Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease

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1 Original Article Trial of a Paclitaxel-Coated for Femoropopliteal Artery Disease Kenneth Rosenfield, M.D., Michael R. Jaff, D.O., Christopher J. White, M.D., Krishna Rocha Singh, M.D., Carlos Mena Hurtado, M.D., D. Christopher Metzger, M.D., Marianne Brodmann, M.D., Ernst Pilger, M.D., Thomas Zeller, M.D., Prakash Krishnan, M.D., Roger Gammon, M.D., Stefan Müller Hülsbeck, M.D., Mark R. Nehler, M.D., James F. Benenati, M.D., and Dierk Scheinert, M.D., for the LEVANT 2 Investigators* ABSTRACT BACKGROUND The treatment of peripheral artery disease with percutaneous transluminal angioplasty is limited by the occurrence of vessel recoil and restenosis. Drug-coated angioplasty balloons deliver antiproliferative agents directly to the artery, potentially improving vessel patency by reducing restenosis. METHODS In this single-blind, randomized trial conducted at 54 sites, we assigned, in a 2:1 ratio, 476 patients with symptomatic intermittent claudication or ischemic pain while at rest and angiographically significant atherosclerotic lesions to angioplasty with a paclitaxel-coated balloon or to standard angioplasty. The primary efficacy end point was primary patency of the target lesion at 12 months (defined as freedom from binary restenosis or from the need for target-lesion revascularization). The primary safety end point was a composite of freedom from perioperative death from any cause and freedom at 12 months from limb-related death (i.e., death from a medical complication related to a limb), amputation, and reintervention. RESULTS The two groups were well matched at baseline; 42.9% of the patients had diabetes, and 34.7% were current smokers. At 12 months, the rate of primary patency among patients who had undergone angioplasty with the drug-coated balloon was superior to that among patients who had undergone conventional angioplasty (65.2% vs. 52.6%, P = 0.02). The proportion of patients free from primary safety events was 83.9% with the drug-coated balloon and 79.0% with standard angioplasty (P = for noninferiority). There were no significant between-group differences in functional outcomes or in the rates of death, amputation, thrombosis, or reintervention. CONCLUSIONS Among patients with symptomatic femoropopliteal peripheral artery disease, percutaneous transluminal angioplasty with a paclitaxel-coated balloon resulted in a rate of primary patency at 12 months that was higher than the rate with angioplasty with a standard balloon. The drug-coated balloon was noninferior to the standard balloon with respect to safety. (Funded by Lutonix Bard; LEVANT 2 ClinicalTrials.gov number, NCT ) From Massachusetts General Hospital, Boston (K.R., M.R.J.); Ochsner Medical Center, New Orleans (C.J.W.); Prairie Heart Institute at St. John s Hospital, Springfield, IL (K.R.-S.); Yale School of Medicine, New Haven, CT (C.M.-H.); Wellmont Cardiovascular Associates Heart Institute, Kingsport, TN (D.C.M.); Medical University of Graz, Graz, Austria (M.B., E.P.); University Heart Center Freiburg Bad Krozingen, Bad Krozingen (T.Z.), Diakonissenanstalt zu Flensburg, Flensburg (S.M.-H.), and Park-Krankenhaus Leipzig and Universitätsklinikum Leipzig, Leipzig (D.S.) all in Germany; Mount Sinai Medical Center, New York (P.K.); Austin Heart, Austin, TX (R.G.); University of Colorado Medical Center, Denver (M.R.N.); and Baptist Cardiac and Vascular Institute, Miami (J.F.B.). Address reprint requests to Dr. Rosenfield at Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114, or at krosenfield1@ partners. org. *A complete list of investigators, committees, and core laboratories in the Lutonix Paclitaxel-Coated for the Prevention of Femoropopliteal Restenosis (LEVANT) 2 trial is provided in the Supplementary Appendix, available at NEJM.org. This article was published on June 24, 2015, at NEJM.org. N Engl J Med 2015;373: DOI: /NEJMoa Copyright 2015 Massachusetts Medical Society. n engl j med 373;2 nejm.org July 9,

