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Vascular and Interventional Radiology |
1 From the Departments of Angiology (R.M.W., A.C.B., E.M.) and Radiotherapy and Radiobiology (B.P., R.P.), Medical University of Vienna, Waehringer Guertel 18, A-1090 Vienna, Austria. Received April 18, 2004; revision requested June 25; revision received July 30; accepted August 26. Address correspondence to R.M.W. (e-mail: roswitha.wolfram{at}hotmail.com).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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MATERIALS AND METHODS: Patients provided written informed consent to participate in this study, which was approved by the ethics committee. A total of 88 patients (mean age, 67.7 years ± 10.1; 57 men [65%], 31 women [35%]) with femoropopliteal lesions (mean treatment length, 16.8 cm ± 7.3) were included. Patients underwent percutaneous transluminal angioplasty (PTA) and stent implantation and were randomized in a double-blind fashion to undergo either gamma brachytherapy with an iridium 192 source or treatment with nonradioactive seeds. A 14-Gy dose of iridium 192 was prescribed at 2 mm into the arterial wall (target depth equals vessel radius plus 2 mm). The primary end point of the study was angiographic binary restenosis of more than 50% at 6-month follow-up. Secondary end point was either percutaneous or surgical target lesion revascularization after 6 months. Continuous data are presented as mean ± standard deviation. Categorical data are expressed as percentages. Student t test was used to compare continuous data; 
2 test was used to compare categorical values. Survival function was calculated with the Kaplan-Meier method. Multivariate Cox proportional hazard regression analysis was performed to enable evaluation of multivariate predictors of recurrence at 6- and 12-month follow-up. Variables included brachytherapy, clinical stage, lesion length, de novo and recurrent lesion, vessel run off, prior stenosis or occlusion, diabetes mellitus, and stent model.
RESULTS: Revascularization and brachytherapy were accomplished successfully in all patients. The overall 6-month recurrence rate was 35% in patients who underwent only stent implantation and 33% in patients who underwent both stent implantation and brachytherapy (P = .89). Nine (10%) patients developed early reocclusion in the segment treated with a stent (two patients [4%] in the stent group and seven [17%] in the stent and brachytherapy group); of these patients, three in the stent and brachytherapy group experienced reocclusion within 24 hours of the intervention. Late (>30 days after intervention) thrombotic occlusion was observed in three patients (7%) in the stent and brachytherapy group.
CONCLUSION: Brachytherapy does not improve 6-month patency after femoropopliteal stent implantation in high-risk patients because of a high incidence of early and late thrombotic occlusion.
© RSNA, 2005
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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On the basis of these criteria, 94 patients were enrolled in this prospective trial. Six patients were excluded from further analysis (two refused to participate after they had provided informed consent, and four were excluded because of an insufficient result [>30% residual stenosis] after stent implantation, as analyzed by an independent investigator). The remaining 88 patients were randomized: 42 underwent PTA, stent implantation, and brachytherapy with an iridium 192 (192Ir) source (men, n = 29 [69%]; women, n = 13 [31%]; mean age, 67.0 years ± 11.2; median age, 70.2 years; age range, 50.0–88.9 years), whereas 46 underwent only PTA and stent implantation (men, n = 28 [61%]; women, n = 18 [39%]; mean age, 68.4 years ± 9.6; median age, 70.7 years; age range, 50.0–82.9 years) after a successful recanalization procedure. Analyzing age with regard to sex, we observed that women were significantly older than men in both the stent group (28 men; mean age, 66.1 years ± 10.0; 18 women; mean age, 72.0 years ± 7.1; P = .038) and the stent and brachytherapy group (29 men; mean age, 65.1 years ± 10.7; 13 women; mean age, 72.2 years ± 6.5; P = .05). There was no significant difference regarding age and sex distribution between the patients who underwent only PTA and those who underwent both PTA and brachytherapy (Table 1). All 88 patients were eligible for 6-month follow-up; however, one patient who underwent stent implantation and brachytherapy was unavailable for 12-month follow-up.
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Brachytherapy was performed by a radiation oncologist (B.P.) who had 3 years of experience with endovascular brachytherapy in 1999 and was involved in the planning and application of irradiation or placebo therapy. Brachytherapy was performed with a remote afterloading device with a high dose rate (microSelectron; Nucletron). Treatment was planned with a computer-assisted standard dose calculation planning system (PLATO-BPS, version 13.2; Nucletron). A dose of 14 Gy was prescribed 2 mm beyond the average luminal radius (ie, vessel radius plus 2 mm) according to the recommendations of the European Society for Therapeutic Radiology and Oncology Working Group (15).
Before beginning endovascular irradiation, the balloons of the centering catheter were inflated to a pressure of 4 atm to allow centering of the source. Afterward, the closed lumen catheter was connected to the afterloading device. An 192Ir source with a diameter of 1.1 mm and a mean activity of 200 GBq (range, 150–366 GBq) was delivered. Radiation length (active source length) covered the entire segment treated with stent implantation and an additional safety margin of 10 mm proximal and distal to the stent to avoid edge effect and geographic miss. After irradiation, the centering catheter and sheath were removed immediately, and the puncture site was manually compressed for approximately 20 minutes in all patients. The puncture site was evaluated in all patients with duplex ultrasonography (US) the day after the procedure.
Patients randomized to undergo only PTA and stent implantation underwent sham treatment after revascularization. The only difference between the patient groups was the application of nonradioactive seeds in the placebo group. All other treatment steps, including dwell time—which corresponded to the respective lesion length—were identical to the group that underwent brachytherapy.
Peri- and Postinterventional Pharmacotherapy
All patients received 5000 IU of standard heparin at the beginning of the procedure (Liquemin; Hoffmann-La Roche, Basel, Switzerland), with further administration of 1000 IU of heparin per hour beginning before transportation to the brachytherapy unit and continuing until after the procedure was complete.
After the procedure, patients were treated with low-molecular-weight heparin until they were discharged from the hospital. Long-term pharmacotherapy with acetylsalicylic acid (100 mg/d, initiated at least 2 weeks prior to the intervention) was combined with administration of 75 mg of clopidogrel (Plavix; Sanofi, Paris, France) per day (loading dose, 300 mg prior to intervention) for at least 1 year.
Follow-Up
Follow-up included clinical examination 1 day, 6 months, and 12 months after the procedure and was performed by a trained vascular specialist (R.W.) who had more than 5 years experience in 1999. Follow-up also involved noninvasive laboratory testing 1 day, 6 months, and 12 months after the procedure and was performed by trained technicians. This testing included ankle-brachial arterial pressure measurement with Doppler US to calculate the ankle-brachial pressure index and treadmill testing, when possible. Data from further follow-up examinations, which are planned in yearly intervals, are not included in this article. Treadmill testing was performed with a constant workload protocol by using a constant speed (3.2 km/h) and inclination (12°). In patients without clinical symptoms, treadmill testing was terminated at 700 m.
Color duplex US of the femoropopliteal segment was performed with a 5-MHz linear-array color probe (XP10; Acuson, Mountain View, Calif). The peak velocity ratio was calculated as the ratio of the maximum peak systolic velocity in the dilated region compared with peak systolic velocity in the preceding normal arterial segment. A focal increase in peak systolic velocity of at least 140% (corresponding to a peak velocity ratio 
2.4) was considered to be equivalent with stenosis of more than 50% (16). Arterial patency was assessed with angiography (scheduled after 6 months) or, in patients who refused to undergo angiography, duplex US. Data were evaluated independently (R.M.W., B.P., A.C.B., and E.M., all with >5 years of work experience in 1999), and consensus was reached in all cases. All investigators involved in the follow-up examinations were blinded to the groups to which patients were randomly assigned.
Definitions
Recurrence was defined as angiographically verified recurrence of more than 50% stenosis of the luminal diameter within the segment in which the stent was implanted when compared with a reference vessel segment at follow-up. In patients with only duplex US images available, a peak velocity ratio of at least 2.4 was used to indicate restenosis.
Thrombotic occlusion was defined as a suddenly occurring total occlusion of the target vessel due to thrombus formation. Early thrombotic occlusion was defined as sudden total occlusion occurring less than 30 days after intervention, and late thrombotic occlusion was defined as sudden total occlusion occurring at least 30 days after the intervention.
Target lesion revascularization was defined as clinically driven further PTA or surgical bypass of the treated lesion that was required because of the presence of at least 50% diameter recurrence of the target lesion.
Target vessel revascularization was defined as clinically driven further PTA or surgical bypass of the target vessel because of the presence of restenosis of at least 50% of the target lesion or any other lesions within the target vessel.
Clinical success was defined as immediate improvement by at least one clinical category, according to the criteria defined by Rutherford and Becker (17), after revascularization.
Clinical patency was defined by sustained clinical success without further intervention. For patients with tissue damage, an improvement of at least two categories was required to be considered a clinical success.
End Points
The primary end point of the study was angiographic binary restenosis of more than 50% at 6-month follow-up. The secondary end point was either percutaneous or surgical target lesion revascularization at 6-month follow-up.
Statistical Analysis
All calculations were performed with SPSS software (version 11.5; SPSS, Chicago, Ill) for Windows (Microsoft, Redmond, Wash). The study was performed with statistical power of 90% with a one-sided 
value of .05 to enable us to detect an absolute reduction of recurrence of 30% between the two treatment groups. Continuous data are presented as mean ± standard deviation. Categorical data were expressed as percentages. The student t test was used to compare continuous data; the 2 test was used to compare categorical values. Survival function was calculated with the Kaplan-Meier method (ie, the curve of the cumulative patency rate vs time). To determine if there was a statistically significant difference between survival curves (P = .05), we used the log-rank test. The binary restenosis rates were compared between groups with the 2 test.
The time of recurrence was judged by recurrence of symptoms. For clinically asymptomatic patients, the date of the regular planned follow-up examination served as the failure date. Patients who died without recurrence were censored with the date of their last follow-up examination.
Multivariate Cox proportional hazard regression analysis was performed to evaluate the multivariate predictors of recurrence at 6- and 12-month follow-up. The variables used in this analysis included brachytherapy, age, sex, clinical stage, lesion length, de novo and recurrent lesion, vessel run-off, prior stenosis or occlusion, diabetes mellitus, and stent model. Independent variables were expressed as hazard ratio with a 95% confidence interval.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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All 88 patients were eligible for 6-month follow-up, and one patient who underwent stent implantation and brachytherapy was lost to 12-month follow-up. Morphologic and procedural characteristics at baseline are presented in Table 2. The data are comparable, except for more frequent use of nitinol stents in patients who underwent both stent implantation and brachytherapy. Follow-up angiograms were available in 40 (87%) of the 46 patients who underwent only stent implantation and 35 (83%) of the 42 patients who underwent both stent implantation and brachytherapy. Four patients died of causes that were not related to therapy after they had completed 12-month follow-up. One patient died after recurrence in the segment treated with a stent.
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Complications
Nine patients experienced minor procedure-related complications. Of these nine patients, five (11%) underwent only PTA (three patients had a small pseudoaneurysm, one experienced minor bleeding, and one experienced distal embolization and underwent embolectomy) and four (10%) underwent both PTA and brachytherapy (three patients had small pseudoaneurysm, and one patient experienced distal embolization and underwent embolectomy). The pseudoaneurysms were successfully treated with US-guided compression therapy. There were no radiation-related complications or in-hospital adverse events.
Morphologic Patency
There was no difference in recurrence rates (includes all types of recurrence: restenosis and early and late thrombotic occlusion) between patients who underwent only stent implantation and those who underwent stent implantation and brachytherapy at 6-month (stent implantation, 35%; stent implantation and brachytherapy, 33%; P = .89) and 12-month (stent implantation, 59%; stent implantation and brachytherapy, 43%; P = .17) follow-up.
Angiographic and clinical characteristics at 6-month follow-up are depicted in Table 3. In patients who experienced early thrombotic occlusion (all nine patients developed early thrombotic occlusion within the first week after intervention), the percentage of diameter reduction was not further analyzed. In the remaining 79 patients, there was a less pronounced diameter reduction at the time of follow-up angiography in the patients who underwent stent implantation and brachytherapy versus those who underwent only stent implantation (46% vs 64%, P = .08).
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Late thrombotic occlusion was observed in three patients (7%) who underwent stent implantation and brachytherapy. In two of these patients, this occurred after withdrawal of clopidogrel.
We performed an additional analysis of patients after excluding those with early thrombotic occlusion. Data are presented in Table 4. After exclusion of patients with early thrombotic occlusion, the recurrence rate at 6-month follow-up was 32% in patients who underwent stent implantation and 20% in those who underwent stent implantation and brachytherapy (P = .24).
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Hemodynamic Results
Ankle-brachial index, peak velocity ratio, and treadmill test results for all patients are given in Table 5.
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2, P = .61), and 12-month (stent implantation, 54%; stent implantation and brachytherapy, 62%; 2, P = .47, respectively) follow-up. Cumulative clinical patency after 24 months was 50% in patients who underwent stent implantation and 57% in those who underwent stent implantation and brachytherapy (P = .50) (Fig 4).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Previous reports have demonstrated the positive effect of endovascular gamma radiation in the prevention of restenosis as an adjunct therapy to conventional revascularization techniques in the coronary and peripheral arteries (9–14). However, recent peripheral trials without stent implantation, which were mostly performed in patient cohorts with predominately short lesions, showed somewhat controversial results. For example, while the Paris Pilot trial seemed to be in favor of brachytherapy, the outcomes of the Paris trial itself were less likely to show a positive effect of brachytherapy in longer lesions (18,19). The positive effects of brachytherapy in the setting of long segment femoropopliteal stent implantation have been emphasized by the promising results of a pilot trial performed at our institution (14). In this pilot trial, 33 patients with a mean treated segment length of 17 cm underwent femoropopliteal stent implantation and consecutive brachytherapy with an 192Ir source. The results showed a rather high incidence of late thrombotic occlusion (seven patients [17%]) but an overall low rate (12%) of in-stent restenosis. After these findings were obtained and according to results from the Washington Radiation for In-Stent Restenosis trials (20,21), all patients began a prolonged antithrombotic regimen with clopidogrel that lasted at least 12 months.
The findings of our study were consistent with former experiences in the coronary arteries and findings of recent trials performed in the femoral arteries (9,14), as only one patient in the brachytherapy group experienced late thrombotic occlusion while undergoing treatment with clopidogrel. In the remaining two patients with late thrombotic occlusion after endovascular brachytherapy, clopidogrel had been withdrawn prior to the event, thus emphasizing the effect of this regimen on late adverse events in peripheral arteries and a possible rebound phenomenon after clopidogrel withdrawal (22).
One of the major concerns of our study was the high number of early thrombotic occlusions in patients who underwent brachytherapy. This phenomenon cannot be attributed to a lack of additional endothelialization, as in patients with late thrombotic occlusion. However, angioplasty and stent implantation with brachytherapy can add anywhere from 4 to 10 minutes to the standard procedure time, especially in this high-risk patient population with long lesions, with a majority of time spent with a balloon inflated within the treated vessel. The rigid centering catheter itself, with a diameter of 8 F, allows only antegrade access, which may lead to more pronounced vascular injury and endothelial denudation with an increased risk of thrombotic occlusion after additional application of radiation treatment. Manual compression of the access in the femoral artery after sheath removal may further contribute to altered blood flow. Finally, lesions in the present investigation were longer than those in previous investigations (22–24), which might further increase the risk of early thrombosis. As for the poor vessel run-off in the investigated cohort, we were unable to detect a correlation with early thrombosis.
Because of this high incidence of early thrombotic occlusion after femoropopliteal stent implantation and brachytherapy, heparin administration might not be a sufficient anticoagulation therapy in this setting. Currently, heparin—in combination with GPIIb/IIIa inhibitors—has shown promising results in patients undergoing stent implantation with and without brachytherapy in the coronary arteries (25–27) and in a small cohort of patients undergoing femoropoliteal PTA without further brachytherapy (28). Thus, despite the limited experience in the lower-limb arteries thus far, we would suggest a modified antithrombotic strategy in patients treated for SFA lesions, as well. A combined regimen of heparin with a GPIIb/IIIa inhibitor should be the subject of future trials. Furthermore, research should focus on the development of smaller and more flexible devices to reduce periinterventional vessel wall injury and the development of smaller radiation sources to enable the use of smaller centering catheters.
Finally, closer monitoring of patients to ensure adequate compliance concerning the necessity to continue antiplatelet therapy with clopidogrel for at least 12 months is crucial to avoid long-term complications.
A limitation of our study was that the brachytherapy procedure could not be performed in the interventional radiology suite because of special shielding requirements for such high-activity gamma sources. The patients' transportation to the brachytherapy unit, however, was performed without any problems after peripheral revascularization. Furthermore, the study was limited to a single center.
In summary, despite the favorable 12-month outcomes after excluding patients with early thrombotic occlusion, femoropopliteal stent implantation with brachytherapy did not reduce the overall recurrence rate in our investigation. We therefore cannot recommend the use of gamma radiation with the currently available devices for prophylaxis of restenosis in this high-risk group of patients.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: PTA = percutaneous transluminal angioplasty
Authors stated no financial relationship to disclose.
Author contributions: Guarantors of integrity of entire study, all authors; study concepts and design, R.M.W., E.M.; literature research, R.M.W., A.C.B.; clinical studies, R.M.W., B.P., E.M.; data acquisition and analysis/interpretation, R.M.W., A.C.B.; statistical analysis, A.C.B.; manuscript preparation, R.M.W., A.C.B., E.M.; manuscript definition of intellectual content, R.M.W., A.C.B., E.M.; manuscript editing, R.M.W., A.C.B.; manuscript revision/review and final version approval, all authors
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References |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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This article has been cited by other articles:
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  C. J. White and W. A. Gray Endovascular Therapies for Peripheral Arterial Disease: An Evidence-Based Review Circulation, November 6, 2007; 116(19): 2203 - 2215. [Abstract] [Full Text] [PDF]
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 C. Klonaris, A. Katsargyris, A. Giannopoulos, and E. Bastounis Advances in Endovascular Treatment of Femoropopliteal Arterial Occlusive Disease Perspectives in Vascular Surgery and Endovascular Therapy, December 1, 2006; 18(4): 329 - 341. [Abstract] [PDF]
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