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Heparin-Bonded Covered Stents Versus Bare-Metal Stents for Complex Femoropopliteal Artery Lesions
Journal of the American College of Cardiology 2013 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 62, No. 15, 2013 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2013.05.079
CLINICAL RESEARCH
Interventional Cardiology
Heparin-Bonded Covered Stents Versus Bare-Metal Stents for Complex Femoropopliteal Artery Lesions The Randomized VIASTAR Trial (Viabahn Endoprosthesis With PROPATEN Bioactive Surface [VIA] Versus Bare Nitinol Stent in the Treatment of Long Lesions in Superficial Femoral Artery Occlusive Disease) Johannes Lammer, MD,* Thomas Zeller, MD,y Klaus A. Hausegger, MD,z Philipp J. Schaefer, MD,x Manfred Gschwendtner, MD,jj Stefan Mueller-Huelsbeck, MD, PHD,{ Thomas Rand, MD,# Martin Funovics, MD,* Florian Wolf, MD,* Aljoscha Rastan, MD,y Michael Gschwandtner, MD,** Stefan Puchner, MD,* Robin Ristl, PHD,yy Maria Schoder, MD* Vienna, Klagenfurt, and Linz, Austria; and Bad Krozingen, Kiel, and Flensburg, Germany Objectives
The hypothesis that endovascular treatment with covered stents has equal risks but higher efficacy than bare-metal stents (BMS) in long femoropopliteal artery disease was tested.
Background
Although endovascular treatment of short superficial femoral artery lesions revealed excellent results, efficacy in long lesions remains unsatisfactory.
Methods
In a prospective, randomized, single-blind, multicenter study, 141 patients with symptomatic peripheral arterial disease were assigned to treatment with heparin-bonded, covered stents (Viabahn 72 patients) or BMS (69 patients). Clinical outcomes and patency rates were assessed at 1, 6, and 12 months.
Results
Mean SD lesion length was 19.0 6.3 cm in the Viabahn group and 17.3 6.6 cm in the BMS group. Major complications within 30 days were observed in 1.4%. The 12-month primary patency rates in the Viabahn and BMS groups were: intention-to-treat (ITT) 70.9% (95% confidence interval [CI]: 0.58 to 0.80) and 55.1% (95% CI: 0.41 to 0.67) (log-rank test p ¼ 0.11); treatment per-protocol (TPP) 78.1% (95% CI: 0.65 to 0.86) and 53.5% (95% CI: 0.39 to 0.65) (hazard ratio: 2.23 [95% CI: 1.14 to 4.34) (log-rank test p ¼ 0.009). In lesions 20 cm, (TransAtlantic InterSociety Consensus class D), the 12-month patency rate was significantly longer in VIA patients in the ITT analysis (VIA 71.3% vs. BMS 36.8%; p ¼ 0.01) and the TPP analysis (VIA 73.3% vs. BMS 33.3%; p ¼ 0.004). Freedom from target lesion revascularization was 84.6% for Viabahn (95% CI: 0.72 to 0.91) versus 77.0% for BMS (95% CI: 0.63 to 0.85; p ¼ 0.37). The ankle-brachial index in the Viabahn group significantly increased to 0.94 0.23 compared with the BMS group (0.85 0.23; p < 0.05) at 12 months.
Conclusions
This randomized trial in symptomatic patients with peripheral arterial disease who underwent endovascular treatment for long femoropopliteal lesions demonstrated significant clinical and patency benefits for heparinbonded covered stents compared with BMS in lesions 20 cm and for all lesions in the TPP analysis. In the ITT analysis for all lesions, which was flawed by major protocol deviations in 8.5% of the patients, the difference was not significant. (GORE VIABAHN endoprosthesis with bioactive propaten surface versus bare nitinol stent in the treatment of TASC B, C and D lesions in superficial femoral artery occlusive disease; ISRCTN48164244) (J Am Coll Cardiol 2013;62:1320–7) ª 2013 by the American College of Cardiology Foundation
From the *Departments of Cardiovascular and Interventional Radiology, Medical University Vienna, Vienna, Austria; yDepartment of Angiology, Universitaets-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany; zDepartment of Diagnostic and Interventional Radiology, Klinikum Klagenfurt, Klagenfurt, Austria; xDepartment of Radiology, University Clinics Schleswig-Holstein, Kiel, Germany; kDepartment of Diagnostic and Interventional Radiology, Elisabethinen Hospital, Linz, Austria; {Department of Diagnostic and Interventional Radiology, Diakonissen
Hospital, Flensburg, Germany; #Department of Radiology, Hietzing Hospital, Vienna, Austria; **Department of Angiology, Medical University Vienna, Vienna, Austria; and the yyCenter for Medical Statistics, Informatics and Intelligent Systems, Medical University Vienna, Austria. Dr. Lammer is a member of the scientific advisory board of Abbott Vascular, Boston Scientific, and WL Gore; and has received lecture fees from Medtronic, WL Gore, and Terumo. Dr. Zeller is a member of the scientific advisory board of Boston Scientific, Medtronic-Invatec, WL Gore, Angioslide,
Lammer et al. Covered vs. BMS for Complex SFA Lesions
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Epidemiological data demonstrate a prevalence as high as 19% in the general population and 29% in patients age >70 years of lower extremity peripheral arterial disease (PAD) in the United States and Europe (1,2). Superficial femoral artery (SFA) stenoses and occlusions are the most common cause of symptomatic PAD (3). Endovascular treatment of short lesions has been recommended by the TransAtlantic InterSociety Consensus (TASC) and by the American Heart Association (4,5). Randomized controlled trials (RCTs)
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The VIASTAR trial is a prospective, randomized, singleblind, multicenter study that was physician initiated. The protocol was developed and conducted in accordance with the International Conference on Harmonisation/Good Clinical Practice Guideline and the Declaration of Helsinki (ISO 14155-1 and ISO 14155-2). It was approved by the local ethics committees and registered at the ISRCTN Register.
All patients had to give written Abbreviations and Acronyms informed consent. Patients were recruited in 7 European centers. ABI = ankle-brachial index Randomization was done by using BMS = bare-metal stent(s) numbered envelopes, and the CI = confidence interval correct sequence was monitored CDUS = color-coded Doppler centrally. Data were recorded on ultrasound an electronic case report form; ePTFE = expanded monitoring was provided by the polytetrafluoroethylene coordination center for clinical ITT = intention-to-treat studies (Koordinierungszentrum PAD = peripheral arterial fuer Klinische Studien) of the disease Medical University Vienna, and PTA = percutaneous 12-month results of color-coded transluminal balloon Doppler ultrasound (CDUS) angioplasty examinations were anonymized RCT = randomized controlled and blinded before review by trial CoreLab Bad Krozingen (Bad SFA = superficial femoral Krozingen, Germany). artery The study hypothesis was that TASC = TransAtlantic Interthe endovascular treatment of Society Consensus symptomatic long SFA lesions TLR = target lesion with a heparin-bonded Viabahn revascularization endoprosthesis (VIA) or a BMS TPP = treatment per-protocol carries equal risks for adverse events within 30 days after VIA = Viabahn endoprosthesis the index procedure, and the WIQ = walking impairment 12-month patency rate of the questionnaire heparin-bonded Viabahn endoprosthesis would be superior by 25%. The ePTFE covering of the Viabahn endoprosthesis may avoid in-growth of neointimal tissue, and the heparin bonding may contribute to the reduction of thrombosis and neointimal hyperplasia. The major inclusion criteria were symptomatic PAD in the Rutherford-Becker clinical stage 2 to 5 (moderate to severe claudication and critical limb ischemia), de novo arteriosclerotic stenosis or occlusion of the SFA and proximal popliteal artery 10 to 35 cm in length (TASC II classes B, C, and D) (4), patent or successfully treated iliac artery inflow, and outflow of at least 1 tibial artery. The major exclusion criteria were untreated inflow lesions, any previous stenting or surgery in the target artery, serum creatinine level >2.5 mg/dl, septicemia, and known intolerance to heparin, antithrombotic study medications, or contrast agents. The primary safety endpoint was a composite of serious procedural adverse events, including death, myocardial infarction, study limb amputation, and access site and treatment site complications requiring surgery, blood transfusion, or prolonged hospital stay within 30 days of the index
Medtronic-Ardian, and Covidien-ev3; and has received lecture fees from sanofiaventis, CR Bard, J&J Cordis, Covidien-ev3, Boston Scientific, Straub Medical, Invatec, Biotronik, and Pathway Medical. Dr. Mueller-Huelsbeck has served as a consultant for Boston Scientific; workshop organizer and lecturer for Termuo; and presented educational cases for Abbott Vascular. Dr. Funovics has received lecture fees
from Bolten Medical. Dr. Schoder has received lecture fees from J&J Cordis and Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received January 7, 2013; revised manuscript received May 3, 2013, accepted May 7, 2013.