2 A therosclerotic disease in the femoral and popliteal (femoropopliteal) arteries compromises perfusion to the legs and feet. Although treatment with percutaneous transluminal angioplasty is effective in initially restoring blood flow, restenosis from vessel recoil and neointimal hyperplasia occur in more than 60% of patients within 1 year after the procedure. 1 Stents act as scaffolds to prevent recoil and reduce the incidence of restenosis, 2-9 but the permanent presence of an intravascular prosthesis may limit subsequent therapeutic options. Stent fracture, although infrequent, can have negative consequences Results with drug-eluting stents in peripheral vessels have varied, although a recent study showed that the rates of restenosis were lower with a paclitaxel-eluting stent than with angioplasty with a standard balloon. 19 Early clinical investigation of the use of paclitaxel-coated angioplasty balloons suggests that an antiproliferative effect may be achieved by delivering an active therapeutic agent directly to the artery wall without a stent This effect requires deposition of the proper dose of paclitaxel, a process that depends on the excipient formulation, drug concentration, and delivery technique Clinical data from persons who underwent angioplasty with the drug-coated balloon used in the current trial showed that among patients treated for symptomatic femoropopliteal peripheral artery disease, late lumen loss was 58% lower among those who underwent angioplasty with the drug-coated balloon than among those who underwent standard percutaneous transluminal angioplasty, and the safety results were similar in the two groups. 26 The purpose of the current trial was to expand on those angiographic findings. Methods Study Design and Oversight The Lutonix Paclitaxel-Coated for the Prevention of Femoropopliteal Restenosis (LEVANT) 2 trial was a prospective, multicenter, randomized, controlled trial. The trial was conducted under a clinical protocol that was approved by the Food and Drug Administration (FDA) and developed by the principal investigators and a steering committee composed of clinical experts (see the Supplementary Appendix, available with the full text of this article at NEJM.org), together with the sponsor (Lutonix Bard). The protocol, available at NEJM.org, was approved by the institutional review board or ethics committee at each study site. The study was monitored in accordance with FDA guidelines by two contract research organizations (Genae Associates and Prairie Education and Research Cooperative [PERC]), which were paid for their services by the sponsor. PERC also provided oversight and monitored an independent clinical-events committee and data and safety monitoring committee. The principal investigators and lead authors prepared the manuscript, and all the authors reviewed it. All the authors vouch for the accuracy and completeness of the data and all the analyses reported, as well as for the fidelity of this report to the trial protocol. Study Population Patients eligible for inclusion in the trial had moderate intermittent claudication (Rutherford stage 2), severe intermittent claudication (Rutherford stage 3), or ischemic pain while at rest (Rutherford stage 4) and an angiographically significant atherosclerotic lesion (diameter of stenosis, 70%) in the superficial femoral or popliteal artery (or both). The total treated lesion length had to be 15 cm or less, and the reference diameter of the target vessel had to be 4 to 6 mm. The complete inclusion and exclusion criteria are listed in Table S1 in the Supplementary Appendix. All the patients provided written informed consent. Study Procedures At each study site, a proctored roll-in angioplasty with a paclitaxel-coated balloon had to be performed before the first patient was enrolled in the randomized study so that the investigators and staff could be trained in procedural and datacollection requirements. Patients included in the roll-in phase met all the protocol requirements but were followed separately from the population that was included in the randomized study. Required study medications were consistent with the standard of care, including acetylsalicylic acid at a dose of 75 to 325 mg per day before the procedure and a dose of 75 to 100 mg per day indefinitely after the procedure. A loading dose of clopidogrel or prasugrel was administered before the procedure, and a dose of 75 mg per day of clopidogrel or 5 to 10 mg per day of 146 n engl j med 373;2 nejm.org July 9, 2015

3 Paclitaxel-Coated for Artery Disease prasugrel (depending on body weight) was required for at least 1 month after the procedure. After the initial screening of the patients but before randomization, angiography was performed to establish eligibility on the basis of the severity of the stenosis. Stenotic lesions were predilated with a standard balloon that was less than 1 mm smaller than the reference diameter of the target vessel. Repeat angiography was then performed, and patients with flow-limiting dissections or clinically significant residual stenosis (>70%) that was likely to require placement of a stent were excluded from randomization. These patients were treated according to the standard of care and followed for 30 days. The remaining patients were randomly assigned, in a 2:1 ratio, to undergo