Randomized Trial of the SMART Stent versus Balloon Angioplasty in Long Superficial Femoral Artery Lesions: The SUPER Study

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1 Cardiovasc Intervent Radiol (2013) 36: DOI /s z CLINICAL INVESTIGATION ARTERIAL INTERVENTIONS Randomized Trial of the SMART Stent versus Balloon Angioplasty in Long Superficial Femoral Artery Lesions: The SUPER Study Nicholas Chalmers Paul T. Walker Anna-Maria Belli Anthony P. Thorpe Paul S. Sidhu Graham Robinson Mariella van Ransbeeck Steven A. Fearn Received: 22 March 2012 / Accepted: 5 July 2012 / Published online: 16 October 2012 Ó Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2012 Abstract Purpose To determine whether primary stenting reduces the rate of restenosis compared with balloon angioplasty alone in the endovascular treatment of long superficial femoral artery lesions; and to assess the effect of treatment on quality of life. Methods A total of 150 patients with superior femoral artery occlusion or severe stenosis of 5 22 cm length from 17 UK centers were randomized to either primary stenting with the SMART stent or balloon angioplasty (i.e., percutaneous transluminal angioplasty, PTA). Bailout stent placement was permitted in case of inadequate result from PTA. The primary end point was restenosis measured by duplex ultrasound at 1 year. Quality-of-life assessments were performed by the EuroQol (EQ)-5D questionnaire. Results Mean lesion length was.0 mm in the stent group and mm in the PTA group. A total of 140 This study was conducted on behalf of the SUPER study investigators. List of lead investigators, study site and number of patients recruited. N. Chalmers (&) Department of Radiology, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK nicholas.chalmers@cmft.nhs.uk P. T. Walker Department of Radiology, James Cook University Hospital, Marton Road, Middlesborough, Cleveland TS4 3BW, UK A.-M. Belli Department of Radiology, St. George s Healthcare NHS Trust, Blackshaw Road, London SW17 0QT, UK A. P. Thorpe Department of Radiology, Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, Scotland, UK (93.3 %) of 150 had total occlusions. At 12 months follow-up, restenosis measured by Duplex ultrasound was not significantly different between the stent and PTA groups by intention-to-treat or as-treated analyses: 47.2 versus 43.5 % (p = 0.84) and 40.8 versus 46.7 % (p = 0.68), respectively. There were fewer target lesion revascularizations in patients randomized to stenting, but this did not reach statistical significance (12.5 vs %, p = 0.26). There was no difference in the rate of amputation. Patients in both groups reported improved quality of life. Conclusion Primary stenting of long lesions in predominantly occluded superficial femoral arteries does not reduce the rate of binary restenosis compared with balloon angioplasty and bailout stenting. Both treatment strategies conferred a meaningful and sustained improvement to the quality of life of patients with severe superficial femoral artery disease. Keywords Balloon angioplasty Long lesions Randomized trial SMART stent Superficial femoral artery P. S. Sidhu Department of Radiology, King s College Hospital, Denmark Hill, London SE5 9RS, UK G. Robinson Department of Radiology, Hull Royal Infirmary, Kingston upon Hull HU3 2JZ, UK M. van Ransbeeck Cordis, Johnson & Johnson Medical NV/SA, Waterloo Office Park, Drève Richelle 161 H, Waterloo 1410, Belgium S. A. Fearn Cordis, Johnson & Johnson Medical Ltd., Pinewood Campus, Nine Mile Ride, Wokingham RG40 9EW, UK

2 354 N. Chalmers et al.: Stent vs. PTA in SFA Lesions Introduction When this study was initiated, the SIROCCO [1, 2] trials and other studies [3, 4] had demonstrated that the Cordis SMART stent was associated with high patency rates in the superior femoral artery (SFA), but at that time, there were no controlled trial data demonstrating any advantage of Nitinol stent placement in the SFA compared with balloon angioplasty (i.e., percutaneous transluminal angioplasty, PTA) alone. Our hypothesis was that stents would deliver improved patency compared with PTA in patients with long segments of disease and total occlusions. We therefore undertook a multicenter randomized, controlled trial to test this. We also sought to assess whether stent placement was more effective than angioplasty in improving quality of life. Materials and Methods Study Device The study device was the Cordis SMART Nitinol stent, a self-expandable stent indicated for use in a vessel with a diameter 1 2 mm smaller than the nominal stent diameter. Stents of up to 120 cm in length were supplied in 6.0 and 7.0 mm unconstrained diameters, constrained in a 6F delivery system that accommodated a in. guide wire. Patient Selection and Randomization Patients with atherosclerotic disease of