Results of a randomized clinical trial of external beam radiation to prevent restenosis after superficial femoral artery stenting

Results of a randomized clinical trial of external beam radiation to prevent restenosis after superficial femoral artery stenting

Results of a randomized clinical trial of external beam radiation to prevent restenosis after superficial femoral artery stenting Eric Therasse, MD,a,b...

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Results of a randomized clinical trial of external beam radiation to prevent restenosis after superficial femoral artery stenting Eric Therasse, MD,a,b David Donath, MD,c Stéphane Elkouri, MD,d Jacques Lespérance, MD,e Marie-France Giroux, MD,a Vincent L. Oliva, MD,a Marie-Claude Guertin, PhD,f Louis Bouchard, MD,a Pierre Perreault, MD,a Patrick Gilbert, MD,a and Gilles Soulez, MD,a,b Montreal, Quebec, Canada Objective: The objective of this study was to evaluate the safety and efficacy of external beam radiation (EBR) in preventing restenosis after superficial femoral artery (SFA) stenting in comparison with a control group treated with SFA stenting only. Methods: In this Institutional Review Board-approved study, patients who provided written informed consent were randomly assigned to 0 Gy or 14 Gy of EBR to the stent site 24 hours after SFA stenting. The primary end point was the angiographic binary restenosis rate 2 years after stenting. Categorical and continuous end points were respectively analyzed using logistic regression models and Wilcoxon tests. End points expressed as time to event were analyzed using a log-rank test. Results: The study included 155 patients, 46 women and 109 men (mean age, 66 years; range, 45-85 years). In the 0 and 14 Gy groups, binary restenosis was present, respectively, in 44% (34/77) and 68% (52/76; P [ .003) 2 years after stenting. Stent thrombosis occurred in 13% (10/78) of the 0 Gy group and in 33% (25/77) of the 14 Gy group (P [ .003). Target lesion revascularization at 2 years was 26% (25/78) in the 0 Gy group and 30% (23/77) in the 14 Gy group (P [ .56). There were no significant differences in total walking distances change from baseline to 2 years (46 6 100 and 26 6 79 m, respectively, in the 0 Gy and 14 Gy group; P [ .25). There were no procedure-related deaths and no major amputations. Conclusions: A single 14 Gy dose of EBR to the SFA stenting site did not prevent in-stent restenosis. (J Vasc Surg 2016;63:1531-40.)

Percutaneous transluminal angioplasty (PTA) has a high technical success rate in the treatment of short superficial femoral artery (SFA) obstruction, but long lesions often require stenting because of elastic recoil or extensive dissection.1,2 Despite excellent initial angiographic results, From the Department of Radiology,a Department of Radiation Oncology,c and Department of Surgery,d Centre Hospitalier de l’Université de Montréal (CHUM); the Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)b; and the Department of Radiologye and Department of Biostatistics,f Montreal Heart Institute. The study was funded by a grant from the Canadian Institute of Health Research (MCT-78566) and by a grant from Johnson & Johnson Medical System, Inc. Clinical Trial registration: ISRCTN74370657 (http://www.isrctn.com). Author conflict of interest: E.T. holds a research grant from Johnson & Johnson Medical System, Inc. G.S. receives honoraria as invited speaker from Abbott Vascular, Cook Medical, Bracco Diagnostics, Inc and Siemens Medical and holds research grant from Siemens Medical, TVA Medical, and Bracco Diagnostics. G.S. is supported by a National Scientist Award from the Fonds de la Recherche en Santé du Québec. P.G. is a consultant for Cook Medical, Abbott, and Covidien. Correspondence: Eric Therasse, MD, Department of Radiology, CHUMHôtel-Dieu, 3840 St Urbain St, Montreal, Quebec H2W 1T8, Canada (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2016 by the Society for Vascular Surgery. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jvs.2016.02.023

SFA stenting remains plagued by a high restenosis rate due to intimal hyperplasia.2 Radiation has been used to limit intimal hyperplasia after endovascular interventions, and endovascular brachytherapy was proved to be effective in reducing restenosis after PTA in the coronary arteries3,4 and peripheral arteries5-9 almost 2 decades ago. However, vascular brachytherapy requires endovascular manipulations that are cumbersome and associated with thromboembolic events, and it is sometimes technically impossible to deliver the radiation.8,10 Edge restenoses with radioactive stents were due to decreasing radiation dose (mismatch) at the stent edges that were subjected to vascular trauma by stenting. Vascular brachytherapy addresses dose mismatch, but the vessel wall dose is inhomogeneous because radiation rapidly decreases with the distance to the radioactive source and also because it is difficult to center the source into irregular and calcified vessels. Dose inhomogeneity results in vessel segments that receive either too much or not enough radiation, which could explain thrombotic occlusion with brachytherapy. With external beam radiation (EBR), radiation dose to the vessel wall is homogeneous, and dose mismatch can easily be prevented because the full dose of radiation can be administered well beyond the edges of the treated segments. Therefore, EBR appeared to be an advantageous way to administer radiation after SFA stenting. In comparison with brachytherapy, EBR does not have to be delivered immediately after stenting. It does not 1531