percutaneous transluminal angioplasty with the use of either a paclitaxel-coated balloon (Lutonix) or a standard angioplasty balloon. Details regarding the study device and procedure are provided in the Supplementary Appendix. The clinician was aware of the index treatment because the drug-coated balloon looked different from a standard balloon; however, according to the study protocol, the patients, investigators who completed followup, vascular-laboratory personnel, core laboratory evaluators, and members of the clinical-events committee were unaware of the treatment received. Clinicians were to make treatment decisions subsequent to the initial procedure on the basis of the symptoms of the patients during follow-up, without knowledge of treatment assignment or findings on duplex ultrasonography. Follow-up clinical evaluations, calculation of ankle brachial indexes, duplex ultrasonography, and assessments of quality of life with the use of questionnaires were performed after the procedure and at 30 days, 6 months, and 12 months. Investigators recorded procedural and follow-up data on Web-based, standardized, electronic report forms. Independent core laboratories were used for the analysis of the angiographic films (SynvaCor) and duplex ultrasonographic images (VasCore, Massachusetts General Hospital, Boston). Study End Points The primary effectiveness measure was primary patency of the target lesion at 12 months. Primary patency was defined as the absence of evidence of binary restenosis, as detected by means of duplex ultrasonography and adjudicated by staff at the ultrasonographic core laboratory, and freedom from target-lesion revascularization, as adjudicated by the clinical-events committee. The primary safety measure was a composite of freedom from perioperative death from any cause ( 30 days after the procedure) and freedom at 12 months from index-limb amputation, indexlimb revascularization, and index-limb related death (i.e., death from a medical complication related to a limb), as adjudicated by the clinicalevents committee. Secondary effectiveness measures included procedural success, clinically driven target-lesion revascularization, and changes from baseline in the Rutherford classification (the Rutherford scale ranges from 0 to 6, with higher numbers indicating worse disease), Walking Impairment Questionnaire scores (scores range from 0 to 100, with lower scores indicating more difficulty in walking), and quality-of-life measures (the Euro- Qol Group 5-Dimension Self-Report Questionnaire [scores range from 0 to 1, with higher values indicating a better quality of life] and the Medical Outcomes Study 36-Item Short-Form Health Survey scores). Secondary safety measures included the rates of death from any cause, amputationfree survival, target-vessel revascularization, and reintervention for thrombosis. Definitions of key terms and end points are provided in Table S2 in the Supplementary Appendix. Statistical Analysis We calculated that a sample of 405 patients, randomly assigned in a 2:1 ratio, would be required to provide the study with 90% power to detect a between-group difference of 17 percentage points in the primary efficacy end point at 12 months (59% in the drug-coated balloon group and 42% in the standard-angioplasty group), at a two-sided alpha level of These estimates were based on a 12-month extrapolation of data on freedom from target-lesion revascularization and duplex ultrasonographic data regarding restenosis from the LEVANT 1 trial. The population of 476 patients who underwent randomization accounted for an expected 15% loss of patients from the final analysis owing to study withdrawal or missing imaging data. The primary efficacy and safety end points were analyzed on a modified intention-to-treat basis (with patients who had missing data for an end point excluded from the analysis of that end n engl j med 373;2 nejm.org July 9,

4 point) through the close of the 12-month followup window on day 395. Primary patency (the primary efficacy end point) was calculated with the use of an asymptotic likelihood-ratio chisquare test for inequality of binomial proportions (two-sided test, with an alpha level of 0.05). The primary composite safety end point was analyzed with the use of a Farrington Manning test for noninferiority of proportions (one-sided test, with an alpha level of 0.025) with a noninferiority margin of 5 percentage points. The primary safety and efficacy end points were also assessed with the use of prespecified Kaplan Meier timeto-event analyses. Additional prespecified sensitivity analyses included worst-case analyses (i.e., in the analysis of the primary end point, missing data were