the SFA were randomized to either PTA alone or PTA followed by implantation of the SMART stent. From April 2005 to December 2006, a total occlusion of at least 5 cm was required. As a result of slow recruitment and publication of new data [5], the protocol was then amended to include stenosis of[70 % associated with a minimum length of disease of 5 cm and a maximum length of 22 cm. A block randomization, with blocks of four subjects, stratified per center, was used. Randomization was performed within 6 weeks of obtaining the written consent of the patients, during the procedure, and after catheter sheath introducer placement, but before crossing the occlusion with the guide wire. The study was conducted in accordance with the guidelines for good clinical practices, the Declaration of Helsinki, the European Standard ISO 14155, and applicable local regulatory guidelines. Ethical and institutional approval was obtained before the commencement of enrolment, and all patients provided written informed consent after receiving a description of the study, including follow-up requirements and risks related to the study. Inclusion and exclusion criteria are listed in Table 1. Procedures and Follow-up Antegrade or contralateral retrograde arterial puncture was followed by placement of a sheath introducer. The target lesion was traversed with a catheter and guide wire according to the operator s usual practice in the transluminal or subintimal plane. Cases of failure to cross the lesion and reenter the true lumen at an appropriate level were considered treatment failures and were analyzed according to the intention-to-treat principle. For patients randomized to PTA, balloon selection and dilatation was performed according to the operator s normal practice. Bailout stenting was allowed if the postangioplasty angiogram showed an unsatisfactory result such as flow-limiting dissection or persistent stenosis, according to the operator s local practice. For patients randomized to stenting, predilatation of the lesion was recommended with a balloon smaller than the diameter of the reference vessel and with a length shorter than the anticipated lesion length. The appropriate stent size was selected after the investigator s review of the patient s baseline angiogram with a requirement that the diameter of the stent be 1 2 mm larger than the reference vessel diameter. A maximum of two stents was permitted, and where a second stent was required, an overlap of cm was specified. Stents were to be placed such that they extended at least 5 mm proximal and distal to the diseased segment. Angiograms were taken in the same projections as the preimplant dilatation to compare the preimplant and postimplant minimum lumen diameters. The procedure was considered to have been completed once all the delivery material, including catheter sheath introducer had been removed. A Doppler ultrasound (DUS) of the treated segment was completed before discharge. Antithrombotic medication was provided according to normal clinical practice at each site. Periprocedurally, anticoagulation with at least U of heparin was recommended, with additional infusion or overnight treatment also permitted. A combination of two antiplatelet drugs such as clopidogrel and aspirin, or one antiplatelet drug combined with a low-molecular-weight heparin, for at least 3 4 weeks after the procedure, was recommended. Aspirin was recommended to be continued indefinitely. Follow-up clinical evaluations were conducted before hospital discharge, at 3 months? 7 days, at 6 months? 14 days, and at 12 months? 30 days after the procedure. Study End Points The primary end point was the binary restenosis rate at 1 year after the index procedure as measured by DUS, the results of which were evaluated by an independent core laboratory (Harvard Clinical Research Institute). Binary restenosis by DUS was defined as[50 % restenosis on the

3 N. Chalmers et al.: Stent vs. PTA in SFA Lesions 355 Table 1 Inclusion and exclusion criteria Inclusion criteria Age C30 years Symptomatic leg ischemia by Rutherford/Fontaine classification (category 1, 2, 3, 4, or 5); duration of intermittent claudication (category 1 3) should be at least 6 months One superficial femoral artery de novo or restenotic lesion (C70 % stenosis or occlusions), with a lesion length of C5 B22 cm Patent popliteal artery on the index side, i.e., single vessel runoff or better with at least 1 of 3 vessels patent to the lower third of the calf before the day of the procedure. Additional intervention to further improve blood flow to the lower limb is acceptable during the index procedure, but after successful treatment of the study lesions Vessel diameter C4 and B6 mm Exclusion criteria Aneurysm in the superficial femoral artery or popliteal artery Tandem lesion requiring