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Fig 1. Trial flow diagram. The study used a 1:1 randomized control design and intent to treat analysis of primary end point at 24 months. There were 509 consecutive patients screened for enrollment. Among these, 354 patients were excluded for various reasons: the referring physicians did not want the patient to participate in the study (13 patients), the patients refused to participate in the study (133 patients), the patients did not meet the inclusion criteria (91 patients) or presented at least one exclusion criterion (59), and percutaneous transluminal angioplasty (PTA) had to be done on an emergency basis before the scheduled protocol procedure (18 patients). Therefore, 155 patients were randomized, 78 patients in the 0 Gy group and 77 patients in the 14 Gy group. Four patients died of unrelated causes before follow-up angiography, and 15 patients declined to undergo follow-up angiography or were lost to follow-up. Primary end point analysis at 24 months was done in 66 patients in the stent-only group and 70 patients in the stent and external beam radiation (EBR) group. SFA, Superficial femoral artery.

interfere with or prolong the procedure. It requires neither large introducer sheaths nor occluding centering devices. EBR dosimetry is also more precise and is not affected by lesion eccentricity or calcification. Despite these advantages, the experience with EBR to prevent restenosis in peripheral vascular diseases, with various doses and fractions, is limited and contradictory.9,11-14 A dosefinding trial demonstrated that 14 Gy of EBR was effective in reducing restenosis after PTA of SFA lesions, but its effectiveness after stenting of longer lesions has never been demonstrated.9 Therefore, the objective of this study was to evaluate the safety and efficacy of EBR in preventing restenosis after SFA stenting in comparison with a control group treated with SFA stenting only. METHODS Study design and study population. Approval of this study was obtained from the Scientific Review and Ethics Committees of all four participating centers, and the study was overseen by an independent data safety monitoring

committee. All eligible patients who agreed to participate provided written informed consent after the goals and steps of the study were explained to them. The clinical criteria for study entry were moderate to severe intermittent claudication (Rutherford stages 2 and 3), chronic critical limb ischemia with rest pain (Rutherford stage 4), and chronic critical limb ischemia with ischemic ulcers or tissue loss (Rutherford stages 5 and 6) due to either a de novo lesion or a restenosis after prior SFA dilation. The anatomic inclusion criteria were lumen diameter stenosis >70% or occlusion of the SFA at least 4 cm above the knee joint, a target lesion length <15 cm that could be treated with two or fewer stents, and ankle-brachial index (ABI) at rest #0.85. In 2008, inclusion criteria were extended to lesions <20 cm and ABI #0.95 because many patients who underwent SFA stenting in the participating centers were excluded from the trial only because of these criteria. The exclusion criteria were a contraindication to angiography or to clopidogrel, a recurrent lesion that had already been stented, prior irradiation to or infection

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Table I. Baseline characteristics of the patients

Mean age, years Male sex Statin treatment Coronary artery disease Diabetes mellitus Hypertension History of stroke Current or former smoker eGFR, mL/min Body mass indexb Baseline ABI Poststenting ABI Rutherford stagec 1-3: claudication 4: rest pain 5-6: tissue loss 6MWT distanced Distance to claudication, m Total distance, m EQ VAS WIQ domainsd Claudication pain Walking distance Walking speed Stair climbing

Table II. Baseline angiographic and interventional data

0 Gya

14 Gya

65.3 6 9.3 51/78 (65) 63/78 (81) 24/78 (31) 23/78 (30) 58/78 (74) 8/78 (10) 50/78 (64) 80 6 20 27.1 6 3.9 0.70 6 0.16 0.98 6 0.14

66.1 6 8.4 58/77 (75) 65/77 (84) 35/77 (46) 30/77 (39) 58/77 (75) 4/77 (5) 41/77 (53) 83 6 22 27.9 6 4.4 0.68 6 0.16 0.93 6 0.13

68/78 (87) 2/78 (3) 8/78 (10)

65/76 (85) 2/76 (3) 9/76 (11)