considered to be treatment failures in the drug-coated balloon group and treatment successes in the standard-angioplasty group) and tipping-point analyses, in which assumptions about missing data varied from worst case to best case to examine at what point the missing data would alter the results of the analysis. Continuous variables were compared with the use of Student s t-tests and Wilcoxon nonparametric tests for means; categorical variables were compared with the use of the chi-square test for proportions. Results Study Population and Treatment Between July 20, 2011, and July 10, 2012, we enrolled 543 patients at 54 sites in the United States and Europe. A total of 56 patients were enrolled in the roll-in phase, 11 patients with predilation results indicating flow-limiting dissection or clinically significant residual stenosis were excluded from randomization but were treated according to the standard of care and followed for 30 days (standard-practice subgroup), and 476 patients were randomly assigned, in a 2:1 ratio, to undergo angioplasty with a drugcoated balloon (316 patients) or standard angioplasty (160). Among the eligible patients who did not withdraw from the trial, 96.6% of the patients in the drug-coated balloon group and 95.9% of those in the standard-angioplasty group completed the 12-month follow-up. Among all the patients who underwent randomization, 83.5% of the patients in the drug-coated balloon group and 84.4% of those in the standardangioplasty group could be evaluated for the primary efficacy end point and 90.5% and 89.4%, respectively, could be evaluated for the primary safety end point (Fig. S1 in the Supplementary Appendix). The two treatment groups were well matched at baseline, with coexisting conditions that are expected in patients with peripheral artery disease (Table 1). The characteristics of the lesions at baseline were also similar in the two groups (Table S3 in the Supplementary Appendix); the overall mean lesion length was 62.8±41.0 mm, the total treated length was 107.9±47.8 mm, and 21.0% of the lesions were occlusions. Procedural success was similar in the two treatment groups (88.9% with the drug-coated balloon and 86.8% with standard angioplasty, P = 0.50); however, there were some observed procedural differences (Table S4 in the Supplementary Appendix). Provisional stent placement was observed less frequently in the drug-coated balloon group than in the standard-angioplasty group (2.5% vs. 6.9%, P = 0.02). There was no significant difference in the embolization rates between the groups; the rates of procedural embolism were 0.6% in the drug-coated balloon group and 1.9% in the standard-angioplasty group (P = 0.21). Primary Efficacy and Safety Outcomes The proportion of patients who had primary patency at 12 months (the primary efficacy end point) was significantly greater with the drugcoated balloon than with the standard angioplasty balloon (65.2% vs. 52.6%, P = 0.02) (Table 2). In the prespecified Kaplan Meier survival analysis (Fig. 1, and Table S5 in the Supplementary Appendix), the rate of primary patency was also significantly higher with the drug-coated balloon than with the standard angioplasty balloon at 12 months (73.5% vs. 56.8%, P<0.001). With respect to the primary composite safety end point, the proportion of patients free from perioperative death from any cause or free at 12 months from index-limb amputation, indexlimb reintervention, and index-limb related death was 83.9% in the drug-coated balloon group versus 79.0% in the standard-angioplasty group, which met the prespecified criterion for noninferiority (P = for noninferiority) (Table 2). In the prespecified Kaplan Meier survival analysis (Fig. 2, and Table S6 in the Supplementary Appendix), the rate of event-free survival at 12 months did not differ significantly between the drug-coated balloon group and the 148 n engl j med 373;2 nejm.org July 9, 2015

5 Paclitaxel-Coated for Artery Disease Table 1. Demographic Characteristics and Medical History of the Patients at Baseline.