nonoverlapping stents Procedures which require stent in stent placement, to obtain patency, such as severe calcification resistant to stenting Poor aortoiliac or common femoral inflow, which would be deemed inadequate to support a femoropopliteal bypass graft Revascularization involving the same limb within 7 days before the index procedure or a planned revascularization within 7 days after the index procedure Subject having total occlusions of the iliac artery on the same side must be excluded. However, intervention to restore adequate blood flow before the index procedure is allowed during the same procedure and before the treatment of the study lesion Previously implanted stent or stents in the to-be-treated artery at the same site Requiring stent placement in the popliteal artery Presence of a femoral vascular prosthesis basis of a peak systolic velocity ratio C2.5, or absent flow indicating total occlusion. Secondary end points prespecified in the protocol, but not subject to power calculation, included postprocedural residual stenosis measured by angiography, technical success, primary patency, ankle brachial index (ABI), Rutherford/Fontaine grade, and quality of life. Clinical event recording included all-cause mortality, myocardial infarction, ipsilateral amputation, target vessel revascularization (TVR), and target lesion revascularization (TLR). All events were adjudicated by a blinded clinical events committee. Technical success was defined as achievement of a residual diameter stenosis of \30 % by angiography using the assigned device only. A procedure-related serious adverse event was defined as an adverse event related to the treated limb or index procedure that required the patient to be hospitalized, that prolonged hospitalization, that necessitated intervention, or that was fatal. ABI was calculated as the highest systolic pressure in the ankle of the index limb/highest brachial pressure. Health-related quality of life was measured by the EuroQol (EQ)-5D utilities and the visual analog scale (VAS) [6, 7]. Statistical Methods With 60 patients in each treatment arm, a clinically meaningful odds ratio of 3.03 in the primary end point could be detected with a power of 80 % at a two-sided significance level of 0.05, assuming a 1 year binary restenosis rate of 63 % in patients who received balloon angioplasty and 36 % in patients who received a stent. The intention was to recruit 150 patients (75 patients per treatment group) to allow for an estimated 20 % noncompliance to follow-up and unavailable data at 12 months. Continuous variables were presented as mean ± standard deviation (SD) or median and 25/75 percentiles. Comparisons of continuous variables used the Student s t test or the Wilcoxon rank sum (Mann Whitney) test. For categorical variables, the absolute (n) and relative frequency (%) were tabulated, and binary variables were compared by Fisher s exact test. Primary analyses were conducted on an intentionto-treat basis according to randomization. As-treated results are also reported. Additional quality-of-life analyses, prespecified in the economic evaluation plan, were conducted to identify and validate the EQ-5D utilities and VAS scores associated with preprocedural Rutherford/ Fontaine classifications and differences between patients who did and did not incur binary restenosis or require TLR/TVR at follow-up. These data are shown irrespective of which treatment an individual patient was randomized to, because the purpose of this analysis was to determine the utilities associated with each of these end points. Categorization by presence or absence of restenosis excluded patients who had a TLR/TVR in order to assess whether DUS restenosis alone, in the absence of symptom recurrence sufficient to warrant TLR/TVR, had any impact on quality of life.

4 356 N. Chalmers et al.: Stent vs. PTA in SFA Lesions Fig. 1 Flow of patients through the study to 12 months Results Recruitment and Patient Population Between April 2005 and April 2008, 150 patients with SFA lesions across 17 UK centers were enrolled onto the study. Of these, 74 were randomized to stenting and 76 to PTA. Figure 1 shows the flow of patients through the study to 12 months. Fifty-three patients in the stent arm and 46 patients in the PTA arm were available for primary end point analysis. Six patients randomized to the stent group and one patient randomized to the PTA group did not receive any treatment as a result of failure to cross the lesion. Four patients in the stent group received PTA only and four patients in the PTA group underwent bailout stenting. Baseline patient demographics and clinical characteristics are shown in Table 2. There were minor imbalances between the two groups, none of which reached statistical significance, apart from age, where patients