106 6 88 276 6 111 65 6 17

120 6 80 285 6 111 65 6 16

0.35 0.28 0.44 0.45

6 6 6 6

0.25 0.24 0.27 0.28

0.42 0.24 0.33 0.42

6 6 6 6

0.25 0.22 0.25 0.27

ABI, Ankle-brachial index; eGFR, estimated glomerular filtration rate; EQ VAS, EuroQol visual analog rating scale of health-related quality of life questionnaire; 6MWT, 6-minute walk test; WIQ , Walking Impairment Questionnaire. a Except where indicated, continuous data are presented as means 6 standard deviations. Categorical data are given as numbers of patients, with percentages in parentheses. b The body mass index is the weight in kilograms divided by the square of the height in meters. c Rutherford stage 3 corresponds to intermittent claudication, stage 4 to ischemic rest pain, and stage 5 to ischemic ulcers. d For claudicating patient only.

of the expected radiation site, prior use of doxorubicin or other radiosensitizing agent, pregnancy, untreated hemodynamically significant lesions above the femoropopliteal lesion, inability to give informed consent or to complete follow-up, and life expectancy <2 years. End points. The primary study end point was the rate of binary restenosis ($50% of the lumen diameter) in the irradiated segment (within the stent plus the 30-mm segments proximal and distal to the stented segment) 24 months after SFA stenting as measured by quantitative angiography. Secondary end points were (1) the angiographic degree of restenosis in the stented and in the irradiated segments measured by the percentage of lumen diameter reduction, the minimum lumen diameter (MLD), and the late lumen loss (LLL) at 24 months; (2) the time to restenosis on color duplex ultrasonography (CDU) at 24 months; (3) the time to ABI decline >0.15 at 24 months; (4) the time to target lesion revascularization (TLR) or target vessel thrombosis on CDU at 24 months; (5) the clinical improvement at 24 months as assessed by the 6-minute walk test (6MWT) distance, the EuroQol visual analog

Stenosis $50% after stenting Stented segment Irradiated segment Percentage diameter stenosis Stented segment Before stenting After stenting Irradiated segment Before stenting After stenting MLD Stented segment Before stenting, mm After stenting, mm Irradiated segment Before stenting, mm After stenting, mm Length of target lesion, mm Length of stented segment, mm Occlusion, No. of patients Lesion calcification, No. of patientsb None or mild Moderate Severe No. of tibial vessels, No. of patients 0 vessel 1 vessel 2 vessels 3 vessels No. of stents 1 stent 2 stents

0 Gya

14 Gya

P value

0/77 (0) 5/77 (7)

1/77 (1) 7/77 (9)

1.00 .55

82 6 15 18.0 6 9.1

82 6 15 22 6 11

.88 .021

82 6 15 34 6 11

82 6 15 35 6 10

.88 .30

0.88 6 0.78 0.94 6 0.85 4.41 6 0.60 4.38 6 0.75

.81 .82

6 0.78 0.94 6 0.85 6 0.72 3.65 6 0.78 6 40 73 6 46 6 49 112 6 50

.81 .44 .15 .61

0.88 3.54 60 107

24/77 (31)

25/77 (33)

45/76 (59) 15/76 (20) 16/76 (21)

43/77 (56) 16/77 (21) 18/77 (23)

.86 .91

.68 5/78 10/78 16/78 47/78

(6) (13) (21) (60)

8/76 7/76 13/76 48/76

(10) (9) (17) (63) .56

58/78 (74) 20/78 (25)

54/77 (70) 23/77 (29)

MLD, Minimum lumen diameter. a Except where indicated, continuous data are presented as means 6 standard deviations. Categorical data are given as numbers of patients, with percentages in parentheses. b Calcification was determined by angiography.

rating scale of health-related quality of life questionnaire (EQ VAS), and the Walking Impairment Questionnaire (WIQ) scores; and (6) the safety of the intervention as measured by the number of reinterventions, the amputation rate, and the side effects and complications in both groups at 24 months. All follow-up data and the relationship of major adverse events to the study procedure or device were adjudicated in a blinded fashion by the investigators before the patients’ treatment assignments were known. Stenting procedure. All SFA stentings were performed through a 6F sheath under local anesthesia. Digital subtraction angiography of the target limb was performed from the common femoral artery to the foot in posteroanterior (PA) views. Digital subtraction angiography of the target lesion was performed with magnification with a PA view and at least one more view of 30 degrees or more from the PA view. Three 28-mm-diameter metal coins