See page 1328
comparing percutaneous transluminal balloon angioplasty (PTA) and primary stenting in short lesions of the SFA have demonstrated the superiority of primary stent placement (6,7). More recently, drug-eluting balloons and drug-eluting stents have been evaluated in RCTs, although only in short lesions (8–11). With advancing technologies, endovascular recanalization of long lesions (TASC II classes C and D) is technically feasible in a large percentage of patients (12), but the durability of PTA of long SFA lesions remains poor (13,14). Primary stent placement in long SFA lesions has shown promising results in a single-arm study (15). However, bare-metal stents (BMS) do not prevent neointimal hyperplasia, and the risk for in-stent restenosis and stent fracture grows with lesion length (16). An expanded polytetrafluoroethylene (ePTFE) covering of stents prevents in-growth of neointimal tissue regardless of lesion length. Therefore, the use of ePTFE-covered stents in long femoropopliteal artery lesions may increase the patency rate. It has been demonstrated in animal studies that immobilized heparin on ePTFE vascular grafts may reduce platelet deposition and neointimal hyperplasia (17,18). To evaluate the hypothesis that heparin-bonded ePTFEcovered stents are superior to BMS in patients with symptomatic PAD and long SFA lesions, including the proximal popliteal artery, the VIASTAR (Viabahn Endoprosthesis With PROPATEN Bioactive Surface [VIA] Versus Bare Nitinol Stent in the Treatment of Long Lesions in Superficial Femoral Artery Occlusive Disease) trial was initiated. Methods
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Lammer et al. Covered vs. BMS for Complex SFA Lesions
procedure. The primary efficacy endpoint was the primary patency rate measured at 1 year post-procedure. Primary patency was defined as no evidence of restenosis 50% or occlusion within the study lesion based on CDUS with a peak systolic velocity ratio 2.5 and no target lesion revascularization (TLR) within 12 months (19). Secondary endpoints were clinical improvement according to the Rutherford category at 1, 6, and 12 months, walking distance according to the walking impairment questionnaire (WIQ), change of the ankle-brachial Doppler index (ABI) at discharge and 1, 6, and 12 months, secondary patency, and freedom from TLR. The intervention was performed percutaneously with an antegrade or crossover femoral artery access under local anesthesia. Successful wire traversal of the target lesion was an entry criterion for the study. Angiography of the target lesion was performed in 2 planes before and after intervention. VIA and BMS were inserted through a 6- or 7-F sheath. In the VIA group, the Viabahn endoprosthesis (WL Gore, Flagstaff, Arizona) with the contoured proximal edge and heparin-bonded surface (PROPATEN Bioactive Surface) was used. The BMS used were the Life-Stent (BARD Peripheral Vascular, Inc., Tempe, Arizona), the Protégé EverFlex Stent (ev3 Inc., Plymouth, Minnesota), and the SMART-Control Stent (Cordis Corporation, Johnson & Johnson, Warren, Massachusetts). These stents were selected because of reported patency rates 80% at 1 year (7,20,21). The BMS choice was at the operators’ discretion. As study medication, all patients received 5,000 IU of heparin during the procedure. After treatment, patients were to take 100 mg of aspirin daily for life and 75 mg of clopidogrel (Plavix, Sanofi, Hoechst, Germany) daily for at least 6 months. Most patients started taking clopidogrel 1 or 2 days before the index procedure; for those who did not, a loading dose of 300 mg was given before or during the intervention. The follow-up patient visits were scheduled at discharge and 1, 6, and 12 months; if patients were symptomatic, these visits included physical examination, WIQ, ABI, and CDUS. In addition, peripheral computed tomography angiography was performed at 12 months in a study subcohort. Statistical analysis. It was calculated that 140 patients would need to be enrolled for the study to have a statistical power of 80% to detect an absolute difference of patency of 25% at 12 months. A 2-sided p value of 0.05 was considered to indicate statistical significance. Analysis of the data for the primary and secondary patency rate, and the freedom from TLR, was performed according to the intention-to-treat (ITT) group and the treatment per-protocol (TPP) group. Primary patency, secondary patency, and freedom from TLR rates were calculated by using Kaplan-Meier product-limit estimation, and the log-rank test was used to test for differences between groups. Hazard ratios for primary patency were calculated from a Cox proportional hazards regression model accounting for treatment group and stented length. Metric variables were described by mean SD, and the equality between the treatment groups was analyzed by using
JACC Vol. 62, No. 15, 2013 October 8, 2013:1320–7
Student t tests. Categorial variables were described by absolute and relative frequencies, and the homogeneity of distributions between the 2 treatment groups was analyzed by using chi-square tests or, if the test assumption was violated, by the Fisher exact test. Descriptive statistics were calculated for the ITT data. Calculations were performed by using SAS version 9.3 (SAS Institute, Inc., Cary, North Carolina). Results Study patients. From March 2009 to March 2011, a total of 141 patients (100 men, 41 women; mean age 69 9 years; age range 47 to 90 years) were included. Demographic and clinical characteristics were similar, with no significant differences between groups, except in length of the stented segment (Tables 1 and 2). The mean lesion length was 19.0 6.3 cm in the VIA group and 17.3 6.6 cm in the BMS group (p ¼ 0.13). Acute technical success was achieved in all but 1 patient who had a malposition of a BMS that needed surgical removal followed by bypass. At discharge, ABI had significantly improved in the VIA and BMS groups, from 0.58 0.17 and 0.58 0.16 (p ¼ 0.94) to 0.93 0.18 and 0.96 0.14 (p ¼ 0.24), respectively. Complications within 30 days after the index procedure were recorded in 20 patients, 11 (15%) in the VIA group and 9 (13%) in the BMS group (Table 2). Severe adverse events within 30 days were observed once in each group: a pseudoaneurysm and hematoma (VIA group), which needed surgery, and a malposition of the stent (BMS group), which was removed surgically, followed by bypass (2 of 141 Table 1
Demographic and Clinical Characteristics of the Patients VIA (n ¼ 72)
BMS (n ¼ 69)
68.85 8.59
69.44 8.96
Male
48 (67)
52 (75)
0.34
Smoker at baseline
50 (69)
48 (70)
0.87
Hypertension
60 (83)
58 (84)
0.91
Hyperlipidemia
49 (68)
47 (68)
0.86
Coronary heart disease
16 (22)
15 (22)
0.89
Diabetes
25 (35)
25 (36)
0.99
Renal failure
12 (17)
5 (7)
0.14
Antithrombotic treatment
60 (83)
59 (86)
0.90
Statin therapy
41 (57)
42 (61)
0.76
Antihypertensive therapy
20 (28)
22 (32)
Characteristic Age (yrs)
Clinical stage of peripheral artery disease*
0.72
Rutherford 2
13 (18)
11 (17)
Rutherford 3
48 (68)
43 (65)
Rutherford 4
2 (3)
5 (8)
Rutherford 5
8 (11)
7 (11)
Baseline ankle-brachial indexy
p Value
0.58 0.17
0.58 0.16
0.94
Values are mean SD or n (%). *Rutherford stages 2 and 3 correspond to intermittent claudication, stage 4 to ischemic pain while the patient is resting, and stage 5 to ischemic ulcers. yRatio of the blood pressure in the lower legs to the blood pressure in the arms. BMS ¼ bare-metal nitinol stent(s); VIA ¼ Viabahn endoprosthesis.