randomized to PTA were 3.9 years older (p \ 0.01). Lesion characteristics are listed in Table 3. Mean lesion length was [11 cm in both arms of the study, with a very high proportion of vessels being totally occluded (95.9 and 90.8 % in the stent and PTA groups, respectively). Patients randomized to stenting had significantly longer occlusions than those randomized to PTA (83.9 ± 46.3 vs ± 37.1 mm, p \ 0.01); all other baseline lesions characteristics were similar. Procedural and Clinical Outcomes Procedural and clinical outcomes are summarized in Table 4. In patients randomized to stenting, the postprocedural residual stenosis was significantly lower and technical success was significantly higher. The primary end point of restenosis by DUS at 12 months was not significantly different between the stent and PTA groups: 47.2 versus 43.5 % respectively (p = 0.84). Primary patency at 12 months was 45.9 versus 42.6 % (p = 0.86). Table 2 Baseline patient demographics and clinical characteristics Characteristic Stent (n = 74) PTA (n = 76) p Age (year) 65.9 ± ± 8.5 \0.01 Male 58 (78.4) 65 (85.5) 0.29 Coronary heart disease 26 (35.1) 32 (42.1) 0.41 Diabetes 23 (31.1) 29 (38.2) 0.39 Current smoker 18 (24.3) 20 (26.3) 0.85 Hypertension 49 (66.2) 51 (67.1) 1.00 Renal impairment 11 (14.9) 6 (7.9) 0.21 Critical limb ischemia a 11 (14.9) 16 (21.1) 0.40 ABI 0.61 ± ± AWD (mo) ± ± Values are presented as mean ± SD or n (%) PTA percutaneous transluminal angioplasty, ABI ankle brachial index, AWD alive with disease a Rutherford 4, 5, 6 or Fontaine III, IV Table 3 Baseline lesion characteristics Characteristic Stent (n = 74) PTA (n = 76) Lesion length Total (mm).0 ± ± B6.5 cm 16.2 % 17.1 % 6.5 B11 cm 35.1 % 36.8 % 11 B15 cm 20.3 % 21.1 % [15 cm 28.4 % 25.0 % Length of occlusion (mm) 83.9 ± ± 37.1 \0.01 Total occlusions 95.9 % 90.8 % 0.33 Restenotic 6.8 % 6.6 % 1.00 Calcification 56.8 % 47.4 % 0.26 Reference vessel diameter (mm) 5.4 ± ± Values are presented as mean ± SD or percentages PTA percutaneous transluminal angioplasty There were five deaths in the stent arm and two in the PTA arm of the study, which were unrelated to the procedures or to peripheral arterial disease. There were four p

5 N. Chalmers et al.: Stent vs. PTA in SFA Lesions 357 Table 4 Procedural and clinical outcomes Outcome Stent (n = 74) PTA (n = 76) p Table 5 EQ-5D utility scores at baseline grouped by Rutherford/ Fontaine category Rutherford/Fontaine category EQ-5D utility EQ-5D VAS Stenosis after procedure 10.0 ± ± 19.6 \0.001 (%) Technical success 60/65 (92.3) 50/74 (67.6) \0.001 Clinical outcomes to 12 mo Restenosis by DUS only 25/53 (47.2) 20/46 (43.5) 0.84 (primary end point) Primary patency 28/61 (45.9) 26/61 (42.6) 0.86 As-treated restenosis by 20/49 (40.8) 21/45 (46.7) 0.68 DUS As-treated primary 29/56 (51.8) 24/61 (39.3) 0.29 patency Death 5/72 (6.9) 2/72 (2.8) 0.44 MI 0/72 (0.0) 0/72 (0.0) Ipsilateral amputation 2/72 (2.8) 2/72 (2.8) 1.00 Clinically driven TLR 9/72 (12.5) 15/72 (20.8) 0.26 As-treated TLR 8/67 (11.9) 16/72 (22.2) 0.12 ABI 0.83 ± ± Values are presented as mean ± SD, n/n (%), or n (%). Results are based on intention to treat unless otherwise specified PTA percutaneous transluminal angioplasty, DUS Doppler ultrasound, MI myocardial infarction, TLR target lesion revascularization, ABI ankle brachial index ipsilateral amputations in total, two in each group, which all occurred in patients who initially presented with critical limb ischemia. Two patients randomized to stenting underwent amputation at the foot, with one requiring a further amputation below the knee. One patient randomized to PTA required amputation at the foot and one above the knee. There were fewer clinically driven TLRs in the patients randomized to stenting, but this did not reach statistical significance (12.5 vs %, p = 0.26). ABI increased from baseline in both groups, but there was no significant difference between the groups at 12 months follow-up. As-treated outcomes for stent vs. PTA at 12 months were restenosis by DUS 40.8 versus 46.7 % (p = 0.68), primary patency 51.8 versus 39.3 % (p = 0.29), and TLR 11.9 versus 22.2 % (p = 0.12). Quality of Life Preprocedural EQ-5D scores for patients in each Rutherford/Fontaine class are shown in Table 5. The notation R1 FIIA refers to patients classified as either Rutherford 1 or Fontaine IIA at the preprocedural assessment; the same logic applies to the other groups. Both EQ-5D scoring systems showed generally lower values with increasing disease severity as described by the Rutherford/Fontaine classification. However, the utility score may better discriminate between mild and moderate intermittent claudication than the VAS score. R1 FIIA 0.55 ± 0.25 (16) 66.4 ± 16.2 (15) R2 FIIB 0.43 ± 0.30 (56) 65.7 ± 17.8 (56) R3 FIIC 0.36 ± 0.31 (42) 59.6 ± 17.1 (42) R4 FIII 