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Table III. Quantitative angiographic results in stented and in irradiated segments at 24 months of follow-up Outcomes Restenosis $50% Stented segment Irradiated segment Percentage diameter stenosis Stented segmentb Irradiated segmentb MLD Stented segment, mmb Irradiated segment, mmb Late luminal loss Stented segment, mmb Irradiated segment, mmb Stent thrombosis Stent fracture No fracture Type I Type II Type III

0 Gya

14 Gya

P value

29/77 (37) 34/77 (44)

37/76 (48) 52/76 (68)

.18c .0029c

41 (30, 61) 47 (33, 68)

46 (28, 100) 58 (45, 100)

.64d .0044d

2.9 (1.8, 3.7) 2.7 (1.4, 3.4)

3.4 (0.0, 4.3) 2.4 (0.0, 3.3)

.54d .12d

1.4 (0.9, 2.6) 1.5 (0.9, 2.7) 10/78 (13)

1.5 (0.1, 3.7) 1.9 (0.9, 3.7) 25/77 (33)

.52d .25d .0034e

54/59 2/59 2/59 1/59

45/53 3/53 4/53 1/53

.71e

(92) (3) (3) (2)

(85) (6) (8) (2)

Irradiated segment, Stented segment and 3-cm proximal and distal margins; MLD, minimum lumen diameter. a Categorical data are given as numbers of patients, with percentages in parentheses. b Data are medians. Numbers in parentheses are the interquartile range (lower quartile [Q1], upper quartile [Q3]). c P value coming from logistic regression. d P value coming from Wilcoxon test. e P value coming from c2 test.

were taped on the inner part of the patient’s thigh for calibration. After intra-arterial heparin (3000-5000 U) was given, stenting was performed either with or without prior predilation, according to each operator’s preference. All stents were postdilated. Stenting extended at least 10 mm proximally and distally from the margins of the target lesion. When multiple stents were used, stent overlap was at least 10 mm. PTA balloon diameter had to match reference vessel diameter, whereas stent diameter was 1 to 2 mm larger than reference vessel diameter. Dilations before or after stenting were performed only within the stented segment. Self-expanding nitinol stents (SMART Vascular Stent System; Cordis Corporation, Miami Lakes, Fla) were used for all patients. Randomization. Randomization was implemented in blocks of two or four using computer-generated random digits, and patient assignments were sealed in envelopes. Randomization was stratified according to the type of obstruction (stenosis vs occlusion) and the clinical site where the patient had the endovascular intervention. The day after the stenting procedure, patients were randomly assigned to receive either 0 Gy (placebo) or 14 Gy of EBR in the department of radiation oncology. Only the radiation oncologist and the radiation oncology staff knew the patient’s assigned group. The patients, investigators, interventional staff, and research nurses collecting the data were all blinded as to which group each patient belonged. Irradiation methods. The target vessel was treated in a single session, 24 hours after SFA stenting, with four noncoplanar radiotherapy treatment fields, using a 6 MV linear accelerator and three-dimensional conformal radiation. The treated leg was positioned in a customized

Styrofoam cast for each patient. This cast kept the leg position constant between computed tomography planning, radiation simulation, and treatment. The planning target volume was the stent with a 1-cm radial margin and 3-cm upper and lower margins. Image-guided radiation therapy was used with the stent serving as the reference marker for positioning of each of the four fields according to digitally reconstructed radiographs. Patients in the placebo group (0 Gy) underwent a sham radiotherapy session including all steps (instructions, preparation, positioning) of the 14 Gy group during the EBR session except that no radiation was given. Follow-up. All patients were observed on an outpatient basis and were advised to walk regularly and to stop smoking. Clopidogrel 300 mg orally was given after the intervention if the patient was not already receiving this medication. Clopidogrel 75 mg orally daily was given to all patients for 1 year after the intervention. Aspirin 80 mg orally daily was also administered routinely to all patients after the procedure unless contraindicated. CDU examinations were performed at 6, 12, and 18 months after randomization and included the stent and the irradiated margins. Peak systolic velocity ratio >2.5 was considered to correspond to a stenosis of >50%. The ABI was measured at baseline; after the stenting procedure; and at 6, 12, 18, and 24 months after randomization or just before a reintervention in patients who had ischemic symptom recurrences. The 6MWT, WIQ, and EQ-5D questionnaire were performed at 6, 12, 18, and 24 months after randomization. All patients were asked to return for lower limb arteriography 2 years after randomization unless they had prior reintervention