* Characteristic Drug-Coated (N = 316) Standard Angioplasty (N = 160) Total (N = 476) Age yr 67.8± ± ±9.7 Sex no. (%) Male 193 (61.1) 107 (66.9) 300 (63.0) Female 123 (38.9) 53 (33.1) 176 (37.0) Race no. (%) White 287 (90.8) 136 (85.0) 423 (88.9) Black 12 (3.8) 13 (8.1) 25 (5.3) Asian 4 (1.3) 4 (2.5) 8 (1.7) Not indicated 13 (4.1) 7 (4.4) 20 (4.2) Geographic region no. (%) United States 199 (63.0) 102 (63.8) 301 (63.2) Europe 117 (37.0) 58 (36.2) 175 (36.8) Height cm 169.3± ± ±10.2 Weight kg 83.1± ± ±17.0 Body-mass index Mean 29.0± ± ± no. (%) 110 (34.8) 49 (30.6) 159 (33.4) Smoking status no. (%) Current smoker 111 (35.1) 54 (33.8) 165 (34.7) Former smoker 139 (44.0) 78 (48.8) 217 (45.6) Never smoked 66 (20.9) 28 (17.5) 94 (19.7) Diabetes mellitus no. (%) 137 (43.4) 67 (41.9) 204 (42.9) Hypertension no. (%) 282 (89.2) 140 (87.5) 422 (88.7) Hypercholesterolemia no. (%) 283 (89.6) 138 (86.2) 421 (88.4) Previous CAD no. (%) 157 (49.7) 77 (48.1) 234 (49.2) Previous myocardial infarction no. (%) 63 (19.9) 28 (17.5) 91 (19.1) Renal failure no. (%) 11 (3.5) 7 (4.4) 18 (3.8) Congestive heart failure no. (%) 18 (5.7) 5 (3.1) 23 (4.8) History of coronary-artery revascularization no. (%) 132 (41.8) 62 (38.8) 194 (40.8) Previous stroke no. (%) 36 (11.4) 18 (11.2) 54 (11.3) Previous target-limb intervention no. (%) 74 (23.4) 28 (17.5) 102 (21.4) Rutherford stage no. (%) 2 93 (29.4) 55 (34.4) 148 (31.1) (62.7) 92 (57.5) 290 (60.9) 4 25 (7.9) 13 (8.1) 38 (8.0) Target-limb ankle brachial index 0.74± ± ±0.20 * Plus minus values are means ±SD. There were no significant differences between the groups (P>0.05). Analyses were performed with the use of Student s t-tests for means and the chi-square test for proportions. CAD denotes coronary artery disease. Race was self-reported. The body-mass index is the weight in kilograms divided by the square of the height in meters. A body-mass index of 30 or more indicates obesity. The Rutherford scale ranges from 0 to 6, with higher numbers indicating worse disease. Rutherford stage 2 indicates moderate intermittent claudication, stage 3 severe intermittent claudication, and stage 4 ischemic pain while the patient is at rest. n engl j med 373;2 nejm.org July 9,

6 Table 2. Primary and Secondary End Points.* End Point Drug-Coated Standard Angioplasty Difference P Value no./total no. (%) percentage points (95% CI) Primary end points Primary patency at 12 mo 172/264 (65.2) 71/135 (52.6) 12.6 (2.4 to 22.8) 0.02 Restenosis without target- 57/92 (62.0) 40/64 (62.5) 0.5 ( 16.0 to 14.9) lesion revascularization Target-lesion revascularization 35/92 (38.0) 24/64 (37.5) 0.5 ( 14.9 to 16.0) Safety composite 240/286 (83.9) 113/143 (79.0) 4.9 ( 2.6 to 12.3) Perioperative death 0/308 0/155 0** Index-limb amputation 1/286 (0.3) 0/ ( 0.3 to 1.0) Index-limb reintervention 44/285 (15.4) 30/143 (21.0) 5.5 ( 13.4 to 2.3) Index-limb related death 0/285 0/140 0 Secondary end points Total target-lesion revascularization 35/285 (12.3) 24/143 (16.8) 4.5 ( 11.7 to 2.7) 0.21 Total target-vessel revascularization 38/285 (13.3) 26/143 (18.2) 4.8 ( 12.3 to 2.6) 0.19 Death 7/290 (2.4) 4/144 (2.8) 0.4 ( 3.6 to 2.8) 0.82 Major amputation 1/286 (0.3) 0/ ( 0.3 to 1.0) 0.37 Reintervention for thrombosis 1/285 (0.4) 1/140 (0.7) 0.4 ( 1.9 to 1.2) 0.62 * All the end-point events, including primary end-point events, secondary end-point events, safety events, and adverse events, were adjudicated by the clinical-events committee. Between-group differences do not necessarily sum correctly, owing to rounding. Primary patency was defined as the absence of target-lesion restenosis (as assessed by means of duplex ultrasonography and adjudicated by the blinded core laboratory) and freedom from target-lesion revascularization (adjudicated by the clinical-events committee). The P value was based on an asymptotic likelihood-ratio test. Confidence intervals for the difference are asymptotic. The denominator of 92 in the drug-coated balloon group indicates the number of patients with patency failure in this group at 12 months (among 264 patients, 172 had patency at 12 months and 92 had patency failure). The denominator of 64 in the standard-angioplasty group indicates the number of patients with patency failure in this group at 12 months (among 135 patients, 71 had patency at 12 months and 64 had patency failure). The denominator was used to determine the percentage of patency failures caused by restenosis and targetlesion revascularization. The safety end point was a composite of freedom from perioperative death from any cause ( 30 days after the procedure) or freedom at 12 months from index-limb amputation, index-limb reintervention, and index-limb related death. The P value was a measure of noninferiority, with a margin of noninferiority of 5%. The P value and confidence interval for difference were based on the Farrington Manning method. Confidence intervals are asymptotic. ** The nominal confidence interval for the between-group difference in this component of the safety end point was calculated by the Farrington Manning method. Confidence intervals are asymptotic. standard-angioplasty group (86.7% and 81.5%, respectively; P = for noninferiority). Sensitivity analyses were performed to evaluate the effect of various assumptions about the missing end-point data on the primary efficacy and safety