Lammer et al. Covered vs. BMS for Complex SFA Lesions
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[1.4% for both groups]). There were no deaths, myocardial infarctions, or study limb amputations. Thus, the hypothesis of the primary safety endpoint was met. Follow-up. Six patients in each group had to be excluded from ITT analysis because of major protocol violations: 6 due to screening failure (patients with lesions <10 cm and >35 cm, and/or no tibial artery run-off), 4 due to incorrect treatment (PTA only without any device placement, “spot stenting” with <50% covering of the lesion after PTA), 1 who did not take any of the antithrombotic study medication, and 1 patient withdrew the informed consent after discharge (Fig. 1). Of the 141 randomized patients (ITT), 129 patients (VIA 66; BMS 63) were available for the TPP analysis. Causes for exclusion from ITT analysis are shown in Figure 1. At 12 months, 63 of 72 VIA patients and 54 of 69 BMS patients were available for follow-up and 57 of 66 VIA patients and 52 of 63 BMS patients for TPP analysis. At 1 year, the primary patency rate of all patients, including those with major protocol violations (ITT), was 70.9% (95% confidence interval [CI]: 0.58 to 0.80) versus 55.1% (95% CI: 0.41 to 0.67; log-rank test p ¼ 0.11) in the VIA versus BMS group, respectively. In patients treated according to the study protocol (TPP), 50% restenoses were observed in 9 versus 22 patients and occlusions in 6 versus 4 patients in the VIA versus BMS group. Four of 6 VIA occlusions and 2 of 4 BMS occlusions occurred within the first 6 months despite double antiplatelet therapy. The remaining occlusions occurred between 6 and 12 months with aspirin medication only. The VIA occlusions were treated in 3 patients by fibrinolysis and in the other 3 patients by bypass surgery. One patient with an acutely thrombosed VIA presented with acute limb ischemia. The 4 BMS occlusions were treated in 2 patients (1 bypass, 1 fibrinolysis) and remained untreated in the other 2 patients. In the 9 relevant (50%) VIA restenoses, edge stenosis at the proximal or distal end was observed. In the 22 relevant (50%) restenoses of BMS, diffuse instent restenosis was seen most commonly, but edge stenoses were observed as well. Therefore, at 1 year in patients treated according to the study protocol, the primary patency rate (TPP) was 78.1% (95% CI: 0.65 to 0.86) versus 53.5% (95% CI: 0.39 to 0.65; log-rank test p ¼ 0.009) in the VIA versus BMS group, respectively (Table 3, Figs. 2A and 2B). Thus, within the first year after the index procedure, the risk of binary restenosis, occlusion, and TLR was 2.23 (95% CI: 1.15 to 4.35) times more likely when using a BMS. The hazard ratio of BMS versus VIA calculated from a multiple Cox proportional hazards model accounting for treatment group and length of treated segment was 2.71 (95% CI: 1.36 to 5.39). Length of stented segment was included in the model because significant differences in this variable were observed between treatment groups. Freedom from clinically driven TLR was 84.6% (95% CI: 0.72 to 0.91) in the VIA group versus 77.0% (95% CI: 0.63 to 0.85) in the BMS group at 1-year follow-up (log-rank test p ¼ 0.37). The secondary patency rate (TPP) after TLR and bypass surgery was 89.9%
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(95% CI: 0.78 to 0.95) versus 75.2% (95% CI: 0.61 to 0.84) in the VIA versus BMS group (log-rank test p ¼ 0.058). A stratified analysis was performed to evaluate the effect of TASC classification and lesion length on primary patency. At 12 months, patients with long lesions (20 cm, TASC class D) had a significantly higher primary patency rate when treated with Viabahn endoprosthesis at ITT analysis (VIA 71.3% [95% CI: 0.53 to 0.83]; BMS 36.8% [95% CI: 0.17 to 0.57]; log-rank test p ¼ 0.01) and at TPP analysis (VIA 73.3% [95% CI: 0.54 to 0.85]; BMS 33.3% [95% CI: 0.13 to 0.54]; log-rank test p ¼ 0.004) (Figs. 3A and 3B). In the group with lesion length <20 cm, a trend toward higher patency rate after VIA was seen (VIA 86.4%; BMS 63.0%), but the difference was not significant (logrank test p ¼ 0.106). In a Cox proportional hazards regression model, sex, clinical stage according to the Rutherford category, diabetes, renal failure, calcification severity, Table 2
Baseline Angiographic and Interventional Data VIA (n ¼ 72)
BMS (n ¼ 69)
p Value
Length of target lesion (mm)
189.8 63
173.2 66
0.13
Length of stented segment (mm)
236.8 77
203.1 77
0.01
Target vessel diameter (mm)
6.08 0.6
6.25 0.7
0.88
Target vessel diameter (mm)
6.08 0.6
6.25 0.7
0.88
56 (79)
46 (70)
Occlusion Target-lesion calcification* None or mild
16 (23)
12 (17)
Moderate
44 (62)
34 (49)
Severe
11 (15)
19 (28)
Not applicable
4 (6)
TASC II classy TASC A
0.21 0.15
0.09 0
2 (3)
TASC B >10 cm
20 (28)
29 (42)
TASC C
18 (25)
16 (23)
TASC D
34 (47)
22 (32)
3
32 (44)
29 (42)
2
28 (39)
27 (40)
1
10 (14)
10 (14)
0
2 (3)
3 (4)
0
2 (3)
0 (0)
1
18 (26)
29 (42)
2
41 (57)
36 (52)
3
11 (15)
4 (6)
11 (15)
9 (13)
Peripheral embolization
4
1
Hematoma
2
2
Pseudoaneurysm
1
0
Other
3
2
Death
0
0
Study limb amputation
0
0
1 (1.4)
1 (1.4)
1.0
0.93 0.18
0.96 0.14
0.24
No. of crural runoff vessels
0.96
No. of implants
Adverse events
Severe adverse events ABI before discharge
0.04
0.77
Values are mean SD or n (%). *Calcification was assessed by the investigator. yTransAtlantic Inter-Society Consensus (TASC) II classification is a lesion classification according to the InterSociety Consensus for the Management of Peripheral Arterial Disease. Abbreviations as in Table 1.
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Figure 1
Lammer et al. Covered vs. BMS for Complex SFA Lesions
JACC Vol. 62, No. 15, 2013 October 8, 2013:1320–7
Randomization and Follow-Up of Study Patients
*Screening failures: patients with lesions <10 cm and >35 cm, no tibial run-off. yIncorrect treatment: percutaneous transluminal balloon angioplasty (PTA) only without any device placement, “spot stenting” with <50% covering of the lesion after PTA. ITT ¼ intention-to-treat; TPP ¼ treatment per-protocol.
Table 3
Outcomes in Study Patients at 12 Months Follow-Up
ITT Analysis Restenosis PSVR in >50% stenosis Reocclusion
VIA (n ¼ 63/72)
95% CI
BMS (n ¼ 54/69)
13
24
2.72 1.29
3.25 2.03
8
6
95% CI
p Value
0.54
Primary patency rate (all)
70.9%
0.58–0.80
55.1%
0.41–0.67
0.11
Primary patency rate (lesion 20 cm)
71.3%
0.53–0.83
36.8%
0.17–0.57
0.01
TLR ABI (mean) TPP Analysis Restenosis Reocclusion
13
16
0.93 0.23
0.85 0.23
VIA (n ¼ 57/66)
BMS (n ¼ 52/63)
95% CI
9
0.1 95% CI
p Value
22
6
4
Primary patency rate (all)
78.1%
0.65–0.86
53.5%
0.39–0.65
0.009
Primary patency rate (lesion 20 cm)
73.3%
0.54–0.85
33.3%
0.13–0.54
0.004
0.37
TLR
9
13
Freedom from TLR rate
84.6%
0.72–0.91
77.0%
0.63–0.85
Secondary patency rate
89.9%
0.78–0.95
75.2%
0.61–0.84
ABI (mean) Rutherford category improvement 1 (%) Walking distance (according to WIQ) (m)
0.94 0.23
0.85 0.23
84
84
785.8
565.9 m
0.058 0.048
0.17
Values are n, mean SD, or %. ABI ¼ ankle-brachial index; CI ¼ confidence interval; ITT ¼ intention-to-treat; PSVR ¼ peak systolic velocity ratio; TLR ¼ target lesion revascularization; TPP ¼ treatment per-protocol; WIQ ¼ walking impairment questionnaire; other abbreviations as in Table 1.
Lammer et al. Covered vs. BMS for Complex SFA Lesions
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Figure 2
Patency Rate of All Lesions
Primary patency of Viabahn endoprosthesis (VIA) (red) versus bare-metal stent (BMS) (black) in the superficial femoral artery lesions of patients with symptomatic peripheral arterial disease. (A) ITT: at 12 months VIA 70.9% (95% confidence interval [CI]: 0.58 to 0.80) versus BMS 55.1% (95% CI: 0.41 to 0.67; log-rank test p ¼ 0.11). (B) TPP: at 12 months VIA 78.1% (95% CI: 0.65 to 0.86) versus BMS 53.5% (95% CI: 0.39 to 0.65) (hazard ratio 2.23 [95% CI: 1.14 to 4.34]; log-rank test p ¼ 0.009). Abbreviations as in Figure 1.
and stenosis versus occlusion had no significant influence on outcomes. The ABI (at discharge 0.93 0.18 vs. 0.97 0.14) of the VIA group versus BMS group was 0.96 0.19 vs. 0.98 0.14 [p ¼ NS], 0.94 0.24 vs. 0.87 0.24, and 0.94 0.23 vs. 0.85 0.23 [p < 0.05] at 1, 6, and 12 months, respectively (Table 3). An improvement by 1 Rutherford category was reported in 84.0% in both groups at 12 months (Fig. 4A). The mean walking distance according to the WIQ was 136.3 m versus 115.1 m (p ¼ 0.13) at baseline and 785.8 m versus 565.9 m (p ¼ 0.17) in the VIA versus BMS cohort at 12 months, respectively (Fig. 4B). These data include patients after TLR and bypass. Discussion The purpose of the current study was to evaluate whether a heparin-bonded ePTFE-covered endoprosthesis such as
Figure 3
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Patency Rate of Lesions 20 cm
Primary patency of VIA (red) versus BMS (black) in superficial femoral artery lesions of patients with symptomatic peripheral arterial disease and lesions 20 cm. (A) ITT: at 12 months VIA: 71.3% (95% CI: 0.53 to 0.83) versus BMS: 36.8% (95% CI: 0.17 to 0.57; log-rank test p ¼ 0.01). (B) TPP: at 12 months VIA: 73.3% (95% CI: 0.54 to 0.85) versus BMS: 33.3% (95% CI: 0.13 to 0.54; log-rank test p ¼ 0.004). Abbreviations as in Figures 1 and 2.
the VIA is superior to bare-metal nitinol stents (BMS) in patients with symptomatic PAD and long lesions of the SFA and proximal popliteal artery. The ITT analysis did not show a significant difference but a trend in favor of the heparin-bonded ePTFE-covered endoprosthesis (VIA 71%; BMS 55%; log-rank test p ¼ 0.11). However, it was flawed by major protocol deviations in 8.5% of the patients. In the TPP analysis, the Viabahn endoprosthesis showed a primary patency rate of 78.1% versus 53.5% (p ¼ 0.009) for BMS at 12 months. Thus, within the first year after the index procedure, the risk of a binary restenosis, occlusion, and TLR was 2.23 times more likely when using a BMS. This confirmed the original study hypothesis. The fact that the TPP was significantly at odds with the ITT analysis testifies that the rate of protocol violations was high and diluted the statistical power. In lesions 20 cm (TASC class D), the 12-month patency rate was significantly higher in VIA patients in the ITT analysis (VIA 71.3% vs. BMS 36.8%;
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Figure 4
Lammer et al. Covered vs. BMS for Complex SFA Lesions
Clinical Improvement
Categorized according to (A) Rutherford category and (B) walking distance (in meters) according to the walking impairment questionnaire (WIQ) of the VIA versus BMS in superficial femoral artery lesions of patients with symptomatic peripheral arterial disease. Relative frequencies are displayed as stacked bar plots. Range is between grade 3 (indicating markedly improved) and –3 (indicating markedly worsening). Abbreviations as in Figure 2.
p ¼ 0.01) and the TPP analysis (VIA 73.3% vs. BMS 33.3%; p ¼ 0.004). Compared with baseline, ABI was improved in both study cohorts with a higher ABI in the Viabahn cohort of 0.94 0.23 versus a BMS ABI of 0.85 0.23 (p < 0.05) at 12 months. Thus, objective parameters showed a significant benefit. However, this improved primary patency and ABI for the Viabahn endoprosthesis group did not translate into a significant reduction of clinically driven TLR at 12 months (84.6% after Viabahn endoprosthesis versus 77.0% after BMS; log-rank test p ¼ 0.37). The relatively low clinically driven TLR rate in the BMS group in relation to the high rate of instent restenosis is difficult to explain. One could argue that instent restenosis in BMS still enables collateral flow through side branches, which may mitigate symptoms. However, 70% of the lesions in the BMS group were total occlusions without side branches. The lower TLR rate may be due to the slow progressive narrowing of the stent lumen due to diffuse intimal hyperplasia in BMS. An additional postinterventional exercise effect may have caused less obvious recurrence of claudication. In the VIA group, the recurrence was in one-third of the patients due to a total thrombotic
JACC Vol. 62, No. 15, 2013 October 8, 2013:1320–7
occlusion that caused a rapid deterioration of the walking distance. In 1 of 6 patients, the thrombotic occlusion caused an acute limb ischemia. The number of occlusions in the VIA group was higher (6 vs. 4); this finding, however, was not significant. The VIA occlusions were treated in 3 patients by fibrinolysis and in the other 3 patients by bypass. The observed mean walking distance according to the WIQ was longer in the VIA cohort at 12 months but did not reach statistical significance (785.8 m vs. 565.9 m; p ¼ 0.17). The clinical improvement of 1 according to the Rutherford classification was 84.0% in both groups. However, the reported ABI, walking distance, and clinical improvement are parameters that correspond to the secondary patency rate because they also include patients after TLR and bypass. The endovascular treatment of PAD has the advantages of low morbidity and mortality rates, and early recovery, and it can be done as an outpatient procedure. BMS, drugeluting stents, and drug-eluting balloons have demonstrated their superiority over plain PTA in short lesions only (6–11). However, a prospective RCT for long lesions focusing on various endovascular techniques has not yet been published. In a prospective single-arm study with BMS in long SFA lesions, 1-year freedom from TLR was reported in 68.2% (15). This finding was even lower than the freedom of BMS from TLR in the current study (77%). The freedom from TLR in the Viabahn arm of this study was 85%. Bypass surgery with venous conduits must still be considered as the gold standard when comparing primary patency rates. However, considering the high secondary patency rate of 89.9% in the Viabahn arm of this study, it was demonstrated that similar results compared with surgery could be achieved at a low procedural risk. In the current study, the rate of severe complications requiring surgery or prolonged hospital stay was 1.4%, and no deaths or study limb amputations were observed. Thus, the overall risk compared with surgery seems to be less (3,22). In the event that no vein is available or that the vein should be preserved for aorto-coronary bypass surgery, the 1-year patency rate after synthetic graft femoropopliteal above-knee bypass drops to 76%, as has been shown in a recent RCT (23). Covered stents have the advantage of no in-growth of neointimal tissue, which is the drawback of BMS. However, graft thrombosis as disadvantage has been observed. In this study, the Viabahn endoprosthesis with the heparin-bonded surface (PROPATEN bioactive surface) was used (24,25). The stably bound, endpoint immobilized heparin at the inner surface of the ePTFE graft has been shown in the Scandinavian Propaten trial to significantly prolong the primary patency rate to 86.4% for heparin-bonded ePTFE grafts versus 79.9% for plain ePTFE grafts (p ¼ 0.043) at 1 year (26). All patients were on antiplatelet medication with aspirin 100 mg daily for life and clopidogrel 75 mg daily for at least 6 months, which may be necessary to achieve a low thrombosis rate. Study limitations. Twelve (8.5%) of the 141 patients had a major protocol violation. There were 6 violations in each study arm, and they were randomly distributed.
Lammer et al. Covered vs. BMS for Complex SFA Lesions
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A strength of the study is that it is the first published RCT in symptomatic PAD patients and endovascular treatment of long femoropopliteal artery lesions. Clinical and imaging endpoints were both considered, and both study endpoints were met. Conclusions
11. 12.
13.
The clinical implication of the current study is that it demonstrates, when treating PAD in patients with long diffuse femoropopliteal artery disease, heparin-bonded ePTFE-covered stents yield clinical and patency benefits compared with BMS.
15.
Acknowledgments
16.
The authors thank Mrs. Johanna Moyses, research coordinator at the division of Cardiovascular and Interventional Radiology, Medical University Vienna, for the data management, WL Gore for the financial support for the CoreLab review of the 12-month CDUS studies, and the Medical University Vienna for monitoring by the Clinical Coordination Center Koordinierungszentrum fuer Klinische Studien.
14.
17.
18.
19.
Reprint requests and correspondence: Dr. Johannes Lammer, Department of Cardiovascular and Interventional Radiology, Vienna General Hospital, Medical University Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria. E-mail: johannes. [email protected].