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Table IV. Quantitative angiographic results in irradiated vessel segments proximal and distal to the stented vessel segment Outcomes Stenosis >50% Proximal After stenting At 24 months Distal After stenting At 24 months Percentage diameter stenosis Proximal Before stenting After stenting At 24 months Distal Before stenting After stenting At 24 months MLD Proximal Before stenting, mm After stenting, mm At 24 months, mm Distal Before stenting, mm After stenting, mm At 24 months, mm Late luminal loss Proximal, mm Distal, mm

0 Gya

14 Gya

P value

5/77 (7) 18/66 (27)

5/77 (7) 38/70 (54)

.0015b

0/77 (0) 14/66 (21)

2/77 (3) 30/70 (43)

.0075b

24 (16, 32) 30 (22, 39) 31 (22, 50)

25 (17, 32) 34 (21, 41) 53 (37, 100)

<.0001c

24 (14, 31) 24 (14, 34) 24 (17, 40)

25 (13, 32) 26 (16, 34) 38 (25, 100)

.0005c

3.9 (3.0, 4.3) 3.8 (3.2, 4.2) 3.3 (2.2, 4.2)

3.9 (3.4, 4.5) 3.9 (3.1, 4.5) 2.7 (0.0, 3.6)

.023c

3.9 (3.2, 4.4) 4.1 (3.3, 4.6) 3.8 (2.8, 4.7)

3.8 (3.1, 4.8) 4.1 (3.5, 5.2) 3.3 (0.0, 4.3)

.098

0.86 (0.20, 2.96) 0.86 (0.10, 2.90)

.0030 .0029

0.29 (0.27, 1.34) 0.21 (0.25, 1.01)

MLD, Minimum lumen diameter. a Categorical data are given as numbers of patients, with percentages in parentheses. Continuous data are presented as medians, and numbers in parentheses are the interquartile range (lower quartile [Q1], upper quartile [Q3]). b P value coming from logistic regression. c P value coming from Wilcoxon test.

of the target vessel or if prior CDU demonstrated complete absence of flow in the treated segment (total occlusion). Follow-up arteriography was done before 24 months in patients with recurrent clinical symptoms severe enough to warrant reintervention. If these patients had no evidence of restenosis in the treated segment on angiography, they were asked to return for another angiography at 24 months. Radiography of the thigh with flexion and extension of the knee was obtained 2 years after randomization or at the time of reintervention for evaluation of stent fractures. Quantitative angiographic measurements. Angiograms were analyzed by an independent core laboratory whose personnel were unaware of the patient randomization group. All angiograms were analyzed quantitatively by experienced technicians, supervised by a cardiovascular radiologist, using edge detection techniques, with a computer-assisted method developed by Clinical Measurements Solutions (QCA-CMS, version 6.0; Medis Imaging Systems, Leiden, The Netherlands).15 A first analysis included the stented vessel segment as well as the 3-cm proximal and distal margins, and a second analysis was confined to the stented vessel segment. Proximal and distal margins, excluding the stented segment, were also analyzed and reported separately.

Statistical analysis. Given an expected restenosis rate of 45% in the 0 Gy group and 23% in the 14 Gy group at 24 months and a maximum dropout rate of 15%, we estimated that 214 patients would be required to have a statistical power of 90% to detect this 50% restenosis rate reduction with a two-sided .05 significance level. The primary end point was analyzed using a logistic regression model, including a term group (0 Gy vs 14 Gy) and a term for type of obstruction (stenosis vs occlusion). Other categorical end points were analyzed similarly. Continuous end points, such as MLD at 24 months, were analyzed using Wilcoxon tests. End points expressed as time to event, such as time to restenosis on CDU, were analyzed using a log-rank test stratified for type of obstruction and graphically presented using Kaplan-Meier curves. End points expressed as change from baseline were analyzed using an analysis of covariance model with a term for group, for type of obstruction, and for baseline value of the end point. Safety end points were compared between groups using Mantel-Haenszel tests stratified for type of obstruction. Total occlusion at 24 months of follow-up (% diameter stenosis ¼ 100% and MLD ¼ 0) was imputed in patients who had no follow-up angiography available and who had a reintervention, an amputation, or a

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Fig 2. Two-year freedom from restenosis on color duplex ultrasonography (CDU). Freedom from restenosis on CDU was calculated with Kaplan-Meier analysis in 155 patients with superficial femoral artery (SFA) disease who were randomly assigned to receive 0 Gy (placebo) or 14 Gy of external beam radiation (EBR) to the SFA stenting site, the day after SFA stenting. The rates of freedom from restenosis were not significantly different (P ¼ .50) between the two study groups.

Fig 3. Two-year freedom from ankle-brachial index (ABI) decline >0.15. Freedom from ABI decline >0.15 was calculated with Kaplan-Meier analysis in 155 patients with superficial femoral artery (SFA) disease who were randomly assigned to receive 0 Gy (placebo) or 14 Gy of external beam radiation (EBR) to the SFA stenting site, the day after SFA stenting. The rates of freedom from ABI decline >0.15 were not significantly different (P ¼ .22) between the two study groups.

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Table V. Clinical outcomes in the study patients Outcome Twenty-four-month functional outcomes Change in 6MWT from baselineb Distance to claudication, m Total distance, m Change from baseline EQ VAS score Change in WIQ domains from baseline Claudication pain score Walking distance score Walking speed score Stair climbing score Severe adverse events Death within 24 months Target limb amputation within 24 monthsc Acute thrombosisd All severe adverse events TLR within 24 months Endovascular Bypass surgery Total Local side effects Thigh pain Thigh edema/redness

0 Gya

14 Gya

P value

38 6 82 46 6100 3 6 15

11 6 77 26 6 79 2 6 16

.11e .26e .73e

6 6 6 6

0.34 0.32 0.31 0.31

0.28 0.34 0.27 0.19

6 6 6 6

0.33 0.37 0.34 0.37

.13e .24e .13e .092e

3/78 2/78 2/78 28/78

(4) (3) (3) (36)

4/77 2/77 11/77 38/76

(5) (3) (14) (50)

.72f 1.0g .0085f .077f

0.41 0.39 0.30 0.27

13/78 (17) 7/78 (9) 20/78 (26)

12/77 (16) 11/77 (14) 23/77 (30)

.85f .30f .56f

1/78 (1) 2/78 (3)

5/77 (7) 3/77 (4)

.12g .68f

EQ VAS, EuroQol visual analog scale of health-related quality of life questionnaire; 6MWT, 6-minute walk test; TLR, target lesion revascularization; WIQ , Walking Impairment Questionnaire. a Except where indicated, continuous data are presented as means 6 standard deviations. Categorical data are given as numbers of patients, with percentages in parentheses. b Only for patients with claudication. c All were minor amputations. d Defined as an occlusion attributable to thrombus formation that is rapidly evolving as confirmed by the sudden onset of symptoms within 14 days of imaging and documented by duplex ultrasonography and angiography of the index vessel. e P value coming from analysis of the change adjusted for baseline measures. f P value coming from c2 test. g P value coming from Fisher’s exact test.

thrombosis on CDU during their follow-up. Similarly, a restenosis on CDU was imputed if a reintervention, amputation, or thrombosis occurred during follow-up. The same imputation approach was done for ABI decline >0.15. For the 6MWT, EQ-5D, and WIQ, missing values were imputed using the last observation carried forward approach, except for patients who had a reintervention, an amputation, or a thrombosis during their follow-up, in whom the baseline values were used for imputation. The statistical analyses were performed with SAS (version 9.4; SAS Institute, Cary, NC), and a two-sided significance level of .05 was used for all tests. The biostatistician responsible for the analyses was unaware of the group attribution before the database was completed and the data analysis plan established. RESULTS Enrollment was slower than expected, mainly because of strict exclusion criteria, and only 155 patients were randomized between November 2006 and December 2011. Fig 1 shows patient flow through 24-month follow-up. The baseline demographics and clinical characteristics of the patients are listed in Table I. The baseline and poststenting angiographic characteristics of the target lesions

and interventional data are listed in Table II. There was no statistically significant difference in lesion characteristics between the two groups, except for a greater mean stenosis percentage after stenting in the 14 Gy group (22%) in comparison with the placebo group (18%; P ¼ .021). Angiographic analysis. Angiographic results at follow-up are reported in Table III. At last follow-up (24 months or earlier in cases of thrombosis on CDU, amputation, or reintervention), the angiographic binary restenosis rate in the irradiated segment (the primary efficacy end point) was significantly higher in the 14 Gy group (68%) in comparison with the 0 Gy group (44%; P ¼ .0029). The angiographic binary restenosis rate in the stented segment was higher in the 14 Gy group (49%) than in the 0 Gy group (38%), but the difference was not statistically significant (P ¼ .18). The percentage of restenosis, the MLD, and the LLL in the stented and in the irradiated segments were not statistically different between the two groups except for a higher median percentage of stenosis in the irradiated segment in the 14 Gy group (58%) in comparison to the 0 Gy group (47%; P ¼ .0044). There were significantly (P ¼ .003) more stent thromboses in the 14 Gy group (33%) than in the 0 Gy group (13%) at 2-year follow-up. A post hoc analysis of the stented