outcomes. The results of these analyses are shown in Tables S7 and S8 in the Supplementary Appendix. Secondary Outcomes There were fewer events of target-lesion revascularization in the drug-coated balloon group than in the standard-angioplasty group, but this difference did not reach statistical significance (Table 2; the results of a Kaplan Meier assessment of target-lesion revascularization are shown in Fig. S2 and Table S9 in the Supplementary Appendix). The ankle brachial index, Rutherford stage, and Walking Impairment Questionnaire scores each improved significantly (P<0.001 for all comparisons) from before treatment to 12 months after treatment in the drug-coated balloon group and the standard-angioplasty group (Table 3). Only the improvement in the score for the walking-distance component of the Walking Impairment Questionnaire showed a significant between-group difference at 12 months (score difference of 9.3 [95% confidence interval, 1.6 to 150 n engl j med 373;2 nejm.org July 9, 2015

7 Paclitaxel-Coated for Artery Disease 17.0] on a scale of 0 to 100, with lower scores indicating more difficulty in walking, in favor of the drug-coated balloon group). The individual secondary safety end points did not differ significantly between the drugcoated balloon group and the standard-angioplasty group at 12 months. Rates were similar for death (2.4% with the drug-coated balloon and 2.8% with standard angioplasty), amputation (0.3% and 0.0%, respectively), and thrombosis requiring reintervention (0.4% and 0.7%, respectively) (Table 2). All the deaths were adjudicated as unlikely to be related to the device, procedure, or index limb. The single index-limb amputation (in the drug-coated balloon group) in a patient with progressive below-the-knee peripheral artery disease was also adjudicated as unrelated to the device or procedure. Discussion In the LEVANT 2 trial, we evaluated the efficacy and safety of the use of a paclitaxel-coated angioplasty balloon during percutaneous transluminal angioplasty in patients with symptomatic femoropopliteal peripheral artery disease. We found that use of the drug-coated angioplasty balloon resulted in a significantly greater rate of primary patency of the target lesion at 12 months than that achieved with a standard angioplasty balloon. The safety of the drug-coated balloon, as assessed by a composite end point of freedom from perioperative death from any cause and freedom at 1 year from index-limb amputation, index-limb revascularization, and indexlimb related death, was noninferior to that of the standard balloon. Prior randomized trials of the use of drugcoated angioplasty balloons in patients with femoropopliteal peripheral artery disease have shown a benefit of such therapy, but these trials were small and powered to assess only late lumen loss, assessed angiographically, as a surrogate end point for patency The difference in the rate of binary restenosis in our trial, which was based on blinded analysis at a core laboratory, suggests a significant biologic effect of the use of the drug-coated balloon. We did not find a significant difference between the two trial groups in the clinically important end point of target-lesion revascularization at 12 months. This result contrasts with the Patients with Primary Patency (%) Months since Randomization Figure 1. Kaplan Meier Curves for Primary Patency at 12 Months. Primary patency was defined as the absence of target-lesion restenosis (defined by core-laboratory adjudication) and target-lesion revascularization (adjudicated by the clinical-events committee). findings of several smaller trials of drug-coated angioplasty balloons, in which significant differences in target-lesion revascularization were observed Several factors may contribute to Patients with Freedom from Primary Safety Event (%) Drug-coated balloon Standard angioplasty balloon P<0.001 Drug-coated balloon Standard angioplasty balloon P=0.005 for noninferiority Months since Randomization Figure 2. Kaplan Meier Curves for the Composite Safety Outcome at 12 Months. The safety outcome was a composite of freedom from perioperative death from any cause ( 30 days after the procedure) and freedom at 12 months from index-limb amputation, index-limb revascularization, or index-limb related death. n engl j med 373;2 nejm.org July 9,