0.27 ± 0.28 (8) 41.6 ± 22.1 (7) R5 FIV 0.38 ± 0.38 (17) 47.6 ± 24.6 (17) Values are shown as mean ± SD. Final values in parentheses indicate the number of completed questionnaires at each time point EQ-5D EuroQol-5D questionnaire assessing quality of life, VAS visual analog scale Table 6 EQ-5D quality-of-life scores at baseline and at follow-up Score Stent PTA EQ-5D utility score, median (IQR) Baseline 0.52 ( ) (69) 3 mo 0.69* ( ) (59) 6 mo 0.69 ( ) (57) 12 mo 0.69 ( ) (58) EQ-5D visual analog score, mean ± SD 0.59 ( ) (70) 0.73* ( ) (62) 0.69 ( ) (58) 0.71 ( ) (54) Baseline 59.4 ± 21.0 (68) 61.5 ± 18.6 (69) 3 mo 63.3 ± 25.0 (58) 70.3 ± 15.2 (62) 6 mo 66.4 ± 19.4 (57) 65.4 ± 18.5 (61) 12 mo 66.1 ± 20.9 (60) 62.2 ± 21.6 (56) Values are presented as median and IQR if skewed or mean ± SD if normally distributed (D Agostino and Pearson omnibus normality test). Final values in parentheses indicate the number of completed questionnaires at each time point EQ-5D EuroQol-5D questionnaire assessing quality of life, IQR interquartile range, SD standard deviation * p \ versus baseline EQ-5D utility and VAS scores at baseline and follow-up are shown in Table 6. Both sets of scores were similar for both groups of patients at each time point. Both treatment strategies resulted in a marked and statistically significant increase in utility score from baseline to 3 months (p \ for both, Wilcoxon signed-rank test), which was maintained to 12 months, also for both groups. Figure 2 shows EQ-5D utility scores for patients who did or did not have binary restenosis by DUS (Fig. 2A) and did or did not undergo revascularization (Fig. 2B). Patients who required revascularization had a significantly lower median EQ-5D utility at 6 months (0.52 vs. 0.69, p = 0.03), which

6 358 N. Chalmers et al.: Stent vs. PTA in SFA Lesions Fig. 2 EQ-5D utilities in patients who did or did not have restenosis by DUS (A) and patients who did or did not undergo repeat revascularization (B). Values are presented as median and interquartile range. n number of completed questionnaires at each time point returned to the 3 month value at 12 months. Patients with binary restenosis on DUS who did not require revascularization during the study period did not show the same pattern at 6 months, but some patients with restenosis had very low scores at 12 months compared with those who did not, as reflected by a much lower 25th percentile (0.15 vs respectively). Discussion Since starting the SUPER study, four comparable studies involving Nitinol stents [5, 8 10] and a Cochrane review [11] have been published. The Cochrane review concluded that routine stenting of the SFA after PTA could not be recommended, although the authors did note that there was a small, short-term benefit of stenting over PTA when measured by DUS or angiographic patency. Only two of the studies included in this meta-analysis used selfexpanding Nitinol stents [5, 8], which are now the stent technology of choice for the SFA as a result of the superior resistance of Nitinol stents to compression, torsion, flexion, contraction, and extension when compared with stainless steel stents [12]. In this study, the primary end point of 12 month binary restenosis was not significantly reduced by a strategy of primary stenting compared with balloon angioplasty in long (approximately 12 cm) SFA lesions in predominantly totally occluded vessels. This is similar to the findings of the FAST [8] study but in contrast to the ABSOLUTE [5] and ASTRON [9] studies. The SUPER study recruited patients with lesions 20 % longer than those of any other randomized trial published so far, with 2 times as many total occlusions and a higher proportion of patients with critical limb ischemia. All of these factors have been reported as predisposing toward poorer outcomes with endovascular treatment [13 17] and may have reduced the effect size that was expected. There are several possible explanations for the absence of a greater difference in outcome between stenting and PTA. It is likely that in most cases recanalization was in the subintimal plane. The role of uncovered stents in the subintimal plane is debatable [18 20]. It may be that there is less advantage to stent placement in the subintimal plane than in the true lumen, particularly if the added benefit of the stent is to tack down flow limiting intimal flaps. These generally do not occur in subintimal recanalization except at the entry tear. There were few cases of crossover from PTA to stent placement in this trial. This reflects the observation that the subintimal track generally looks satisfactory on the immediate postdilatation angiogram. There were four instances of crossover from stent to PTA. The usual explanation was low reentry into the true lumen, beyond the distal end of the occlusion, such