12 0.22 6 0.28
.048 .422 .419
37/46 (80)
25/34 (73)
.732
<.001
<.001
Data are shown as mean 6 standard deviation or as number (%).
a
[THUNDER Trial], Paclitaxel-coated Balloons in Femoral Indication to Defeat Restenosis [PACIFIER Trial], The Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropoliteal Restenosis [LEVANT-I Trial], First in Man study to assess the safety and performance of the coated Passeo-18 Lux Paclitaxel releasing PTA Balloon Catheter vs an uncoated balloon catheter in patients with stenosis and occlusion of the femoropopliteal arteries [BIOLUX P1 Trial]),1-4 while outcomes of the RE group appear to be less favorable compared with what has previously been reported for in-stent RE. In particular, TLR rates after treatment of DN stenosis are reported to be 6.9% and 15.1% at 6 and 12 months, respectively. Despite the significant occurrence of femoropopliteal RE in clinical practice, few data are available on the effectiveness of DEB under these conditions. Stabile et al11 reported excellent results after treatment of in-stent RE with DEB angioplasty (7.9% TLR at 1 year)11 in the Femoral Artery In-Stent Restenosis (FAIR) trial of 9.2%,12 and Liistro et al13 reported 13.6%. In our study, TLR of the RE group (with 70% proportion of in-stent RE) was 19% and 32% at 6 and 12 months. The results are better than after standard PTA, with TLR between 39% and 78% after PTA16,17 and 65% at 6 months after cutting balloon.18 The results after DEB are better or similar to technically more demanding strategies such as cryoplasty and stenting,19-21 rotational atherectomy, directed atherectomy, and laser atherectomy, with TLR of 42%,22 31% to 75%,23-27 and 48% to 51%,28,29 respectively. Also the results of directional atherectomy alone24-27 or combined with heparin-coated stent grafts30 could not reach better results at 12 months, with 60% requiring additional PTA.26 The problem of recurrent in-stent RE might not be solved with stenting, debulking technology, or DEB alone; therefore, appropriately powered trials are required to evaluate the role of different technologies and strategies to improve the results of treatment of RE in the peripheral arteries. Promising results could be reached by standard PTA combined with brachytherapy31 or drug-eluting stents (DES),32 but long-term results are still lacking.
Table V. Comparative Rutherford categories, before and at 12 months’ follow-up after drug-eluting balloon (DEB) intervention, of restenotic (RE) or de novo (DN) stenotic femoropopliteal arteries Rutherford classificationa Before DEB At 12 months Improved outcome at 12 months P value before vs 1 year
RE
P value RE vs DN
DN
3 (3-4) 3 (3-3) 1 (0-3) 1 (0-2) 38/48 (80) 26/32 (81) <.001
.201 .814 .819
<.001
a Continuous values are median (interquartile range [25th-75th percentile]) and categoric values are number (%).
Table VI. Target limb revascularization (TLR) at 6 and 12 months including or excluding provisional stenting in restenotic (RE) or de novo (DN) stenotic femoropopliteal arteriesa Including bailout stenting TLR rate Patients, No. 6 months, % 12 months, %
Excluding bailout stenting
Both P value P value groups RE DN RE vs DN RE DN RE vs DN 100 14 26
61 19 32
39 7 15
.093 .021
53 20 32
27 3 10
.028 .007
a The DN stenosis group included only native stenotic vessels, and the RE group included stented and nonstented RE arteries.
Fig 3. Cumulative survival rates by Kaplan-Meier method after drugeluting balloon (DEB) intervention (including provisional stenting) of restenotic (RE) or de novo (DN) stenotic femoropopliteal arteries. Standard errors were #6.1% for RE and #6.8% for DN.
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The disparate results between DN and RE might be due to different efficacies of PTX distribution in DN or RE lesions. Several animal studies demonstrated that PTX reaches the target, the smooth muscle cell (SMC) layer, despite intimal plaque in DN stenotic vessels.33,34 In RE lesions, a vascular injury is seen after PTA and after stenting that leaves a stimulus for subsequent repair mechanism. Stimulation of the mitotic cell cycle is the final common pathway that leads to intimal hyperplasia after vascular injury. SMCs convert from the contractile phenotype to a dedifferentiated synthetic phenotype that starts to secrete extracellular matrix components. RE occurs when this proinflammatory regenerative process is not counterbalanced by appropriate stimuli for matrix-degrading enzymes. The composition of the extracellular matrix components changes from a provisional fibrin-rich to a permanent matrix. These changes are accompanied by a reduced SMC density.35 Because the innermost vessel layer forming the RE consists mainly of noncellular material, the cytotoxic effect of the PTX may not be able to reach the cellular layer.36 Atherectomy could offer the possibility to remove these inner layers enabling the PTX to reach the target cells. In the coronary arteries, DEB angioplasty is currently indicated for in-stent RE.37 Findings from a world-wide registry of the coronary SeQuent Please DEB (B. Braun Melsungen AG, Melsungen, Germany) suggested that PTX-DEB angioplasty is more effective in bare mental stent RE compared with DES RE, independent of stent design.38 Recent studies provide robust evidence suggesting that DEBs are as effective as first-generation DESs for patients with RE after implantation of DESs39 and that the use of a different drug (switch strategy) in patients with coronary DES in-stent RE has been advocated from the Restenosis Intra-Stent: Balloon Angioplasty vs DrugEluting Stent (RIBS III) trial by Alfonso et al.40 Even if the outcomes of same therapy concepts can be different between the coronary and peripheral arteries, the advantage of DEBs is the combination of effectiveness and simplicity of use. By removing the need for an additional stent layer, DEBs might become the treatment of choice in the future. Results with DEBs are likely to vary according to the underlying arterial wall composition (ie, neointimal hyperplasia, neoatherosclerosis). In the future, imageguided procedures could enable characterization of the heterogenous tissue causing RE and theoretically drive the decision on an optimal, tailored treatment to ultimately improve outcomes.41,42 The main limitation of our study is the limited patient numbers treated with two different DEBs and the lack of randomization. In addition, the inferior results in the RE group are driven by the high percentage of patients treated for in-stent RE. Furthermore, the lower baseline ABIs and the longer lesions in the RE group imply that those lesions are at higher risk and that the RE group could be expected to have lower patency after the DEB angioplasty. However, the results were obtained under real-life conditions in consecutively treated patients.