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Fig 4. Two-year freedom from major adverse limb event (MALE). Freedom from MALE was calculated with Kaplan-Meier analysis in 155 patients with superficial femoral artery (SFA) disease who were randomly assigned to receive 0 Gy (placebo) or 14 Gy of external beam radiation (EBR) to the SFA stenting site, the day after SFA stenting. The rates of freedom from MALE were not significantly different (P ¼ .98) between the two study groups.

segment, excluding the 13 patients with acute stent thrombosis, showed no significant difference in binary (37% vs 41%; P ¼ .64) and mean percentage of restenosis (40% vs 40%; P ¼ .40) but significantly smaller LLL (0.97 vs 1.39 mm; P ¼ .048) and larger MLD (3.5 vs 2.9 mm; P ¼ .044) in the 14 Gy group than in the 0 Gy group. There were no significant differences in stent fractures between the two groups. Table IV presents the angiographic results in vessel segments that were irradiated proximal and distal to the stent. At last follow-up, the binary restenosis rates, the maximal degree of stenosis, and the LLL were all statistically significantly higher in the 14 Gy group than in the 0 Gy group in vessel segments that were proximal and distal to the stent. At last follow-up, the MLD was also significantly smaller in the 14 Gy group than in the 0 Gy group in the proximal segment. CDU and ABI. Kaplan-Meier curves for freedom from restenosis on CDU and freedom from ABI decline >0.15 are reported in Figs 2 and 3, respectively. There was no significant difference between the two groups. Clinical outcomes and side effects. Clinical outcomes 2 years after randomization are reported in Table V. There were no significant differences between groups in distance to claudication and the total walking distance recorded with the 6MWT. There were no significant differences in the four domains of the WIQ and in the EQ VAS. There were no significant differences in severe adverse events between groups except for a higher rate of acute

thrombosis in the 14 Gy group (P ¼ .009). There were no procedure- or radiation-related deaths. TLRs were not significantly different between groups. Kaplan-Meier analysis of freedom from major adverse limb event showed no significant difference between the 0 Gy and the 14 Gy groups (Fig 4). However, Kaplan-Meier analysis of survival without TLR or target vessel thrombosis on CDU was significantly lower in the 14 Gy group than in the 0 Gy group (P ¼ .049; Fig 5). One patient (1%) in the 0 Gy group and five patients (7%) in the 14 Gy group had transient thigh pain that lasted a few months after stenting and that was severe enough for the patient to seek medical consultation. A diagnosis of myositis was made in one patient (1%) in the 0 Gy group and in four patients (5%) in the 14 Gy group. DISCUSSION This study provides conclusive evidence that a single dose of 14 Gy of EBR, given 24 hours after SFA stenting, does not reduce restenosis at 2-year follow-up. In comparison with the placebo group, 14 Gy of EBR even resulted in a significantly higher binary restenosis rate and median percentage of stenosis in the irradiated segment at followup. Worse results in the EBR group were mainly due to greater restenosis rate in the arterial segments proximal and distal to the stent despite the fact that these segments were treated with full-dose radiation and that there was no endovascular injury in the EBR dose fall-off areas (3 cm proximal and distal to the stent). Also, contrary to previous

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Therasse et al 1539

Fig 5. Two-year freedom from target lesion revascularization (TLR) or target vessel thrombosis (TVT). Freedom from TLR or TVT was calculated with Kaplan-Meier analysis in 155 patients with superficial femoral artery (SFA) disease who were randomly assigned to receive 0 Gy (placebo) or 14 Gy of external beam radiation (EBR) to the SFA stenting site, the day after SFA stenting. The rate of freedom from TLR or TVT was significantly lower (P ¼ .049) in the 14 Gy group than in the 0 Gy group.

experience, EBR did not prevent restenosis in the stented segment.12-14 Absence of EBR efficacy to prevent in-stent restenosis could have been explained by a greater number of stent occlusions in the EBR group than in the placebo group. However, the in-stent binary restenosis, maximal percentage of stenosis, MLD, and LLL were not improved in the EBR group even when all acute stent thromboses were excluded from the analysis. Given the prior positive result of EBR on restenosis after PTA,9 it seems that the main reason for its lack of effectiveness in this trial may be due to its association with stenting. In comparison with previous trials using EBR after PTA, the presence of a metallic stent in our study may have modified the dose distribution and interaction with vascular tissues.9 This was also reported with the use of brachytherapy after femoropopliteal stenting.16 Whether changing EBR timing, fractionating the dose, and increasing it above 14 Gy could have changed the outcome is unlikely. Brachytherapy trials have demonstrated a preventive effect against restenosis at doses of 12 Gy and higher,3-5 and although brachytherapy radiation doses >20 Gy have been frequently administered to the intima without short-term side effects, large doses must be fractionated to be safely delivered with EBR.17 Decreasing the irradiated volume could also decrease or eliminate treatment side effects18 but is unlikely to improve treatment efficacy. The main limitation of this study is that the number of patients enrolled in the study is lower than the sample size

calculated to provide statistical power to detect a 50% reduction of the binary restenosis rate we aimed to demonstrate. However, our data clearly showed a negative effect of EBR on restenosis. In addition, with the recent advent of effective drug-eluting stents to treat femoropopliteal lesions, even if it is effective, radiation treatment would now require much greater benefit to be preferred over drugeluting stents.19,20

CONCLUSIONS This study demonstrated that a single dose of 14 Gy of EBR 24 hours after SFA stenting yields no improvement of in-stent restenosis at 24 months after the intervention and even leads to a significantly higher restenosis rate in the vascular segment proximal and distal to the stent. The authors thank Andrée Cliche, RN, and Line Julien, RN, for their invaluable help during the course of this study, and Mr Ovid Da Silva for editing assistance. We are also indebted to Jean Cusson, MD, and Michal Abrahamowicz, PhD, for methodological assistance in the trial design and conduct and also Denis Cournoyer, MD, Bernard Montreuil, MD, and David Valenti, MD, who participated on the data and safety monitoring committee. We also thank Colette Desjardins, RT, and Marie-Josée Dussault, RT, for all quantitative angiographic measurements and Asmaa Mansour for statistical assistance. The authors express their gratitude to Michel Dubé, MD,

1540 Therasse et al

Martin Francoeur, MD, and Errol Camlioglu, MD, for patient enrollment in this trial. AUTHOR CONTRIBUTIONS Conception and design: ET, DD Analysis and interpretation: ET, DD, SE, JL, MCG, GS Data collection: ET, DD, SE, MFG, VO, LB, PP, PG, GS Writing the article: ET Critical revision of the article: DD, SE, JL, MFG, VO, MCG, LB, PP, PG, GS Final approval of the article: ET, DD, SE, JL, MFG, VO, MCG, LB, PP, PG, GS Statistical analysis: MCG Obtained funding: ET, DD, SE, JL, GS Overall responsibility: ET REFERENCES 1. Schillinger M, Sabeti S, Loewe C, Dick P, Amighi J, Mlekusch W, et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. N Engl J Med 2006;354:1879-88. 2. Matsumura JS, Yamanouchi D, Goldstein JA, Pollock CW, Bosiers M, Schultz GA, et al. The United States StuDy for EvalUating EndovasculaR TreAtments of Lesions in the Superficial Femoral Artery and Proximal Popliteal By usIng the Protégé EverfLex NitInol STent SYstem II (DURABILITY II). J Vasc Surg 2013;58:73-83. 3. Leon MB, Teirstein PS, Moses JW, Tripuraneni P, Lansky AJ, Jani S, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001;344:250-6. 4. Verin V, Popowski Y, de Bruyne B, Baumgart D, Sauerwein W, Lins M, et al. Endoluminal beta-radiation therapy for the prevention of coronary restenosis after balloon angioplasty. N Engl J Med 2001;344: 243-9. 5. Minar E, Pokrajac B, Maca T, Ahmadi R, Fellner C, Mittlböck M, et al. Endovascular brachytherapy for prophylaxis of restenosis after femoropopliteal angioplasty: results of a prospective randomized study. Circulation 2000;102:2694-9. 6. Krueger K, Zaehringer M, Bendel M, Stuetzer H, Strohe D, Nolte M, et al. De novo femoropopliteal stenoses: endovascular gamma irradiation following angioplastydangiographic and clinical follow-up in a prospective randomized controlled trial. Radiology 2004;231:546-54. 7. Pokrajac B, Pötter R, Wolfram RM, Budinsky AC, Kirisits C, Lileg B, et al. Endovascular brachytherapy prevents restenosis after femoropopliteal angioplasty: results of the Vienna-3 randomised multicenter study. Radiother Oncol 2005;74:3-9. 8. Zehnder T, von Briel C, Baumgartner I, Triller J, Greiner R, Mahler F, et al. Endovascular brachytherapy after percutaneous transluminal angioplasty of recurrent femoropopliteal obstructions. J Endovasc Ther 2003;10:304-11.

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Submitted Nov 26, 2015; accepted Feb 2, 2016.