that the operator considered stent placement to be contraindicated. There may have been instances of suboptimal stent technique, including failure to stent the entire diseased segment from normal to normal vessel, the result of there being no truly disease-free arterial segment in the SFA in some cases, with the associated risk of disease progression in the unstented portion. In addition, despite randomization, patients assigned to stenting had a preprocedural occlusion length that was 21 mm longer than those assigned to PTA, which may have disadvantaged the stenting arm of the study. There were also a higher proportion of total occlusions and a larger number of failures to traverse the occlusion in the stent group. The as-treated analysis removes the cases of failure to cross the lesion. This leads to a small, nonsignificant numerical benefit from stenting. Primary stenting did not result in improvements in ABI at 12 months compared with PTA alone, and EQ-5D utility scores were virtually identical at each point of

7 N. Chalmers et al.: Stent vs. PTA in SFA Lesions 359 measurement, indicating that neither treatment strategy conferred any measurable health benefit over the other. Quality-of-life measures are highly relevant to current health policy as the collection of patient-reported outcomes is becoming an increasingly important measure of the effectiveness and quality of treatment. A previous study has shown that quality of life measured by the SF-36 questionnaire improves significantly after SFA intervention and that restenosis adversely affects quality of life [21]. The EQ-5D is the preferred generic measure of health status by both the National Health Service (NHS) in England [22] and by the National Institute for Health and Clinical Excellence (NICE) [23]. There was good agreement between the established Rutherford/Fontaine clinical categorization of peripheral arterial disease and preprocedural EQ-5D utility scores, which lends support to the validity of using the EQ-5D to assess outcomes in these patients. A similar relation between EQ-5D and preprocedural Rutherford classification has been reported by de Vries et al. [24], although the mean EQ-5D scores in this Dutch population were higher than those found in SUPER study patients. The BASIL study [25], which similarly recruited UK patients, reported a mean EQ-5D utility score of 0.26 ± 0.32 for patients with ischemic rest pain or tissue loss before angioplasty, which is comparable with the scores recorded for SUPER study patients categorized as Rutherford 4/Fontaine III (0.27 ± 0.28) and Rutherford 5/Fontaine IV (0.38 ± 0.38). These data highlight the serious impact of symptomatic peripheral arterial disease on patients when compared with other cardiovascular conditions that warrant intervention. For example, Longworth et al. [26] reported mean EQ-5D utilities of 0.36 (95 % confidence interval ) in patients with Canadian Cardiovascular Society grade IV angina pectoris, whereas Serruys et al. [27] reported preprocedural utilities of 0.69 ± 0.20 in patients with multivessel coronary artery disease in the ARTS study. If comparability of utilities between disease states is assumed, even patients with mild intermittent claudication in the SUPER study scored themselves as having a worse quality of life than patients with symptomatic multivessel coronary artery disease. Both randomized groups showed significant improvements in quality of life at 3 months compared with the preprocedure scores, and this was maintained to 12 months follow-up, indicating that endovascular treatment yielded lasting health benefits. Some patients presented with very poor preprocedural health-related quality of life, as indicated by the low 25th percentile values in Table 6. This lower limit of the interquartile range was notably higher at all points of follow-up, suggesting that revascularization was beneficial in these severely symptomatic patients. Restenosis determined by DUS is an end point in most of the comparable trials of SFA intervention [1, 2, 5, 8, 9, 28]. However, when patients were categorized according to the presence or absence of binary restenosis by DUS, EQ-5D utilities (excluding those who required repeat revascularization) were almost identical at each point of follow-up, suggesting that binary restenosis in the absence of symptoms sufficient to warrant repeat revascularization is not a good indicator of health status. Stratification of all randomized patients according to whether they underwent revascularization revealed a statistically significant reduction in quality of life at 6 months, to below the preprocedural value, indicating the negative impact of symptom recurrence on some patients with recurrent SFA disease. Reintervention provided effective relief, as evidenced by the return to 3 