REFERENCES
1. Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D. The prevalence of peripheral arterial disease in a defined population. Circulation 1985;71:510–51. 2. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001;286:1317–24. 3. White C. Intermittent claudication. N Engl J Med 2007;356:1241–50. 4. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg 2007;33 Suppl 1:S1–75. 5. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease. Circulation 2006;113:e463–5. 6. Schillinger M, Sabeti S, Loewe C, et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. N Engl J Med 2006;354:1879–88. 7. Laird JR, Katzen BT, Scheinert D, et al., RESILIENT Investigators. Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery: twelve-month results from the RESILIENT randomized trial. Circ Cardiovasc Interv 2010;3:267–76. 8. Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med 2008; 358:689–99. 9. Werk M, Langner S, Reinkensmeier B, et al. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation 2008; 118:1358–65. 10. Dake MD, Ansel GM, Jaff MR, et al., Zilver PTX Investigators. Paclitaxel-eluting stents show superiority to balloon angioplasty and
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bare metal stents in femoropopliteal disease: twelve-month Zilver PTX randomized study results. Circ Cardiovasc Interv 2010;4:495–504. Stabile E, Virga V, Salemme L, et al. Drug-eluting balloon for treatment of superficial femoral artery in-stent restenosis. J Am Coll Cardiol 2012;60:1739–42. Beschorner U, Sixt S, Schwarzwälder U, et al. Recanalization of chronic occlusions of the superficial femoral artery using the Outback re-entry catheter: a single centre experience. Cath Cardiovasc Intervent 2009;74: 934–8. Kougias P, Chen A, Cagiannos C, Bechara CF, Huynh TT, Lin PH. Subintimal placement of covered stent versus subintimal balloon angioplasty in the treatment of long-segment superficial femoral artery occlusion. Am J Surg 2009;198:645–9. Dick P, Wallner H, Sabeti S, et al. Balloon angioplasty versus stenting with nitinol stents in intermediate length superficial femoral artery lesions. Catheter Cardiovasc Intervent 2009;74:1090–5. Bosiers M, Deloose K, Callaert J, et al. Results of the Protégé EverFlex 200-mm-long nitinol stent (ev3) in TASC C and D femoropopliteal lesions. J Vasc Surg 2011;54:1042–50. Scheinert D, Scheinert S, Sax J, et al. Prevalence and clinical impact of stent fractures after femoropopliteal stenting. J Am Coll Cardiol 2005; 45:312–5. Lin PH, Chen C, Bush RL, Yao Q, Lumsden AB, Hanson SR. Smallcaliber heparin-coated ePTFE grafts reduce platelet deposition and neointimal hyperplasia in a baboon model. J Vasc Surg 2004;39: 1322–8. Pedersen G, Laxdal E, Ellensen V, Jonung T, Mattsson E. Improved patency and reduced intimal hyperplasia in PTFE grafts with luminal immobilized heparin compared with standard PTFE grafts at six months in a sheep model. J Cardiovasc Surg 2010;51:443–8. Mohler ER 3rd, Gornik HL, Gerhard-Herman M, et al. ACCF, ACR, AIUM, ASE, ASN, ICAVL, SCAI, SCCT, SIR, SVM, SVS ACCF/ACR/AIUM/ASE/ASN/ICAVL/SCAI/SCCT/SIR/SVM/SVS 2012 appropriate use criteria for peripheral vascular ultrasound and physiological testing part I: arterial ultrasound and physiological testing: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American College of Radiology, American Institute of Ultrasound in Medicine, American Society of Echocardiography, American Society of Nephrology, Intersocietal Commission for the Accreditation of Vascular Laboratories, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Interventional Radiology, Society for Vascular Medicine, and Society for Vascular Surgery. J Am Coll Cardiol 2012;60:242–76. Bosiers M, Torsello G, Gissler HM, et al. Nitinol stent implantation in long superficial femoral artery lesions: 12-month results of the DURABILITY I study. J Endovasc Ther 2009;16:261–9. Suzuki K, Iida O, Soga J, et al. Long-term results of the S.M.A.R.T. Control(TM) stent for superficial femoral artery lesions, J-SMART registry. Circ J 2011;75:939–44. Siracuse JJ, Giles KA, Pomposelli FB, et al. Results for primary bypass versus primary angioplasty/stent for intermittent claudication due to superficial femoral artery occlusive disease. J Vasc Surg 2012;55: 1001–7. McQuade K, Gable D, Pearl G, Theune B, Black S. Four-year randomized prospective comparison of percutaneous ePTFE/nitinol self-expanding stent graft versus prosthetic femoral-popliteal bypass in the treatment of superficial femoral artery occlusive disease. J Vasc Surg 2010;52:584–90. Olsson P, Sanchez J, Mollnes TE, Riesenfeld J. On the blood compatibility of end-point immobilized heparin. J Biomater Sci Polym Ed 2000;11:1261–73. Lin PH, Bush RL, Yao Q, Lumsden AB, Chen C. Evaluation of platelet deposition and neointimal hyperplasia of heparin-coated smallcaliber ePTFE grafts in a canine femoral artery bypass model. J Surg Res 2004;118:45–52. Lindholt JS, Gottschalksen B, Johannesen N, et al. The Scandinavian Propaten() trial: 1-year patency of PTFE vascular prostheses with heparin-bonded luminal surfaces compared to ordinary pure PTFE vascular prosthesesda randomised clinical controlled multi-centre trial. Eur J Vasc Endovasc Surg 2011;41:668–73.
Key Words: angioplasty - covered stent - peripheral arterial disease stent - stent graft - superficial femoral artery.
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Vol. 62, No. 15, 2013 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2013.05.079
CLINICAL RESEARCH
Interventional Cardiology
Heparin-Bonded Covered Stents Versus Bare-Metal Stents for Complex Femoropopliteal Artery Lesions The Randomized VIASTAR Trial (Viabahn Endoprosthesis With PROPATEN Bioactive Surface [VIA] Versus Bare Nitinol Stent in the Treatment of Long Lesions in Superficial Femoral Artery Occlusive Disease) Johannes Lammer, MD,* Thomas Zeller, MD,y Klaus A. Hausegger, MD,z Philipp J. Schaefer, MD,x Manfred Gschwendtner, MD,jj Stefan Mueller-Huelsbeck, MD, PHD,{ Thomas Rand, MD,# Martin Funovics, MD,* Florian Wolf, MD,* Aljoscha Rastan, MD,y Michael Gschwandtner, MD,** Stefan Puchner, MD,* Robin Ristl, PHD,yy Maria Schoder, MD* Vienna, Klagenfurt, and Linz, Austria; and Bad Krozingen, Kiel, and Flensburg, Germany Objectives
The hypothesis that endovascular treatment with covered stents has equal risks but higher efficacy than bare-metal stents (BMS) in long femoropopliteal artery disease was tested.
Background
Although endovascular treatment of short superficial femoral artery lesions revealed excellent results, efficacy in long lesions remains unsatisfactory.
Methods
In a prospective, randomized, single-blind, multicenter study, 141 patients with symptomatic peripheral arterial disease were assigned to treatment with heparin-bonded, covered stents (Viabahn 72 patients) or BMS (69 patients). Clinical outcomes and patency rates were assessed at 1, 6, and 12 months.
Results
Mean SD lesion length was 19.0 6.3 cm in the Viabahn group and 17.3 6.6 cm in the BMS group. Major complications within 30 days were observed in 1.4%. The 12-month primary patency rates in the Viabahn and BMS groups were: intention-to-treat (ITT) 70.9% (95% confidence interval [CI]: 0.58 to 0.80) and 55.1% (95% CI: 0.41 to 0.67) (log-rank test p ¼ 0.11); treatment per-protocol (TPP) 78.1% (95% CI: 0.65 to 0.86) and 53.5% (95% CI: 0.39 to 0.65) (hazard ratio: 2.23 [95% CI: 1.14 to 4.34) (log-rank test p ¼ 0.009). In lesions 20 cm, (TransAtlantic InterSociety Consensus class D), the 12-month patency rate was significantly longer in VIA patients in the ITT analysis (VIA 71.3% vs. BMS 36.8%; p ¼ 0.01) and the TPP analysis (VIA 73.3% vs. BMS 33.3%; p ¼ 0.004). Freedom from target lesion revascularization was 84.6% for Viabahn (95% CI: 0.72 to 0.91) versus 77.0% for BMS (95% CI: 0.63 to 0.85; p ¼ 0.37). The ankle-brachial index in the Viabahn group significantly increased to 0.94 0.23 compared with the BMS group (0.85 0.23; p < 0.05) at 12 months.
Conclusions
This randomized trial in symptomatic patients with peripheral arterial disease who underwent endovascular treatment for long femoropopliteal lesions demonstrated significant clinical and patency benefits for heparinbonded covered stents compared with BMS in lesions 20 cm and for all lesions in the TPP analysis. In the ITT analysis for all lesions, which was flawed by major protocol deviations in 8.5% of the patients, the difference was not significant. (GORE VIABAHN endoprosthesis with bioactive propaten surface versus bare nitinol stent in the treatment of TASC B, C and D lesions in superficial femoral artery occlusive disease; ISRCTN48164244) (J Am Coll Cardiol 2013;62:1320–7) ª 2013 by the American College of Cardiology Foundation
From the *Departments of Cardiovascular and Interventional Radiology, Medical University Vienna, Vienna, Austria; yDepartment of Angiology, Universitaets-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany; zDepartment of Diagnostic and Interventional Radiology, Klinikum Klagenfurt, Klagenfurt, Austria; xDepartment of Radiology, University Clinics Schleswig-Holstein, Kiel, Germany; kDepartment of Diagnostic and Interventional Radiology, Elisabethinen Hospital, Linz, Austria; {Department of Diagnostic and Interventional Radiology, Diakonissen
Hospital, Flensburg, Germany; #Department of Radiology, Hietzing Hospital, Vienna, Austria; **Department of Angiology, Medical University Vienna, Vienna, Austria; and the yyCenter for Medical Statistics, Informatics and Intelligent Systems, Medical University Vienna, Austria. Dr. Lammer is a member of the scientific advisory board of Abbott Vascular, Boston Scientific, and WL Gore; and has received lecture fees from Medtronic, WL Gore, and Terumo. Dr. Zeller is a member of the scientific advisory board of Boston Scientific, Medtronic-Invatec, WL Gore, Angioslide,
Lammer et al. Covered vs. BMS for Complex SFA Lesions
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Epidemiological data demonstrate a prevalence as high as 19% in the general population and 29% in patients age >70 years of lower extremity peripheral arterial disease (PAD) in the United States and Europe (1,2). Superficial femoral artery (SFA) stenoses and occlusions are the most common cause of symptomatic PAD (3). Endovascular treatment of short lesions has been recommended by the TransAtlantic InterSociety Consensus (TASC) and by the American Heart Association (4,5). Randomized controlled trials (RCTs)
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The VIASTAR trial is a prospective, randomized, singleblind, multicenter study that was physician initiated. The protocol was developed and conducted in accordance with the International Conference on Harmonisation/Good Clinical Practice Guideline and the Declaration of Helsinki (ISO 14155-1 and ISO 14155-2). It was approved by the local ethics committees and registered at the ISRCTN Register.
All patients had to give written Abbreviations and Acronyms informed consent. Patients were recruited in 7 European centers. ABI = ankle-brachial index Randomization was done by using BMS = bare-metal stent(s) numbered envelopes, and the CI = confidence interval correct sequence was monitored CDUS = color-coded Doppler centrally. Data were recorded on ultrasound an electronic case report form; ePTFE = expanded monitoring was provided by the polytetrafluoroethylene coordination center for clinical ITT = intention-to-treat studies (Koordinierungszentrum PAD = peripheral arterial fuer Klinische Studien) of the disease Medical University Vienna, and PTA = percutaneous 12-month results of color-coded transluminal balloon Doppler ultrasound (CDUS) angioplasty examinations were anonymized RCT = randomized controlled and blinded before review by trial CoreLab Bad Krozingen (Bad SFA = superficial femoral Krozingen, Germany). artery The study hypothesis was that TASC = TransAtlantic Interthe endovascular treatment of Society Consensus symptomatic long SFA lesions TLR = target lesion with a heparin-bonded Viabahn revascularization endoprosthesis (VIA) or a BMS TPP = treatment per-protocol carries equal risks for adverse events within 30 days after VIA = Viabahn endoprosthesis the index procedure, and the WIQ = walking impairment 12-month patency rate of the questionnaire heparin-bonded Viabahn endoprosthesis would be superior by 25%. The ePTFE covering of the Viabahn endoprosthesis may avoid in-growth of neointimal tissue, and the heparin bonding may contribute to the reduction of thrombosis and neointimal hyperplasia. The major inclusion criteria were symptomatic PAD in the Rutherford-Becker clinical stage 2 to 5 (moderate to severe claudication and critical limb ischemia), de novo arteriosclerotic stenosis or occlusion of the SFA and proximal popliteal artery 10 to 35 cm in length (TASC II classes B, C, and D) (4), patent or successfully treated iliac artery inflow, and outflow of at least 1 tibial artery. The major exclusion criteria were untreated inflow lesions, any previous stenting or surgery in the target artery, serum creatinine level >2.5 mg/dl, septicemia, and known intolerance to heparin, antithrombotic study medications, or contrast agents. The primary safety endpoint was a composite of serious procedural adverse events, including death, myocardial infarction, study limb amputation, and access site and treatment site complications requiring surgery, blood transfusion, or prolonged hospital stay within 30 days of the index
Medtronic-Ardian, and Covidien-ev3; and has received lecture fees from sanofiaventis, CR Bard, J&J Cordis, Covidien-ev3, Boston Scientific, Straub Medical, Invatec, Biotronik, and Pathway Medical. Dr. Mueller-Huelsbeck has served as a consultant for Boston Scientific; workshop organizer and lecturer for Termuo; and presented educational cases for Abbott Vascular. Dr. Funovics has received lecture fees
from Bolten Medical. Dr. Schoder has received lecture fees from J&J Cordis and Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received January 7, 2013; revised manuscript received May 3, 2013, accepted May 7, 2013.
See page 1328
comparing percutaneous transluminal balloon angioplasty (PTA) and primary stenting in short lesions of the SFA have demonstrated the superiority of primary stent placement (6,7). More recently, drug-eluting balloons and drug-eluting stents have been evaluated in RCTs, although only in short lesions (8–11). With advancing technologies, endovascular recanalization of long lesions (TASC II classes C and D) is technically feasible in a large percentage of patients (12), but the durability of PTA of long SFA lesions remains poor (13,14). Primary stent placement in long SFA lesions has shown promising results in a single-arm study (15). However, bare-metal stents (BMS) do not prevent neointimal hyperplasia, and the risk for in-stent restenosis and stent fracture grows with lesion length (16). An expanded polytetrafluoroethylene (ePTFE) covering of stents prevents in-growth of neointimal tissue regardless of lesion length. Therefore, the use of ePTFE-covered stents in long femoropopliteal artery lesions may increase the patency rate. It has been demonstrated in animal studies that immobilized heparin on ePTFE vascular grafts may reduce platelet deposition and neointimal hyperplasia (17,18). To evaluate the hypothesis that heparin-bonded ePTFEcovered stents are superior to BMS in patients with symptomatic PAD and long SFA lesions, including the proximal popliteal artery, the VIASTAR (Viabahn Endoprosthesis With PROPATEN Bioactive Surface [VIA] Versus Bare Nitinol Stent in the Treatment of Long Lesions in Superficial Femoral Artery Occlusive Disease) trial was initiated. Methods
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Lammer et al. Covered vs. BMS for Complex SFA Lesions
procedure. The primary efficacy endpoint was the primary patency rate measured at 1 year post-procedure. Primary patency was defined as no evidence of restenosis 50% or occlusion within the study lesion based on CDUS with a peak systolic velocity ratio 2.5 and no target lesion revascularization (TLR) within 12 months (19). Secondary endpoints were clinical improvement according to the Rutherford category at 1, 6, and 12 months, walking distance according to the walking impairment questionnaire (WIQ), change of the ankle-brachial Doppler index (ABI) at discharge and 1, 6, and 12 months, secondary patency, and freedom from TLR. The intervention was performed percutaneously with an antegrade or crossover femoral artery access under local anesthesia. Successful wire traversal of the target lesion was an entry criterion for the study. Angiography of the target lesion was performed in 2 planes before and after intervention. VIA and BMS were inserted through a 6- or 7-F sheath. In the VIA group, the Viabahn endoprosthesis (WL Gore, Flagstaff, Arizona) with the contoured proximal edge and heparin-bonded surface (PROPATEN Bioactive Surface) was used. The BMS used were the Life-Stent (BARD Peripheral Vascular, Inc., Tempe, Arizona), the Protégé EverFlex Stent (ev3 Inc., Plymouth, Minnesota), and the SMART-Control Stent (Cordis Corporation, Johnson & Johnson, Warren, Massachusetts). These stents were selected because of reported patency rates 80% at 1 year (7,20,21). The BMS choice was at the operators’ discretion. As study medication, all patients received 5,000 IU of heparin during the procedure. After treatment, patients were to take 100 mg of aspirin daily for life and 75 mg of clopidogrel (Plavix, Sanofi, Hoechst, Germany) daily for at least 6 months. Most patients started taking clopidogrel 1 or 2 days before the index procedure; for those who did not, a loading dose of 300 mg was given before or during the intervention. The follow-up patient visits were scheduled at discharge and 1, 6, and 12 months; if patients were symptomatic, these visits included physical examination, WIQ, ABI, and CDUS. In addition, peripheral computed tomography angiography was performed at 12 months in a study subcohort. Statistical analysis. It was calculated that 140 patients would need to be enrolled for the study to have a statistical power of 80% to detect an absolute difference of patency of 25% at 12 months. A 2-sided p value of 0.05 was considered to indicate statistical significance. Analysis of the data for the primary and secondary patency rate, and the freedom from TLR, was performed according to the intention-to-treat (ITT) group and the treatment per-protocol (TPP) group. Primary patency, secondary patency, and freedom from TLR rates were calculated by using Kaplan-Meier product-limit estimation, and the log-rank test was used to test for differences between groups. Hazard ratios for primary patency were calculated from a Cox proportional hazards regression model accounting for treatment group and stented length. Metric variables were described by mean SD, and the equality between the treatment groups was analyzed by using
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Student t tests. Categorial variables were described by absolute and relative frequencies, and the homogeneity of distributions between the 2 treatment groups was analyzed by using chi-square tests or, if the test assumption was violated, by the Fisher exact test. Descriptive statistics were calculated for the ITT data. Calculations were performed by using SAS version 9.3 (SAS Institute, Inc., Cary, North Carolina). Results Study patients. From March 2009 to March 2011, a total of 141 patients (100 men, 41 women; mean age 69 9 years; age range 47 to 90 years) were included. Demographic and clinical characteristics were similar, with no significant differences between groups, except in length of the stented segment (Tables 1 and 2). The mean lesion length was 19.0 6.3 cm in the VIA group and 17.3 6.6 cm in the BMS group (p ¼ 0.13). Acute technical success was achieved in all but 1 patient who had a malposition of a BMS that needed surgical removal followed by bypass. At discharge, ABI had significantly improved in the VIA and BMS groups, from 0.58 0.17 and 0.58 0.16 (p ¼ 0.94) to 0.93 0.18 and 0.96 0.14 (p ¼ 0.24), respectively. Complications within 30 days after the index procedure were recorded in 20 patients, 11 (15%) in the VIA group and 9 (13%) in the BMS group (Table 2). Severe adverse events within 30 days were observed once in each group: a pseudoaneurysm and hematoma (VIA group), which needed surgery, and a malposition of the stent (BMS group), which was removed surgically, followed by bypass (2 of 141 Table 1
Demographic and Clinical Characteristics of the Patients VIA (n ¼ 72)
BMS (n ¼ 69)
68.85 8.59
69.44 8.96
Male
48 (67)
52 (75)
0.34
Smoker at baseline
50 (69)
48 (70)
0.87
Hypertension
60 (83)
58 (84)
0.91
Hyperlipidemia
49 (68)
47 (68)
0.86
Coronary heart disease
16 (22)
15 (22)
0.89
Diabetes
25 (35)
25 (36)
0.99
Renal failure
12 (17)
5 (7)
0.14
Antithrombotic treatment
60 (83)
59 (86)
0.90
Statin therapy
41 (57)
42 (61)
0.76
Antihypertensive therapy
20 (28)
22 (32)
Characteristic Age (yrs)
Clinical stage of peripheral artery disease*
0.72
Rutherford 2
13 (18)
11 (17)
Rutherford 3
48 (68)
43 (65)
Rutherford 4
2 (3)
5 (8)
Rutherford 5
8 (11)
7 (11)
Baseline ankle-brachial indexy
p Value
0.58 0.17
0.58 0.16
0.94
Values are mean SD or n (%). *Rutherford stages 2 and 3 correspond to intermittent claudication, stage 4 to ischemic pain while the patient is resting, and stage 5 to ischemic ulcers. yRatio of the blood pressure in the lower legs to the blood pressure in the arms. BMS ¼ bare-metal nitinol stent(s); VIA ¼ Viabahn endoprosthesis.
Lammer et al. Covered vs. BMS for Complex SFA Lesions
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[1.4% for both groups]). There were no deaths, myocardial infarctions, or study limb amputations. Thus, the hypothesis of the primary safety endpoint was met. Follow-up. Six patients in each group had to be excluded from ITT analysis because of major protocol violations: 6 due to screening failure (patients with lesions <10 cm and >35 cm, and/or no tibial artery run-off), 4 due to incorrect treatment (PTA only without any device placement, “spot stenting” with <50% covering of the lesion after PTA), 1 who did not take any of the antithrombotic study medication, and 1 patient withdrew the informed consent after discharge (Fig. 1). Of the 141 randomized patients (ITT), 129 patients (VIA 66; BMS 63) were available for the TPP analysis. Causes for exclusion from ITT analysis are shown in Figure 1. At 12 months, 63 of 72 VIA patients and 54 of 69 BMS patients were available for follow-up and 57 of 66 VIA patients and 52 of 63 BMS patients for TPP analysis. At 1 year, the primary patency rate of all patients, including those with major protocol violations (ITT), was 70.9% (95% confidence interval [CI]: 0.58 to 0.80) versus 55.1% (95% CI: 0.41 to 0.67; log-rank test p ¼ 0.11) in the VIA versus BMS group, respectively. In patients treated according to the study protocol (TPP), 50% restenoses were observed in 9 versus 22 patients and occlusions in 6 versus 4 patients in the VIA versus BMS group. Four of 6 VIA occlusions and 2 of 4 BMS occlusions occurred within the first 6 months despite double antiplatelet therapy. The remaining occlusions occurred between 6 and 12 months with aspirin medication only. The VIA occlusions were treated in 3 patients by fibrinolysis and in the other 3 patients by bypass surgery. One patient with an acutely thrombosed VIA presented with acute limb ischemia. The 4 BMS occlusions were treated in 2 patients (1 bypass, 1 fibrinolysis) and remained untreated in the other 2 patients. In the 9 relevant (50%) VIA restenoses, edge stenosis at the proximal or distal end was observed. In the 22 relevant (50%) restenoses of BMS, diffuse instent restenosis was seen most commonly, but edge stenoses were observed as well. Therefore, at 1 year in patients treated according to the study protocol, the primary patency rate (TPP) was 78.1% (95% CI: 0.65 to 0.86) versus 53.5% (95% CI: 0.39 to 0.65; log-rank test p ¼ 0.009) in the VIA versus BMS group, respectively (Table 3, Figs. 2A and 2B). Thus, within the first year after the index procedure, the risk of binary restenosis, occlusion, and TLR was 2.23 (95% CI: 1.15 to 4.35) times more likely when using a BMS. The hazard ratio of BMS versus VIA calculated from a multiple Cox proportional hazards model accounting for treatment group and length of treated segment was 2.71 (95% CI: 1.36 to 5.39). Length of stented segment was included in the model because significant differences in this variable were observed between treatment groups. Freedom from clinically driven TLR was 84.6% (95% CI: 0.72 to 0.91) in the VIA group versus 77.0% (95% CI: 0.63 to 0.85) in the BMS group at 1-year follow-up (log-rank test p ¼ 0.37). The secondary patency rate (TPP) after TLR and bypass surgery was 89.9%
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(95% CI: 0.78 to 0.95) versus 75.2% (95% CI: 0.61 to 0.84) in the VIA versus BMS group (log-rank test p ¼ 0.058). A stratified analysis was performed to evaluate the effect of TASC classification and lesion length on primary patency. At 12 months, patients with long lesions (20 cm, TASC class D) had a significantly higher primary patency rate when treated with Viabahn endoprosthesis at ITT analysis (VIA 71.3% [95% CI: 0.53 to 0.83]; BMS 36.8% [95% CI: 0.17 to 0.57]; log-rank test p ¼ 0.01) and at TPP analysis (VIA 73.3% [95% CI: 0.54 to 0.85]; BMS 33.3% [95% CI: 0.13 to 0.54]; log-rank test p ¼ 0.004) (Figs. 3A and 3B). In the group with lesion length <20 cm, a trend toward higher patency rate after VIA was seen (VIA 86.4%; BMS 63.0%), but the difference was not significant (logrank test p ¼ 0.106). In a Cox proportional hazards regression model, sex, clinical stage according to the Rutherford category, diabetes, renal failure, calcification severity, Table 2
Baseline Angiographic and Interventional Data VIA (n ¼ 72)
BMS (n ¼ 69)
p Value
Length of target lesion (mm)
189.8 63
173.2 66
0.13
Length of stented segment (mm)
236.8 77
203.1 77
0.01
Target vessel diameter (mm)
6.08 0.6
6.25 0.7
0.88
Target vessel diameter (mm)
6.08 0.6
6.25 0.7
0.88
56 (79)
46 (70)
Occlusion Target-lesion calcification* None or mild
16 (23)
12 (17)
Moderate
44 (62)
34 (49)
Severe
11 (15)
19 (28)
Not applicable
4 (6)
TASC II classy TASC A
0.21 0.15
0.09 0
2 (3)
TASC B >10 cm
20 (28)
29 (42)
TASC C
18 (25)
16 (23)
TASC D
34 (47)
22 (32)
3
32 (44)
29 (42)
2
28 (39)
27 (40)
1
10 (14)
10 (14)
0
2 (3)
3 (4)
0
2 (3)
0 (0)
1
18 (26)
29 (42)
2
41 (57)
36 (52)
3
11 (15)
4 (6)
11 (15)
9 (13)
Peripheral embolization
4
1
Hematoma
2
2
Pseudoaneurysm
1
0
Other
3
2
Death
0
0
Study limb amputation
0
0
1 (1.4)
1 (1.4)
1.0
0.93 0.18
0.96 0.14
0.24
No. of crural runoff vessels
0.96
No. of implants
Adverse events
Severe adverse events ABI before discharge
0.04
0.77
Values are mean SD or n (%). *Calcification was assessed by the investigator. yTransAtlantic Inter-Society Consensus (TASC) II classification is a lesion classification according to the InterSociety Consensus for the Management of Peripheral Arterial Disease. Abbreviations as in Table 1.
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Figure 1
Lammer et al. Covered vs. BMS for Complex SFA Lesions
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Randomization and Follow-Up of Study Patients
*Screening failures: patients with lesions <10 cm and >35 cm, no tibial run-off. yIncorrect treatment: percutaneous transluminal balloon angioplasty (PTA) only without any device placement, “spot stenting” with <50% covering of the lesion after PTA. ITT ¼ intention-to-treat; TPP ¼ treatment per-protocol.
Table 3
Outcomes in Study Patients at 12 Months Follow-Up
ITT Analysis Restenosis PSVR in >50% stenosis Reocclusion
VIA (n ¼ 63/72)
95% CI
BMS (n ¼ 54/69)
13
24
2.72 1.29
3.25 2.03
8
6
95% CI
p Value
0.54
Primary patency rate (all)
70.9%
0.58–0.80
55.1%
0.41–0.67
0.11
Primary patency rate (lesion 20 cm)
71.3%
0.53–0.83
36.8%
0.17–0.57
0.01
TLR ABI (mean) TPP Analysis Restenosis Reocclusion
13
16
0.93 0.23
0.85 0.23
VIA (n ¼ 57/66)
BMS (n ¼ 52/63)
95% CI
9
0.1 95% CI
p Value
22
6
4
Primary patency rate (all)
78.1%
0.65–0.86
53.5%
0.39–0.65
0.009
Primary patency rate (lesion 20 cm)
73.3%
0.54–0.85
33.3%
0.13–0.54
0.004
0.37
TLR
9
13
Freedom from TLR rate
84.6%
0.72–0.91
77.0%
0.63–0.85
Secondary patency rate
89.9%
0.78–0.95
75.2%
0.61–0.84
ABI (mean) Rutherford category improvement 1 (%) Walking distance (according to WIQ) (m)
0.94 0.23
0.85 0.23
84
84
785.8
565.9 m
0.058 0.048
0.17
Values are n, mean SD, or %. ABI ¼ ankle-brachial index; CI ¼ confidence interval; ITT ¼ intention-to-treat; PSVR ¼ peak systolic velocity ratio; TLR ¼ target lesion revascularization; TPP ¼ treatment per-protocol; WIQ ¼ walking impairment questionnaire; other abbreviations as in Table 1.
Lammer et al. Covered vs. BMS for Complex SFA Lesions
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Figure 2
Patency Rate of All Lesions
Primary patency of Viabahn endoprosthesis (VIA) (red) versus bare-metal stent (BMS) (black) in the superficial femoral artery lesions of patients with symptomatic peripheral arterial disease. (A) ITT: at 12 months VIA 70.9% (95% confidence interval [CI]: 0.58 to 0.80) versus BMS 55.1% (95% CI: 0.41 to 0.67; log-rank test p ¼ 0.11). (B) TPP: at 12 months VIA 78.1% (95% CI: 0.65 to 0.86) versus BMS 53.5% (95% CI: 0.39 to 0.65) (hazard ratio 2.23 [95% CI: 1.14 to 4.34]; log-rank test p ¼ 0.009). Abbreviations as in Figure 1.
and stenosis versus occlusion had no significant influence on outcomes. The ABI (at discharge 0.93 0.18 vs. 0.97 0.14) of the VIA group versus BMS group was 0.96 0.19 vs. 0.98 0.14 [p ¼ NS], 0.94 0.24 vs. 0.87 0.24, and 0.94 0.23 vs. 0.85 0.23 [p < 0.05] at 1, 6, and 12 months, respectively (Table 3). An improvement by 1 Rutherford category was reported in 84.0% in both groups at 12 months (Fig. 4A). The mean walking distance according to the WIQ was 136.3 m versus 115.1 m (p ¼ 0.13) at baseline and 785.8 m versus 565.9 m (p ¼ 0.17) in the VIA versus BMS cohort at 12 months, respectively (Fig. 4B). These data include patients after TLR and bypass. Discussion The purpose of the current study was to evaluate whether a heparin-bonded ePTFE-covered endoprosthesis such as
Figure 3
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Patency Rate of Lesions 20 cm
Primary patency of VIA (red) versus BMS (black) in superficial femoral artery lesions of patients with symptomatic peripheral arterial disease and lesions 20 cm. (A) ITT: at 12 months VIA: 71.3% (95% CI: 0.53 to 0.83) versus BMS: 36.8% (95% CI: 0.17 to 0.57; log-rank test p ¼ 0.01). (B) TPP: at 12 months VIA: 73.3% (95% CI: 0.54 to 0.85) versus BMS: 33.3% (95% CI: 0.13 to 0.54; log-rank test p ¼ 0.004). Abbreviations as in Figures 1 and 2.
the VIA is superior to bare-metal nitinol stents (BMS) in patients with symptomatic PAD and long lesions of the SFA and proximal popliteal artery. The ITT analysis did not show a significant difference but a trend in favor of the heparin-bonded ePTFE-covered endoprosthesis (VIA 71%; BMS 55%; log-rank test p ¼ 0.11). However, it was flawed by major protocol deviations in 8.5% of the patients. In the TPP analysis, the Viabahn endoprosthesis showed a primary patency rate of 78.1% versus 53.5% (p ¼ 0.009) for BMS at 12 months. Thus, within the first year after the index procedure, the risk of a binary restenosis, occlusion, and TLR was 2.23 times more likely when using a BMS. This confirmed the original study hypothesis. The fact that the TPP was significantly at odds with the ITT analysis testifies that the rate of protocol violations was high and diluted the statistical power. In lesions 20 cm (TASC class D), the 12-month patency rate was significantly higher in VIA patients in the ITT analysis (VIA 71.3% vs. BMS 36.8%;
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Figure 4
Lammer et al. Covered vs. BMS for Complex SFA Lesions
Clinical Improvement
Categorized according to (A) Rutherford category and (B) walking distance (in meters) according to the walking impairment questionnaire (WIQ) of the VIA versus BMS in superficial femoral artery lesions of patients with symptomatic peripheral arterial disease. Relative frequencies are displayed as stacked bar plots. Range is between grade 3 (indicating markedly improved) and –3 (indicating markedly worsening). Abbreviations as in Figure 2.
p ¼ 0.01) and the TPP analysis (VIA 73.3% vs. BMS 33.3%; p ¼ 0.004). Compared with baseline, ABI was improved in both study cohorts with a higher ABI in the Viabahn cohort of 0.94 0.23 versus a BMS ABI of 0.85 0.23 (p < 0.05) at 12 months. Thus, objective parameters showed a significant benefit. However, this improved primary patency and ABI for the Viabahn endoprosthesis group did not translate into a significant reduction of clinically driven TLR at 12 months (84.6% after Viabahn endoprosthesis versus 77.0% after BMS; log-rank test p ¼ 0.37). The relatively low clinically driven TLR rate in the BMS group in relation to the high rate of instent restenosis is difficult to explain. One could argue that instent restenosis in BMS still enables collateral flow through side branches, which may mitigate symptoms. However, 70% of the lesions in the BMS group were total occlusions without side branches. The lower TLR rate may be due to the slow progressive narrowing of the stent lumen due to diffuse intimal hyperplasia in BMS. An additional postinterventional exercise effect may have caused less obvious recurrence of claudication. In the VIA group, the recurrence was in one-third of the patients due to a total thrombotic
JACC Vol. 62, No. 15, 2013 October 8, 2013:1320–7
occlusion that caused a rapid deterioration of the walking distance. In 1 of 6 patients, the thrombotic occlusion caused an acute limb ischemia. The number of occlusions in the VIA group was higher (6 vs. 4); this finding, however, was not significant. The VIA occlusions were treated in 3 patients by fibrinolysis and in the other 3 patients by bypass. The observed mean walking distance according to the WIQ was longer in the VIA cohort at 12 months but did not reach statistical significance (785.8 m vs. 565.9 m; p ¼ 0.17). The clinical improvement of 1 according to the Rutherford classification was 84.0% in both groups. However, the reported ABI, walking distance, and clinical improvement are parameters that correspond to the secondary patency rate because they also include patients after TLR and bypass. The endovascular treatment of PAD has the advantages of low morbidity and mortality rates, and early recovery, and it can be done as an outpatient procedure. BMS, drugeluting stents, and drug-eluting balloons have demonstrated their superiority over plain PTA in short lesions only (6–11). However, a prospective RCT for long lesions focusing on various endovascular techniques has not yet been published. In a prospective single-arm study with BMS in long SFA lesions, 1-year freedom from TLR was reported in 68.2% (15). This finding was even lower than the freedom of BMS from TLR in the current study (77%). The freedom from TLR in the Viabahn arm of this study was 85%. Bypass surgery with venous conduits must still be considered as the gold standard when comparing primary patency rates. However, considering the high secondary patency rate of 89.9% in the Viabahn arm of this study, it was demonstrated that similar results compared with surgery could be achieved at a low procedural risk. In the current study, the rate of severe complications requiring surgery or prolonged hospital stay was 1.4%, and no deaths or study limb amputations were observed. Thus, the overall risk compared with surgery seems to be less (3,22). In the event that no vein is available or that the vein should be preserved for aorto-coronary bypass surgery, the 1-year patency rate after synthetic graft femoropopliteal above-knee bypass drops to 76%, as has been shown in a recent RCT (23). Covered stents have the advantage of no in-growth of neointimal tissue, which is the drawback of BMS. However, graft thrombosis as disadvantage has been observed. In this study, the Viabahn endoprosthesis with the heparin-bonded surface (PROPATEN bioactive surface) was used (24,25). The stably bound, endpoint immobilized heparin at the inner surface of the ePTFE graft has been shown in the Scandinavian Propaten trial to significantly prolong the primary patency rate to 86.4% for heparin-bonded ePTFE grafts versus 79.9% for plain ePTFE grafts (p ¼ 0.043) at 1 year (26). All patients were on antiplatelet medication with aspirin 100 mg daily for life and clopidogrel 75 mg daily for at least 6 months, which may be necessary to achieve a low thrombosis rate. Study limitations. Twelve (8.5%) of the 141 patients had a major protocol violation. There were 6 violations in each study arm, and they were randomly distributed.
Lammer et al. Covered vs. BMS for Complex SFA Lesions
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A strength of the study is that it is the first published RCT in symptomatic PAD patients and endovascular treatment of long femoropopliteal artery lesions. Clinical and imaging endpoints were both considered, and both study endpoints were met. Conclusions
11. 12.
13.
The clinical implication of the current study is that it demonstrates, when treating PAD in patients with long diffuse femoropopliteal artery disease, heparin-bonded ePTFE-covered stents yield clinical and patency benefits compared with BMS.
15.
Acknowledgments
16.
The authors thank Mrs. Johanna Moyses, research coordinator at the division of Cardiovascular and Interventional Radiology, Medical University Vienna, for the data management, WL Gore for the financial support for the CoreLab review of the 12-month CDUS studies, and the Medical University Vienna for monitoring by the Clinical Coordination Center Koordinierungszentrum fuer Klinische Studien.
14.
17.
18.
19.
Reprint requests and correspondence: Dr. Johannes Lammer, Department of Cardiovascular and Interventional Radiology, Vienna General Hospital, Medical University Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria. E-mail: johannes. [email protected].
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Key Words: angioplasty - covered stent - peripheral arterial disease stent - stent graft - superficial femoral artery.
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