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The present data mirror a tendency toward a treatment modification regarding DEBs for DN and RE lesions. The results do not offer evidence but the necessity to investigate in a future RCT on DEB indication. A proof of concept is still an issue of debate concerning DN and RE lesions. CONCLUSIONS The data suggest that use of DEBs is effective for DN femoropopliteal lesions. The results of DEBs for RE may be inferior and possibly comparable with other more technically demanding strategies. Future evaluation needs to show whether better results can been obtained in combination with debulking procedures. Here, the endovascular approach should ideally combine mechanical and biological effects without additional metal in the artery. The advantage of DEB treatment is that nothing is left behind in contrast to standard of care for long femoropopliteal lesions by stent implantation. Further and secondary revascularizations can be performed more easily without preimplanted foreign material. AUTHOR CONTRIBUTIONS Conception and design: GT, SS Analysis and interpretation: MH, GT, NO, ES, SS Data collection: MH, BI, SS Writing the article: MH, GT, ES, SS Critical revision of the article: MH, GT, BI, NO, ES, SS Final approval of the article: MH, GT, BI, NO, ES, SS Statistical analysis: MH, NO, ES Obtained funding: Not applicable Overall responsibility: MH REFERENCES 1. Tepe G, Zeller T, Albrecht T, Heller S, Schwarzwalder U, Beregi JP, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med 2008;358:689-99. 2. Werk M, Langner S, Reinkensmeier B, Boettcher HF, Tepe G, Dietz U, et al. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation 2008;118:1358-65. 3. Werk M, Albrecht T, Meyer DR, Ahmed MN, Behne A, Dietz U, et al. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv 2012;5:831-40. 4. Deloose K, Lauwers K, Callaert J, Maene L, Keirse K, Verbist J, et al. Drug-eluting technologies in femoral artery lesions. J Cardiovasc Surg 2013;54:217-24. 5. Scheinert D, Duda S, Zeller T, Krankenberg H, Ricke J, Bosiers M, et al. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv 2014;7:10-9. 6. Fanelli F, Cannavale A, Boatta E, Corona M, Lucatelli P, Wlderk A, et al. Lower limb multilevel treatment with drug-eluting balloons: 6month results from the DEBELLUM randomized trial. J Endovasc Ther 2012;19:571-80. 7. Liistro F, Porto I, Angioli P, Grotti S, Ricci L, Ducci K, et al. DrugEluting Balloon in peripherAl inTErvention for Below the Knee Angioplasty Evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia. Circulation 2013;128:615-21.
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8. Micari A, Cioppa A, Vadala G, Castriota F, Liso A, Marchese A, et al. Clinical evaluation of a paclitaxel-eluting balloon for treatment of femoropopliteal arterial disease: 12-month results from a multicenter Italian registry. JACC Cardiovasc Interv 2012;5:331-8. 9. Micari A, Cioppa A, Vadala G, Castriota F, Liso A, Marchese A, et al. 2-year results of paclitaxel-eluting balloons for femoropopliteal artery disease: evidence from a multicenter registry. JACC Cardiovasc Interv 2013;6:282-9. 10. Schmidt A, Piorkowski M, Werner M, Ulrich M, Bausback Y, Braunlich S, et al. First experience with drug-eluting balloons in infrapopliteal arteries: restenosis rate and clinical outcome. J Am Coll Cardiol 2011;58:1105-9. 11. Stabile E, Virga V, Salemme L, Cioppa A, Ambrosini V, Sorropago G, et al. Drug-eluting balloon for treatment of superficial femoral artery in-stent restenosis. J Am Coll Cardiol 2012;60:1739-42. 12. Krankenberg H. FAIR: drug-eluting balloon vs PTA for superficial femoral artery in-stent restenosis. Leipzig, Germany: The Leipzig Interventional Course (LINC); 2014. Available at: http://www. leipzig-interventional-course.com/index.php?option¼com_content&task ¼view&id¼253&Itemid¼354. Accessed May 2, 2014. 13. Liistro F, Angioli P, Porto I, Ricci L, Ducci K, Grotti S, et al. Paclitaxeleluting 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. 14. Cioppa A, Stabile E, Popusoi G, Salemme L, Cota L, Pucciarelli A, et al. Combined treatment of heavy calcified femoro-popliteal lesions using directional atherectomy and a paclitaxel coated balloon: one-year single centre clinical results. Cardiovasc Revasc Med 2012;13:219-23. 15. Sixt S, Carpio Cancino OG, Treszl A, Beschorner U, Macharzina R, Rastan A, et al. Drug-coated balloon angioplasty after directional atherectomy improves outcome in restenotic femoropopliteal arteries. J Vasc Surg 2013;58:682-6. 16. Tosaka A, Soga Y, Iida O, Ishihara T, Hirano K, Suzuki K, et al. Classification and clinical impact of restenosis after femoropopliteal stenting. J Am Coll Cardiol 2012;59:16-23. 17. Armstrong EJ, Singh S, Singh GD, Yeo KK, Ludder S, Westin G, et al. Angiographic characteristics of femoropopliteal in-stent restenosis: association with long-term outcomes after endovascular intervention. Catheter Cardiovasc Interv 2013;82:1168-74. 18. Dick P, Sabeti S, Mlekusch W, Schlager O, Amighi J, Haumer M, et al. Conventional balloon angioplasty versus peripheral cutting balloon angioplasty for treatment of femoropopliteal artery in-stent restenosis: initial experience. Radiology 2008;248:297-302. 19. Banerjee S, Das TS, Abu-Fadel MS, Dippel EJ, Shammas NW, Tran DL, et al. Pilot trial of cryoplasty or conventional balloon postdilation of nitinol stents for revascularization of peripheral arterial segments: the COBRA trial. J Am Coll Cardiol 2012;60:1352-9. 20. Shammas NW, Coiner D, Shammas G, Christensen L, Jerin M. Percutaneous lower extremity arterial interventions using primary balloon angioplasty versus cryoplasty: a randomized pilot trial. Cardiovasc Revasc Med 2012;13:172-6. 21. Shin SH, Baril DT, Chaer RA, Makaroun MS, Marone LK. Cryoplasty offers no advantage over standard balloon angioplasty for the treatment of in-stent stenosis. Vascular 2013 March 14; [Epublication ahead of print]. 22. Silingardi R, Cataldi V, Moratto R, Azzoni I, Veronesi J, Coppi G. Mechanical thrombectomy in in-stent restenosis: preliminary experience at the iliac and femoropopliteal arteries with the Rotarex System. J Cardiovasc Surg 2010;51:543-50. 23. Shammas NW, Shammas GA, Helou TJ, Voelliger CM, Mrad L, Jerin M. Safety and 1-year revascularization outcome of SilverHawk atherectomy in treating in-stent restenosis of femoropopliteal arteries: a retrospective review from a single center. Cardiovasc Revasc Med 2012;13:224-7. 24. Trentmann J, Charalambous N, Djawanscher M, Schafer J, Jahnke T. Safety and efficacy of directional atherectomy for the treatment of instent restenosis of the femoropopliteal artery. J Cardiovasc Surg 2010;51:551-60.
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25. Zeller T, Rastan A, Sixt S, Schwarzwalder U, Schwarz T, Frank U, et al. Long-term results after directional atherectomy of femoro-popliteal lesions. J Am Coll Cardiol 2006;48:1573-8. 26. Beschorner U, Krankenberg H, Scheinert D, Sievert H, Tubler T, Sixt S, et al. Rotational and aspiration atherectomy for infrainguinal instent restenosis. Vasa 2013;42:127-33. 27. Minko P, Katoh M, Jaeger S, Buecker A. Atherectomy of heavily calcified femoropopliteal stenotic lesions. J Vasc Interv Radiol 2011;22: 995-1000. 28. Shammas NW, Shammas GA, Hafez A, Kelly R, Reynolds E, Shammas AN. Safety and one-year revascularization outcome of excimer laser ablation therapy in treating in-stent restenosis of femoropopliteal arteries: a retrospective review from a single center. Cardiovasc Revasc Med 2012;13:341-4. 29. Zeller T. Final results of the PATENT (Photo-Ablation Using the Turbo-Booster and Excimer Laser for In-Stent Restenosis Treatment) registry. Leipzig, Germany: Leipzig International Course (LINC); 2013. 30. Laird JR Jr, Yeo KK, Rocha-Singh K, Das T, Joye J, Dippel E, et al. Excimer laser with adjunctive balloon angioplasty and heparin-coated self-expanding stent grafts for the treatment of femoropopliteal artery in-stent restenosis: twelve-month results from the SALVAGE study. Catheter Cardiovasc Interv 2012;80:852-9. 31. Werner M, Scheinert D, Henn M, Scheinert S, Braunlich S, Bausback Y, et al. Endovascular brachytherapy using liquid betaemitting rhenium-188 for the treatment of long-segment femoropopliteal in-stent stenosis. J Endovasc Ther 2012;19:467-75. 32. Zeller T, Dake MD, Tepe G, Brechtel K, Noory E, Beschorner U, et al. Treatment of femoropopliteal in-stent restenosis with paclitaxel-eluting stents. JACC Cardiovasc Interv 2013;6:274-81. 33. Axel DI, Kunert W, Goggelmann C, Oberhoff M, Herdeg C, Kuttner A, et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation 1997;96:636-45. 34. Schnorr B, Kelsch B, Cremers B, Clever YP, Speck U, Scheller B. Paclitaxel-coated balloonsdsurvey of preclinical data. Minerva Cardioangiol 2010;58:567-82. 35. Yahagi K, Otsuka F, Sakakura K, Sanchez OD, Kutys R, Ladich E, et al. Pathophysiology of superficial femoral artery in-stent restenosis. J Cardiovasc Surg 2014;55:307-23. 36. Van den Berg JC. Towards a better understanding and more efficient treatment of in-stent restenosis. J Cardiovasc Surg 2014;55:305-6. 37. Loh JP, Waksman R. Paclitaxel drug-coated balloons: a review of current status and emerging applications in native coronary artery de novo lesions. JACC Cardiovasc Interv 2012;5:1001-12. 38. Wöhrle J, Zadura M, Mobius-Winkler S, Leschke M, Opitz C, Ahmed W, et al. SeQuent Please World Wide Registry: clinical results of SeQuent Please paclitaxel-coated balloon angioplasty in a largescale, prospective registry study. J Am Coll Cardiol 2012;60: 1733-8. 39. Byrne RA, Neumann FJ, Mehilli J, Pinieck S, Wolff B, Tiroch K, et al. Paclitaxel-eluting balloons, paclitaxel-eluting stents, and balloon angioplasty in patients with restenosis after implantation of a drug-eluting stent (ISAR-DESIRE 3): a randomised, open-label trial. Lancet 2013;381:461-7. 40. Alfonso F, Perez-Vizcayno MJ, Dutary J, Zueco J, Cequier A, GarciaTouchard A, et al. Implantation of a drug-eluting stent with a different drug (switch strategy) in patients with drug-eluting stent restenosis. Results from a prospective multicenter study (RIBS III [Restenosis Intra-Stent: Balloon Angioplasty Versus Drug-Eluting Stent]). JACC Cardiovasc Interv 2012;5:728-37. 41. Alfonso F, Perez-Vizcayno MJ. Drug-eluting balloons for restenosis after stent implantation. Lancet 2013;381:431-3. 42. Steigen SE, Holm NR, Butt N, Maeng M, Otsuka F, Virmani R, et al. Clinical use of optical coherence tomography to identify angiographic silent stent thrombosis. Scand Cardiovasc J 2014;48:156-60.
Submitted May 19, 2014; accepted Aug 1, 2014.
Drug-eluting balloons for femoropopliteal lesions show better performance in de novo stenosis or occlusion than in restenosis Monika Herten, PhD,a Giovanni B. Torsello, PhD,a,b Eva Schönefeld, MD,a,b Britta Imm,a Nani Osada, PhD,a and Stefan Stahlhoff, MD,a Münster, Germany Objective: Although drug-eluting balloons (DEBs) have shown promising results treating de novo (DN) atherosclerotic lesions and appear to have been widely adopted in Europe, their long-term efficacy in the broad spectrum of femoropopliteal restenosis (RE) remains to be proven. The purpose of the study was to assess the efficacy of paclitaxel-DEBs in restenotic (stented and nonstented) vs DN stenotic femoropopliteal arteries. Methods: The study prospectively enrolled 100 patients undergoing femoropopliteal endovascular intervention by DEB for RE or DN stenosis. Patients who received additive atherectomy were excluded. The primary end point was the primary patency (PP) rate at 12 months. Secondary end points were sustained clinical improvement and clinically driven target lesion revascularization. Results: DEBs were used to treat 105 limbs for intermittent claudication (82 [78%]) or critical limb ischemia (23 [22%]) in 100 patients. Of these, 111 lesions were DN stenosis (46 [41%]) or RE (65 [59%]). The overall PP was 86% at 6 months and 74% at 12 months. PP of DN stenosis was higher at 6 months (93% vs 81%) and was significantly (P [ .021) better than RE at 12 months (85% vs 68%). Sustained clinical improvement based on Rutherford classification was significant in both groups (P < .001). Target lesion revascularization was significantly lower in DN stenosis compared with RE at 12 months (15% vs 32%; P [ .021). Conclusions: DEB angioplasty is an effective therapy for DN femoropopliteal lesions. The results of DEB angioplasty for RE are inferior compared with DN stenosis after 12 months. Nevertheless, results of DEB angioplasty for RE seem comparable with technically more demanding literature-derived strategies. (J Vasc Surg 2014;-:1-6.)
The role of the drug-eluting balloon (DEB) in the therapy for atherosclerotic lesions is well established. Recent randomized clinical trials (RCTs) showed paclitaxel (PTX)-DEB angioplasty was superior compared with standard uncoated percutaneous transluminal angioplasty (PTA). Results demonstrated effectiveness in above-theknee lesions,1-5 whereas contradictory outcomes in safety and efficacy have been reported for below-the-knee lesions.6,7 The target lesion revascularization (TLR) rate after PTA of the femoropopliteal region ranges between 22% and 37% at 6 months and between 28% and 48% at 12 months. DEB angioplasty significantly reduced the TLR to 4% to 13% at 6 months and to 7% to 18% at 12 months.1-5 However, most lesions treated within the published studies and registries have been de novo (DN)
From the Department of Vascular and Endovascular Surgery, University of Münstera; and the Department of Vascular Surgery, St. FranziskusHospital Münster.b Author conflict of interest: none. Presented as an oral presentation at the 2014 Vascular Annual Meeting of the Society for Vascular Surgery, Boston, Mass, June 4-7, 2014. Reprint requests: Monika Herten, PhD, Department of Vascular and Endovascular Surgery, University of Münster, University Hospital, Albert-Schweitzer-Campus 1, W30, 48149 Münster, Germany (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2014 by the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvs.2014.08.005
stenosis, ranging from 63% to 100% in above-the-knee13,5,8,9 and from 65% to 100% in below-the-knee studies.6,7,10 For femoropopliteal in-stent restenosis (RE), some data indicate a promising role of DEBs, with a TLR rate at 1 year of 7.9%,11 9.8%,12 and 13.6%.13 DEBs in combination with directed atherectomy achieved TLR rates of 10%14 and 15.3%.15 However, long-term patency rates are still missing. The purpose of the study was to assess the efficacy of PTX-DEB in RE (stented and nonstented) vs DN stenotic femoropopliteal arteries. METHODS This study was conducted in agreement with the International Conference on Harmonization Guidelines, Good Clinical Practice, Declaration of Helsinki, and Ethics Committee requirements. Study population. Between October 2009 and February 2013, 111 lesions in 100 consecutive patients with intermittent claudication (78%) or critical limb ischemia (22%) underwent femoropopliteal endovascular intervention with intention to treat by DEB angioplasty in two centers. Clinical data were collected prospectively (Table I). All patients provided written informed consent before the intervention. Patients and lesions. Lesions were categorized according to their etiology as RE (n ¼ 65), in-stent or not in-stent, or DN (n ¼ 46; Fig 1). Plaque excision with and without DEBs was performed only in short lesions. No other procedures were performed for RE during the study 1
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Table I. Baseline demographic and clinical data Variablea
RE
DN
Patients (n ¼ 100) 61 (61) 39 (39) Limbs (n ¼ 105) 63 (60) 42 (40) Age, years 69.9 6 11.0 66.3 6 10.8 Male 35 (57) 23 (59) Arterial hypertension 50 (82) 33 (85) Diabetes mellitus 23 (38) 10 (26) History of smoking 15 (25) 22 (56) Hyperlipidemia 35 (57) 23 (59) Obesity 15 (25) 15 (38) Dialysis 1 (2) 0 (0) Limbs Intermittent claudication 45 (71) 37 (88) Critical limb ischemia 18 (29) 5 (12) Preinterventional Rutherford classification 3 (1, 5) 3 (2, 5) ABI 0.57 6 0.29 0.68 6 0.25
P value
.104 .875 .731 .211 .001 .875 .140 1.000 .055 .055 .179 .048
ABI, Ankle-brachial index; DN, de novo (the DN stenosis group included only native stenotic vessels); RE, restenosis (the RE group included stented and nonstented restenotic arteries). a Continuous data are shown as mean 6 standard deviation or as median (minimum, maximum) and categoric data as number (%).
period. The evaluation excluded patients who received additional atherectomy. Lesions characteristics are reported in Table II. Because the RE group comprised patients with lower baseline ankle-brachial indices (ABIs) and with longer lesions, those lesions were at higher risk. Procedure and devices. Vascular access was accomplished by a contralateral or ipsilateral transfemoral approach. Heparin (5000 units) was given after vascular access was performed. Predilatation PTA was systematically performed before treatment with IN.PACT Admiral (Medtronic GmbH, Meerbusch, Germany) or Freeway (Eurocor GmbH, Bonn, Germany) PTX-DEB systems. Both DEBs contained PTX at a concentration of 3 mg/mm.2 The procedural details are listed in Table II. In case of persistent flow-limiting dissections or recoil after balloon dilatation, additional self-expanding nitinol stents were implanted as provisional stenting. End points and definitions. Primary end point was the primary patency (PP), defined as freedom from RE >50% of the target lesion by duplex ultrasound imaging based on a peak systolic velocity ratio >2.4 m/s at the lesion site. Hemodynamic parameters by duplex ultrasound imaging were combined with, at minimum, one clinically driven parameter: decrease of Rutherford class $1 or ABI decrease >20%. In a subanalysis, we analyzed PP with or without provisional stenting. Secondary end points were secondary sustained clinical improvement and symptom-driven TLR at 12 months. Secondary sustained clinical improvement was defined as an improvement shift of the Rutherford classification of $1 category for claudicant patients and rest pain resolution for patients with critical limb ischemia. Clinically driven TLR expresses the need for repeated procedures (surgical or endovascular) at the site of the previously treated lesion.
Fig 1. Study flow. ABI, Ankle-brachial index; DEB, drug-eluting balloon; FU, follow-up; ISR, in-stent restenosis.
Statistical analysis. Statistical analysis was performed using SPSS 22.0 software (IBM Corp, Armonk, NY). Continuous variables are presented as mean 6 standard deviation and categoric variables as frequency and percentage. Ordinal parameters (Rutherford classification) are expressed as median with the minimum and maximum or with the interquartile range (25th percentile-75th percentile). Analysis of normal distribution of each continuous variable was performed by the Kolmogorov-Smirnov test before further statistical testing. The Mann-Whitney U test was used for comparison of nonparametric values between two study groups. Paired continuous nonparametric data were compared by the Wilcoxon test; proportions were compared by c2 test and by Fisher exact test, as appropriate. Survival and patency rates were determined with the Kaplan-Meier estimate in a time-to-event model. The logrank test was used for estimating the effect of variables on the clinical outcome. Differences were considered significant at P < .05. RESULTS Baseline characteristics of patients and lesions. The RE and DN groups did not differ significantly except for a significantly higher rate of smokers in the DN group. Preinterventional Rutherford classes were comparable between the groups. Baseline ABIs were significantly lower in the RE than in the DN group (P ¼ .048). Lesion and procedural characteristics are listed in Table II. There was no significant difference in parameters apart from the longer lesion length in the RE group (P ¼ .05). IN.PACT and Freeway were overall used in 95 and 16 cases, respectively,
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Table II. Lesion characteristics and procedural detail Variablea Lesions (n ¼ 111) In-stent RE Superficial femoral artery Popliteal artery involved Lesion length, mm Degree of stenosis, % Total occlusion DEB lesions, No. Length of PTX-DEB, mm PTX-DEB diameter, mm Inflation pressure, bar Inflation time, seconds
RE
DN
65 (59) 46 (71) 49 (75) 16 (24) 99 6 76 82 6 16 16 (25) 1.2 6 0.6 129 6 71 4.9 6 0.5 13 6 7 148 6 80
46 (41) 29 (64) 17 (37) 77 6 68 81 6 18 12 (27) 1.3 6 0.7 122 6 78 4.9 6 0.6 12 6 6 159 6 52
P value
.161 .161 .050 .900 .935 .191 .289 .553 .507 .223
DEB, Drug-eluting balloon; DN, de novo (the DN stenosis group included only native stenotic vessels); PXT, paclitaxel; RE, restenosis (the RE group included stented and nonstented restenotic arteries. a Continuous variables are presented as mean 6 standard deviation and categoric variables as number (%).
and their distribution was not significantly different across the RE (80% and 20%) vs DN groups (93% and 7%; P ¼ .057). Additional stenting was performed in 20 lesions (18%) and was necessary significantly more often in DN (12 lesions [28%]) than in RE (eight lesions [7%]; P ¼ .007). Primary end point. Overall PP was 86% and 74% at 6 and 12 months after DEB application. PP of DN was better than of RE at 6 months (93% vs 81%, P ¼ .093) and was significantly better at 12 months (85% vs 68%; P ¼ .021; Fig 2 and Table III). Subanalysis of PP without provisional stenting revealed superior rates for DN at 6 months (97% vs 80%; P ¼ .028) and at 12 months (89% vs 67%; P ¼ .007; Table III). Secondary end point. The ABI significantly improved, from 0.61 at preintervention to 0.87 at 12 months (P ¼ .037). Within the groups, ABI increased significantly in RE, from 0.57 6 0.29 at preintervention to 0.85 6 0.20 at 12 months (P < .001) and in DN from 0.68 6 0.25 to 0.90 6 0.12, respectively (P < .001; Table IV). In both groups, secondary sustained clinical improvement was demonstrated by the shift of at least one category of the Rutherford classification at 12 months (P < .001) without difference between the two groups (RE, 78%; DN, 83%; P ¼ .568; Table V). TLR after treatment of DN was lower, at 7% and 15% at 6 and 12 months, respectively, compared with 19% and 32% for RE (Table VI). Subanalysis of TLR without provisional stenting revealed superior rates for DN at 6 (3% vs 20%, P ¼ .028) and 12 months (10% vs 32%; P ¼ .007). No amputation was necessary at 12 months of follow-up. No major adverse cardiac or cerebrovascular events occurred during the hospital stay. Seven patients died for reasons not related to the intervention, five from the RE group and two from the DN group. Fig 3 shows that the cumulative survival rates by KaplanMeier method of both groups did not differ significantly (P ¼ .965).
Fig 2. Primary patency (PP) rate by Kaplan-Meier method after drug-eluting balloon (DEB) intervention of restenotic (RE) or de novo (DN) stenotic femoropopliteal arteries. Standard errors were #3.7% for RE and #6.4% for DN.
Table III. Primary patency (PP) at 6 and 12 months, including or excluding provisional stenting in restenotic (RE) or de novo (DN) stenotic femoropopliteal arteriesa Including bailout stenting PP Patients, No. 6 months, % 12 months, %
Excluding bailout stenting
Both P value P value groups RE DN RE vs DN RE DN RE vs DN 100 86 74
61 81 68
39 93 85
.093 .021
53 80 67
27 97 89
.028 .007
a The DN stenosis group included only native stenotic vessels and the RE group included stented and nonstented restenotic arteries.
DISCUSSION The present study shows that PTX-DEBs are safe and effective in treating femoropopliteal lesions. However, the results are significantly better after treatment of DN than after RE lesions. Treatment of femoropopliteal restenotic lesions, particularly after stenting, is associated with inferior outcomes and a higher rate of RE recurrence vs DN lesions. In our study, the results of the DN group are in line with RCTs comparing DEB angioplasty with uncoated-balloon PTA in the superficial femoral artery (Femoral Paclitaxel Randomized Pilot Trial [FemPac Trial], Local Taxan with Short Time Contact for Reduction of Restenosis in Distal Arteries
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Table IV. Comparative ankle-brachial index (ABI) values, before and and at 12 months’ follow-up after drug-eluting balloon (DEB) intervention, of restenotic (RE) or de novo (DN) stenotic femoropopliteal arteries ABI valuea Baseline At 12 months Difference 12 months e baseline Improved outcome at 12 months P value baseline vs 12 months
RE
DN
P value
0.57 6 0.29 0.85 6 0.20 0.25 6 0.25
0.68 6 0.25 0.90 6 0.12 0.22 6 0.28
.048 .422 .419
37/46 (80)
25/34 (73)
.732
<.001
<.001
Data are shown as mean 6 standard deviation or as number (%).
a
[THUNDER Trial], Paclitaxel-coated Balloons in Femoral Indication to Defeat Restenosis [PACIFIER Trial], The Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropoliteal Restenosis [LEVANT-I Trial], First in Man study to assess the safety and performance of the coated Passeo-18 Lux Paclitaxel releasing PTA Balloon Catheter vs an uncoated balloon catheter in patients with stenosis and occlusion of the femoropopliteal arteries [BIOLUX P1 Trial]),1-4 while outcomes of the RE group appear to be less favorable compared with what has previously been reported for in-stent RE. In particular, TLR rates after treatment of DN stenosis are reported to be 6.9% and 15.1% at 6 and 12 months, respectively. Despite the significant occurrence of femoropopliteal RE in clinical practice, few data are available on the effectiveness of DEB under these conditions. Stabile et al11 reported excellent results after treatment of in-stent RE with DEB angioplasty (7.9% TLR at 1 year)11 in the Femoral Artery In-Stent Restenosis (FAIR) trial of 9.2%,12 and Liistro et al13 reported 13.6%. In our study, TLR of the RE group (with 70% proportion of in-stent RE) was 19% and 32% at 6 and 12 months. The results are better than after standard PTA, with TLR between 39% and 78% after PTA16,17 and 65% at 6 months after cutting balloon.18 The results after DEB are better or similar to technically more demanding strategies such as cryoplasty and stenting,19-21 rotational atherectomy, directed atherectomy, and laser atherectomy, with TLR of 42%,22 31% to 75%,23-27 and 48% to 51%,28,29 respectively. Also the results of directional atherectomy alone24-27 or combined with heparin-coated stent grafts30 could not reach better results at 12 months, with 60% requiring additional PTA.26 The problem of recurrent in-stent RE might not be solved with stenting, debulking technology, or DEB alone; therefore, appropriately powered trials are required to evaluate the role of different technologies and strategies to improve the results of treatment of RE in the peripheral arteries. Promising results could be reached by standard PTA combined with brachytherapy31 or drug-eluting stents (DES),32 but long-term results are still lacking.
Table V. Comparative Rutherford categories, before and at 12 months’ follow-up after drug-eluting balloon (DEB) intervention, of restenotic (RE) or de novo (DN) stenotic femoropopliteal arteries Rutherford classificationa Before DEB At 12 months Improved outcome at 12 months P value before vs 1 year
RE
P value RE vs DN
DN
3 (3-4) 3 (3-3) 1 (0-3) 1 (0-2) 38/48 (80) 26/32 (81) <.001
.201 .814 .819
<.001
a Continuous values are median (interquartile range [25th-75th percentile]) and categoric values are number (%).
Table VI. Target limb revascularization (TLR) at 6 and 12 months including or excluding provisional stenting in restenotic (RE) or de novo (DN) stenotic femoropopliteal arteriesa Including bailout stenting TLR rate Patients, No. 6 months, % 12 months, %
Excluding bailout stenting
Both P value P value groups RE DN RE vs DN RE DN RE vs DN 100 14 26
61 19 32
39 7 15
.093 .021
53 20 32
27 3 10
.028 .007
a The DN stenosis group included only native stenotic vessels, and the RE group included stented and nonstented RE arteries.
Fig 3. Cumulative survival rates by Kaplan-Meier method after drugeluting balloon (DEB) intervention (including provisional stenting) of restenotic (RE) or de novo (DN) stenotic femoropopliteal arteries. Standard errors were #6.1% for RE and #6.8% for DN.
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The disparate results between DN and RE might be due to different efficacies of PTX distribution in DN or RE lesions. Several animal studies demonstrated that PTX reaches the target, the smooth muscle cell (SMC) layer, despite intimal plaque in DN stenotic vessels.33,34 In RE lesions, a vascular injury is seen after PTA and after stenting that leaves a stimulus for subsequent repair mechanism. Stimulation of the mitotic cell cycle is the final common pathway that leads to intimal hyperplasia after vascular injury. SMCs convert from the contractile phenotype to a dedifferentiated synthetic phenotype that starts to secrete extracellular matrix components. RE occurs when this proinflammatory regenerative process is not counterbalanced by appropriate stimuli for matrix-degrading enzymes. The composition of the extracellular matrix components changes from a provisional fibrin-rich to a permanent matrix. These changes are accompanied by a reduced SMC density.35 Because the innermost vessel layer forming the RE consists mainly of noncellular material, the cytotoxic effect of the PTX may not be able to reach the cellular layer.36 Atherectomy could offer the possibility to remove these inner layers enabling the PTX to reach the target cells. In the coronary arteries, DEB angioplasty is currently indicated for in-stent RE.37 Findings from a world-wide registry of the coronary SeQuent Please DEB (B. Braun Melsungen AG, Melsungen, Germany) suggested that PTX-DEB angioplasty is more effective in bare mental stent RE compared with DES RE, independent of stent design.38 Recent studies provide robust evidence suggesting that DEBs are as effective as first-generation DESs for patients with RE after implantation of DESs39 and that the use of a different drug (switch strategy) in patients with coronary DES in-stent RE has been advocated from the Restenosis Intra-Stent: Balloon Angioplasty vs DrugEluting Stent (RIBS III) trial by Alfonso et al.40 Even if the outcomes of same therapy concepts can be different between the coronary and peripheral arteries, the advantage of DEBs is the combination of effectiveness and simplicity of use. By removing the need for an additional stent layer, DEBs might become the treatment of choice in the future. Results with DEBs are likely to vary according to the underlying arterial wall composition (ie, neointimal hyperplasia, neoatherosclerosis). In the future, imageguided procedures could enable characterization of the heterogenous tissue causing RE and theoretically drive the decision on an optimal, tailored treatment to ultimately improve outcomes.41,42 The main limitation of our study is the limited patient numbers treated with two different DEBs and the lack of randomization. In addition, the inferior results in the RE group are driven by the high percentage of patients treated for in-stent RE. Furthermore, the lower baseline ABIs and the longer lesions in the RE group imply that those lesions are at higher risk and that the RE group could be expected to have lower patency after the DEB angioplasty. However, the results were obtained under real-life conditions in consecutively treated patients.
Herten et al 5
The present data mirror a tendency toward a treatment modification regarding DEBs for DN and RE lesions. The results do not offer evidence but the necessity to investigate in a future RCT on DEB indication. A proof of concept is still an issue of debate concerning DN and RE lesions. CONCLUSIONS The data suggest that use of DEBs is effective for DN femoropopliteal lesions. The results of DEBs for RE may be inferior and possibly comparable with other more technically demanding strategies. Future evaluation needs to show whether better results can been obtained in combination with debulking procedures. Here, the endovascular approach should ideally combine mechanical and biological effects without additional metal in the artery. The advantage of DEB treatment is that nothing is left behind in contrast to standard of care for long femoropopliteal lesions by stent implantation. Further and secondary revascularizations can be performed more easily without preimplanted foreign material. AUTHOR CONTRIBUTIONS Conception and design: GT, SS Analysis and interpretation: MH, GT, NO, ES, SS Data collection: MH, BI, SS Writing the article: MH, GT, ES, SS Critical revision of the article: MH, GT, BI, NO, ES, SS Final approval of the article: MH, GT, BI, NO, ES, SS Statistical analysis: MH, NO, ES Obtained funding: Not applicable Overall responsibility: MH REFERENCES 1. Tepe G, Zeller T, Albrecht T, Heller S, Schwarzwalder U, Beregi JP, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med 2008;358:689-99. 2. Werk M, Langner S, Reinkensmeier B, Boettcher HF, Tepe G, Dietz U, et al. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation 2008;118:1358-65. 3. Werk M, Albrecht T, Meyer DR, Ahmed MN, Behne A, Dietz U, et al. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv 2012;5:831-40. 4. Deloose K, Lauwers K, Callaert J, Maene L, Keirse K, Verbist J, et al. Drug-eluting technologies in femoral artery lesions. J Cardiovasc Surg 2013;54:217-24. 5. Scheinert D, Duda S, Zeller T, Krankenberg H, Ricke J, Bosiers M, et al. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in-human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv 2014;7:10-9. 6. Fanelli F, Cannavale A, Boatta E, Corona M, Lucatelli P, Wlderk A, et al. Lower limb multilevel treatment with drug-eluting balloons: 6month results from the DEBELLUM randomized trial. J Endovasc Ther 2012;19:571-80. 7. Liistro F, Porto I, Angioli P, Grotti S, Ricci L, Ducci K, et al. DrugEluting Balloon in peripherAl inTErvention for Below the Knee Angioplasty Evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia. Circulation 2013;128:615-21.
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Submitted May 19, 2014; accepted Aug 1, 2014.