month values at 12 months follow-up. These data also suggest that when comparing different interventional strategies or different devices, binary restenosis and composite end points heavily dependent on it may be of limited clinical relevance because its presence or absence appears to have little meaningful effect on the average health status of patients. This is not surprising, as peak systolic velocity ratio measured by DUS is in itself a surrogate for [50 % angiographic stenosis [29], and there may be no difference in the symptomatic status of patients with either 51 or 49 % diameter stenosis, even though one would be categorized with binary restenosis and one without. However, a reduction in the need for repeat revascularization does appear to be associated with a health benefit, and primary stenting was associated with a trend toward reduction in TLR in both the intention-to-treat and as-treated analyses. This mirrors the findings of other comparable trials. A larger-scale trial or meta-analysis, powered on the basis of TLR or quality of life, would be of value. The lack of significant differences between the two arms of the SUPER study does not mean that the use of stents in long SFA lesions should be abandoned. PTA with bailout stenting remains an acceptable approach, but the trend toward reduced TLR, which has also been observed in the comparable trials [8, 30, 31], adds further weight to the European Society of Cardiology recommendations [32] that primary stenting should be considered because the reduction in TLR appears to be a meaningful health outcome for patients. Limitations Recruitment of patients into the SUPER study took 3 years, and it is conceivable that practice patterns may have changed over that time. Slow recruitment suggests that participation was restricted to a small, and therefore possibly unrepresentative, sample of patients with peripheral vascular disease being treated by these centers. The

8 360 N. Chalmers et al.: Stent vs. PTA in SFA Lesions comparison between treatment groups is also confounded by differences in patient age and the length of occlusions, despite randomization. Conclusion The SUPER study has shown that 12 month binary restenosis is not reduced by a strategy of primary stenting compared with balloon angioplasty with bailout stenting in long SFA lesions in predominantly totally occluded vessels. Both treatment groups demonstrated a significant and durable improvement in quality of life, reinforcing the value to patients of endovascular treatment in long and complex SFA lesions. The reduction in the need for TLR associated with stenting in the SUPER study is similar to that seen in other studies, despite a more complex patient population. The EQ-5D appears to be a valid and sensitive tool to detect changes in quality of life associated with intervention and recurrent disease. Acknowledgments The SUPER study was sponsored and funded by Cordis Clinical Research. Conflict of interest SF and MvR are paid employees of Cordis, Johnson & Johnson. The other authors declare that they have no conflict of interest. Appendix: The SUPER study investigators The Investigators of the above study was conducted on behalf of The SUPER study: N. Chalmers, Manchester Royal Infirmary (n = 33 patients recruited); P. Walker, James Cook University Hospital, Middlesbrough (18); A. Belli, St. George s Hospital, London (14); A. Thorpe, Aberdeen Royal Infirmary (14); P. Sidhu, King s College Hospital, London (12); G. Robinson, Hull Royal Infirmary (11); T. Cleveland, Northern General Hospital, Sheffield (9); K. Gill, Pinderfields Hospital, Wakefield (9), R. Ashleigh, Wythenshawe Hospital, Manchester (6); M. Matson, Royal London Hospital (5); J. Cockburn, Norfolk and Norwich University Hospital, Norwich (4); A. Collins, Royal Victoria Hospital, Belfast (4); G. Houston, Ninewells Hospital, Dundee (3); J. Patel, St. James Hospital, Leeds (3); M. Cowling, City General Hospital, Stoke-on-Trent (2); J. Moss, Gartnavel Hospital, Glasgow (2); S. Travis, Royal Cornwall Hospital, Truro (1). References 1. Duda SH, Pusich B, Richter G et al (2002) Sirolimus-eluting stents for the treatment of obstructive superficial femoral artery disease: six-month results. Circulation 106: Duda SH, Bosiers M, Lammer J et al (2005) Sirolimus-eluting versus bare nitinol stent for obstructive superficial femoral artery disease: the SIROCCO II trial. J Vasc Interv Radiol 16: Mewissen MW (2004) Self-expanding Nitinol stents in the femoropopliteal segment: technique and mid-term results. Tech Vasc Interv Radiol 7: Vogel TR, Shindelman LE, Nackman GB, Graham AM (2003) Efficacious use of nitinol stents in the femoral and popliteal arteries. J Vasc Surg 38: Schillinger M, Sabeti S, Loewe C et al (2006) Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. N Engl J