8 Table 3. Change in Functional Outcomes from Baseline to 12 Months.* Outcome Drug-Coated (N = 316) Standard Angioplasty (N = 160) Between-Group Difference (95% CI) Resting ankle brachial index 0.17± ± ±0.23 ( 0.06 to 0.04) Rutherford stage 1.9± ± ±1.1 ( 0.4 to 0.0) Walking Impairment Questionnaire score Total score 23.9± ± ±27.3 ( 1.1 to 10.4) Pain score 25.9± ± ±35.4 ( 12.3 to 13.1) Walking-distance score 31.5± ± ±36.5 (1.6 to 17.0) Walking-speed score 21.2± ± ±29.7 ( 2.7 to 9.7) Stair-climbing score 18.5± ± ±32.9 ( 5.7 to 8.1) EQ-5D 0.09± ± ±0.20 ( 0.03 to 0.05) SF-36 Physical component 6.0± ± ±11.0 ( 1.7 to 2.9) Mental component 0.2± ± ±12.8 ( 2.9 to 2.5) * Plus minus values are means ±SD. Between-group differences do not necessarily sum correctly, owing to rounding. Scores on the Walking Impairment Questionnaire range from 0 to 100, as a weighted combination of the pain, distance, speed, and stairclimbing scores. Each component is scored from 0 to 100, with lower scores indicating more difficulty in walking. The pain score is a relative measure that is based on the patient s assessment of pain on a scale from 0 to 100, with lower scores indicating greater pain during walking. The EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D) is a standardized non disease-specific quality-of-life assessment. Scores range from 0 to 1; as the index approaches 1, the assessed quality of life increases. The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) is a patient-reported survey of health and quality of life. Both the physical-component and mental-component summary scores range from 0 to 100, with 50 considered average and with higher scores indicating a better quality of life. an explanation of this difference between our study and the previous studies. First, the investigators and patients in our trial were unaware of both the index treatment and the duplex ultrasonographic findings during follow-up, which probably reduced potential bias in making the decision to perform a repeat revascularization procedure. Second, the rate of target-lesion revascularization was substantially lower in the standard-angioplasty group in our trial than in the standard-angioplasty groups in previous trials involving patients with similar characteristics and lesions, which would reduce the power of our trial to show a difference. Third, features of the trial design, including the exclusion of patients who were likely to require stents and the prespecified objective criteria for provisional stent placement, resulted in a low rate of stent use. This approach helped to minimize a variable that has confounded the interpretation of many device trials involving patients with peripheral artery disease, in which the rates of provisional stent placement ranged from 14 to 50%. 4,18,20 It is also important to note that our trial was not designed to have the power to detect a difference in rates of target-lesion revascularization; a definitive assessment of this question will require a larger trial. Our trial does not provide definitive guidance concerning the potential role of this paclitaxelcoated balloon in clinical practice. Although the findings are encouraging, long-term follow-up will be useful in determining whether the benefit of this intervention is sustained, increased, or attenuated over time. In addition, further studies may compare the drug-coated balloon with other therapeutic options, such as atherectomy or stenting with bare-metal stents or drugeluting stents. There are some additional limitations of this trial. Although the trial was designed to have the power to detect a difference in the primary end point of patency at 12 months, it was not designed to have the power to assess differences in functional end points or quality-of-life measures. Determinants of these outcomes may not be specific to the study lesion; changes may be due to progression of peripheral artery disease 152 n engl j med 373;2 nejm.org July 9, 2015

9 Paclitaxel-Coated for Artery Disease in other arterial segments or to coexisting conditions that are known to limit physical function rather than to a difference in the device used to treat a specific lesion. In addition, although the patients, core laboratory staff, and clinicians performing the follow-up assessments were unaware of the study-group assignments, the physicians performing the index procedures could not be unaware of the assignments because of the different characteristics of the two types of angioplasty balloons. In conclusion, treatment of femoropopliteal peripheral artery disease with a paclitaxel-coated balloon provided superior vessel patency through 12 months, as compared with a strategy of conventional percutaneous transluminal angioplasty with a standard balloon. The drug-coated balloon was also noninferior to a standard angioplasty balloon with respect to safety. Supported by Lutonix Bard. 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JACC Cardiovasc Interv 2014; 7: Copyright 2015 Massachusetts Medical Society. n engl j med 373;2 nejm.org July 9,