Med 354: EuroQol Group (1990) EuroQol a new facility for the measurement of health-related quality of life. Health Policy 16: Dolan P, Gudex C, Kind P, Williams A (1995) A social tariff for EuroQol: results from a UK general population survey. Centre for Health Economics Discussion Paper 138. CHE, Centre for Health Economics, University of York 8. Krankenberg H, Schlüter M, Steinkamp HJ et al (2007) Nitinol stent implantation versus percutaneous transluminal angioplasty in superficial femoral artery lesions up to 10 cm in length: the Femoral Artery Stenting trial (FAST). Circulation 116: Dick P, Wallner H, Sabeti S et al (2009) Balloon angioplasty versus stenting with nitinol stents in intermediate length superficial femoral artery lesions. Catheter Cardiovasc Interv 74: Laird JR, Katzen BT, Scheinert D et al (2010) Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery. Twelvemonth results from the RESILIENT randomized trial. Circ Cardiovasc Interv 3: Twine CP, Coulston J, Shandall A et al (2009) Angioplasty versus stenting for superficial femoral artery lesions. Cochrane Database Syst Rev 15(2):CD Sabeti S, Schillinger M, Amighi J et al (2004) Primary patency of femoropopliteal arteries treated with nitinol versus stainless steel self-expanding stents: propensity score adjusted analysis. Radiology 232: Tasc II (2007) Inter-Society Consensus for the management of peripheral arterial disease. Eur J Vasc Endovasc Surg 33: Davies MG, Bismuth J, We Saad et al (2010) Outcomes of interventions for recurrent disease after endoluminal intervention for superficial femoral artery disease. J Vasc Surg 52: Cheng SWK, Ting ACW, Wong J (2001) Endovascular stenting of superficial femoral artery stenosis and occlusions: results and risk factor analysis. Cardiovasc Surg 9: Gray BH, Sullivan TM, Childs MB et al (1997) High incidence of restenosis/reocclusion of stents in the percutaneous treatment of long-segment superficial femoral artery disease after suboptimal angioplasty. J Vasc Surg 25: Kim SJ, Kim W, Kim JB et al (2010) Factors of success and patency after subintimal angioplasty in patients with TransAtlantic inter-society consensus C and D severe lower extremity occlusive disease. J Am Coll Cardiol 105(9 Suppl 1):20A 21A 18. Hameed A, Gluege S, Reinhart R (2009) Subintimal angioplasty: to stent or not to stent. J Invasive Cardiol 21:E154 E Bosiers M, Deloose K, Callaert J et al (2012) In lower extremity PTAs intraluminal is better than subintimal. J Cardiovasc Surg (Torino) 53: Schmieder GC, Richardson AI, Scott EC et al (2008) Selective stenting in subintimal angioplasty: analysis of primary stent outcomes. J Vasc Surg 48: Sabeti S, Czerwenka-Wenkstetten A, Dick P et al (2007) Quality of life after balloon angioplasty versus stent implantation in the superficial femoral artery: findings from a randomized controlled trial. J Endovasc Ther 14:

9 N. Chalmers et al.: Stent vs. PTA in SFA Lesions UK Department of Health (2008) Guidance on the routine collection of patient reported outcome measures. Department of Health, London 23. National Institute for Health and Clinical Excellence (2008) Guide to the methods of technology appraisal. National Institute for Health and Clinical Excellence, London, pp de Vries M, Ouwendijk R, Kessels AG et al (2005) Comparison of generic and disease-specific questionnaires for the assessment of quality of life in patients with peripheral arterial disease. J Vasc Surg 41: BASIL Trial Participants (2005) Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL): multicentre, randomised controlled trial. Lancet 366: Longworth L, Buxton MH, Sculpher M et al (2005) Estimating utility data from clinical indicators for patients with stable angina. Eur J Health Econ 6: Serruys PW, Unger F, Sousa JE (2001) Comparison of coronary artery bypass surgery and stenting for the treatment of multivessel disease. N Engl J Med 344: Dake MD, Ansel GM, Jaff MR et al (2011) Paclitaxel-eluting stents show superiority to balloon angioplasty and bare metal stents in femoropopliteal disease. Circ Cardiovasc Interv 4: Schlager O, Francesconi M, Haumer M et al (2007) Duplex sonography versus angiography for assessment of femoropopliteal arterial disease in a real-world setting. J Endovasc Ther 14: Schillinger M, Sabeti S, Dick P et al (2007) Sustained benefit at 2 years of primary femoropopliteal stenting compared with balloon angioplasty with optional stenting. Circulation 115: Laird JR, Katzen BT, Scheinert D et al (2012) Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral and proximal popliteal arteries of patients with claudication: three-year follow-up from the RESILIENT randomised trial. J Endovasc Ther 19: Tendera M, Aboyans V, Bartelink ML et al (2011) ESC guidelines on the diagnosis and treatment of peripheral artery diseases. Eur Heart J 32: