Restenosis is a major limitation of coronary angioplasty.

Transcription

1 Intracoronary -Irradiation With a Liquid Re-Filled Balloon Six-Month Results From a Clinical Safety and Feasibility Study Martin Höher, MD; Jochen Wöhrle, MD; Markus Wohlfrom, MD; Hartmut Hanke, MD; Rainer Voisard, MD; Hans H. Osterhues, MD; Matthias Kochs, MD; Sven N. Reske, MD; Vinzenz Hombach, MD; Jörg Kotzerke, MD Background Coronary irradiation is a new concept to reduce restenosis. We evaluated the feasibility and safety of intracoronary irradiation with a balloon catheter filled with Re, a liquid, high-energy -emitter. Methods and Results Irradiation with 15 Gy at 0.5-mm tissue depth was performed in 28 lesions after balloon dilation (n 9) or stenting (n 19). Lesions included 19 de novo stenoses, 4 occlusions, and 5 restenoses. Irradiation time was seconds in 1 to 4 fractions. There were no procedural complications. One patient died of noncardiac causes at day 23. One asymptomatic patient refused 6-month angiography. Quantitative angiography after intervention showed a reference diameter of mm and a minimal lumen diameter of mm. At 6-month follow-up, minimal lumen diameter was mm (late loss index 0.57). Target lesion restenosis rate ( 50% in diameter) was low (12%; 3 of 26). In addition, we observed 9 stenoses at the proximal or distal end of the irradiation zone, potentially caused by the short irradiation segment and the decreasing irradiation dose at its borders ( edge stenoses). The total restenosis rate was 46% and was significantly lower (29% vs 70%, P 0.042) when the length of the irradiated segment was more than twice the lesion length. Conclusions Coronary irradiation with a Re-filled balloon is technically feasible and safe, requiring only standard percutaneous transluminal coronary angioplasty techniques. The target lesion restenosis rate was low. The observed edge stenoses appear to be avoidable by increasing the length of the irradiated segment. (Circulation. 2000;101: ) Key Words: angioplasty coronary disease radioisotopes restenosis Restenosis is a major limitation of coronary angioplasty. Its biology includes inflammation, proliferation, and migration of smooth muscle cells and remodeling of the vascular wall. 1 Local irradiation has been shown to inhibit neointima formation in animal experiments. 2 4 Initial trials using -sources indicated the clinical effectiveness of coronary brachytherapy. 5,6 In a first randomized trial, Teirstein et al 6 showed a significant reduction of the restenosis rate after intracoronary -irradiation of dilated restenotic lesions. Recently, they demonstrated the persistence of the initial effect and a significantly lower event rate after 2 years. 7 Promising angiographic results have also been reported with 90 Sr/ 90 Y -irradiation. 8,9 A procedural advantage of -radiation is its low penetration depth, minimizing the ionizing exposure of both the patient and the operator. However, the fast decrease of -radiation energy within 2 to 5 mm has raised the question of an inhomogeneous dose delivery to the vascular tissue and the need for centering the radiation device. Re is a high-energy -emitter available in liquid form. The purpose of this study was to evaluate the feasibility and safety of intracoronary -irradiation with a liquid Re-filled balloon. Methods This study was approved by the local ethics committee and the German radiation authorities. Inclusion criteria were written informed consent; age 18 to 80 years; ischemia by symptoms or exercise testing; intended angioplasty of a native coronary artery or a bypass graft; and a reference vessel diameter suitable for a 3.0-mm irradiation balloon. Exclusion criteria were acute myocardial infarction, unprotected main stem disease, strong vessel tortuosity, pregnancy, contraindication to aspirin, ticlopidine or heparin, and illness limiting the survival within 6 months. Radiation Source and Dosimetry Liquid Re is a high-energy -emitter that is available daily from the W/ Re generator (Oak Ridge National Laboratory, Oak Ridge, Tenn) and has a half-life of 17 hours. The -particles have a Received September 29, 1999; revision received December 1, 1999; accepted December 22, From the University of Ulm, Department of Cardiology (M.H., J.W., M.W., H.H., R.V., H.H.O., M.K., V.H.) and Department of Nuclear Medicine (S.N.R., J.K.), Ulm, Germany. Correspondence to Martin Höher, MD, University of Ulm, Department of Cardiology, Robert-Koch-Straße 8, Ulm, Germany. martin.hoeher@medizin.uni-ulm.de 2000 American Heart Association, Inc. Circulation is available at

2 2356 Circulation May 23, 2000 Figure 1. Irradiation balloon was filled with liquid Re manually injected from shielded 3.0- ml syringe by 3-way valve. To avoid radiation exposure of operator, valve was operated with plastic stick. maximal energy of 2.12 MeV and a mean energy of 764 kev. A principle -ray component of 155 kev accounts for 15% of the radiation intensity and allows excellent control of contamination. Before this clinical trial, we performed detailed in vitro studies to evaluate the dosimetry of a liquid Re-filled angioplasty balloon catheter. 10 The dose decrease with increasing distance from the balloon surface was measured and compared with expected values derived from the point kernel function of Re in water. 11 Very good correlation was demonstrated for the energy dose deposited and the fast dose decrease to 50% at 0.5 mm distance and to 10% at 2.5 mm distance from the balloon surface. From these data, the irradiation times required for a targeted dose can be calculated, dependent on the size of the irradiation balloon and the actual specific volume of Re. Irradiation times were calculated to deliver 15 Gy in a tissue depth of 0.5 mm. This corresponds to a dose of 30 Gy at the surface of the balloon. Potential variations in dose delivery caused by minor differences between the actual and the nominal diameter of the irradiation balloon are 10%. 10,12 Carrier-free Re (perrhenate) was obtained from a W/ Re generator by elution with saline and was concentrated by anion exchange columns to a specific volume of GBq/mL ( mci/ml). 13 A volume of 1.3 ml was filled into a 3.0-mL syringe shielded with 5-mm plastic. Because of the -radiation component, a lead container was used for transportation. Previously, we have demonstrated that in the exceptional event of balloon rupture, perchlorate can be administered orally to block the thyroid and gastric mucosa and to reduce the radiation burden to an effective dose of 0.16 msv/mbq Re. 14 Perchlorate was not used prophylactically. Irradiation Procedure All patients were pretreated with 100 mg/d aspirin for 5 days. They received a U bolus of heparin before angioplasty, adjusted to the activated clotting time ( 280 seconds). Aspirin (100 mg/d) was continued throughout the study. Patients with stents additionally received 250 mg ticlopidine BID for 6 weeks. Irradiation was carried out after successful angioplasty with or without stenting. Patient inclusion was based on on-line quantitative coronary angiography. Only patients with a vessel size suitable for a 3.0-mm balloon and an ischemic tolerance of 1 minute during the preceding angioplasty received irradiation. For irradiation, the angioplasty balloon was replaced by a noncompliant balloon of the same diameter and the same length equipped with a proximal and distal radio-opaque marker (Tacker, Cordis Europe). During intermittent contrast injections from the guiding catheter, indicating the position of the lesion and of landmark side branches, the deflated balloon was positioned, covering the target lesion and matching the position of the previous angioplasty balloon. The Re-filled syringe and an empty 50-mL syringe were connected to the balloon by a 3-way valve (Figure 1). With the empty syringe, a negative pressure was applied to the balloon. Afterward, the valve was closed and the empty syringe was replaced by a stopper. The 3-way valve was operated with a 10-cm plastic stick. For irradiation, the balloon was manually inflated with an approximate inflation pressure of 3 to 4 atm. Because of the low viscosity of the liquid Re, this procedure is sufficient for complete filling of the balloon without bubbles, as we know from our in vitro trials. During inflation, the ECG and anginal symptoms were attentively observed. Inflation was stopped and dose delivery was fractionated in the case of severe anginal pain, marked ST-segment changes, decrease of blood pressure, or frequent ventricular arrhythmias. When the irradiation had to be fractionated, the balloon was deflated for 3 to 5 minutes but left in place across the target stenosis to avoid shifts of the balloon and to minimize radiation exposure to other areas. After irradiation, the balloon was removed with forceps, and the whole system including the shielded syringe was brought back to the department of nuclear medicine for decay. Finally, the catheterization laboratory was checked for radiation contamination. Study Design Patients scheduled for coronary angioplasty were informed and gave their written consent for intracoronary irradiation and angiographic follow-up examination. In this safety and feasibility trial, no restrictions were made according to restenosis, bypass grafts, or total occlusions. The inclusion of patients into the study was done after successful angioplasty. Clinical follow-up was performed after 3 months and angiographic follow-up after 6 months. Quantitative Coronary Angiography Coronary angiography before and after angioplasty and at follow-up was performed in the same projections of the treated lesion after intracoronary glycerol-trinitrate. Angiographic measurements were done with the Pie Medical software 2.1 (Pie Medical Imaging). Each projection calibration was done from the unfilled guiding catheter. Statistical Analysis Continuous variables are presented as mean SD and compared with the unpaired Mann-Whitney U test or the paired Wilcoxon test. Discrete variables were expressed as counts and percentages and compared by means of 2 analysis. Statistical significance was set at the 5% -error level (P 0.05).

3 Höher et al Coronary Irradiation With Liquid Re 2357 Figure 2. Angiographic views of representative 6-month result after angioplasty of Cx and irradiation with Re (15 Gy in 0.5 mm tissue depth). Top, right anterior oblique; bottom, left anterior oblique. Left, Before angioplasty; middle, after irradiation; right, after 6 months. Results Between December 1997 and August 1998, 28 patients received irradiation after successful coronary angioplasty. Lesions were located in the left anterior descending coronary artery (n 9), the circumflex artery (Cx, n 8), the right coronary artery (n 10), and a bypass graft (n 1). In 17 patients, stenting was done before irradiation and in another 2 patients, stenting was performed afterward. Abciximab was given in 7 of 28 patients. Irradiation was done with 3.0-mm (n 16) and 3.5-mm (n 12) balloons, with a length of 20 mm (n 24), 30 mm (n 3), and 40 mm (n 1), sufficient to cover the whole lesion. The irradiation balloon was selected with the same diameter and length as the angioplasty balloon. In all patients, the prescribed dose of 15 Gy was delivered. The mean irradiation time was seconds (range 220 to 990). Irradiation was performed in 1 fraction (n 12), 2 fractions (n 7), 3 fractions (n 7), and 4 fractions (n 2) to limit ischemia. There were no adverse effects of the irradiation procedure except anginal pain and ST-segment changes. There was no radiation leakage within a patient. One minimal leak of the 3-way valve contaminated only the underlying water-resistant drape. Clinical and Procedural Data The study collective consisted of 18 men and 10 women with a mean age of years. Four patients had diabetes mellitus, 16 had hyperlipidemia, 18 had hypertension, and 14 had a history of smoking. Single-vessel disease was present in 9 patients, 2-vessel disease in 14 patients, and 3-vessel disease in 5 patients. Left ventricular ejection fraction was 68 15%. Ten patients had a recent myocardial infarction; 11 patients had unstable angina. There were 19 de novo stenoses, 4 occlusions, 3 restenoses, and 2 in-stent restenoses. Lesion morphology included 13 type A/B1 and 15 type B2 lesions. Nonoccluded lesions were predominantly eccentric (n 19). Angioplasty before irradiation was performed with 1 balloon inflation in 4 lesions, with 2 inflations in 8 lesions, and with 3 inflations in 16 lesions (mean inflations). The mean lesion length was mm (range 6.0 to 25.0). Six patients had minor vessel calcifications; no vessel was heavily calcified. Angioplasty resulted in an acute gain of mm. The mean ratio of the irradiation balloon diameter to the reference diameter after angioplasty was mm (range 0.93 to 1.49) and to the largest angioplasty balloon used was mm (range 1.0 to 1.2). The mean difference of the length of the irradiation balloon and the length of initial lesion was mm (range 3.7 to 18.6). The mean ratio of the length of the irradiation balloon to the lesion length was (range 1.23 to 3.36). Follow-Up Data There were no in-hospital complications related to the coronary intervention. One 76-year-old male patient died 23 days after stenting and irradiation of the right coronary artery as the result of kidney failure after unsuccessful percutaneous transluminal angioplasty of a renal artery. Autopsy was declined by his relatives. The remaining 27 patients were followed up for 6 months. Clinical follow-up after 3 months revealed no further death, no myocardial infarctions, and no revascularizations. After 6 months, there were still no further deaths but 1 myocardial infarction caused by a late stent thrombosis 109 days after stenting and irradiation. This patient also had received ticlopidine for the protocol specified for 6 weeks, as specified by the protocol. At 6 months, 13 patients were asymptomatic and 13 had stable angina. One asymptomatic female patient with a negative stress test declined follow-up angiography 6 months after angioplasty and irradiation of the Cx. Follow-up angiography was performed in 26 patients after days. Figure 2 shows an example of a good 6-month result after angioplasty and irradiation of the Cx. The dichotomous restenosis rate ( 50%) restricted to the target lesion was only 12% (3 of 26). In terms of the lesion type, target lesion restenosis occurred in 1 de novo lesion, in 1 occlusion, and in 1 restenosis. Additionally, we observed 9 newly developed stenoses (average 78 16%) outside of the target lesion located at the

4 2358 Circulation May 23, 2000 Figure 3. Example of a new edge stenosis after 6 months, which occurred at proximal end of irradiation zone outside of initial target lesion. Top, Before angioplasty; bottom, after 6 months; middle right, Re-filled balloon during irradiation. Position of balloon was controlled by radiopaque markers (arrows). Target lesion (*) distal to first septal branch ( ) showed no restenosis. (Re)stenosis after 6 months is now at origin of septal branch at former proximal end of irradiation balloon. proximal or distal end of the irradiation zone (Figure 3). Thus, the overall stenosis rate at follow-up was 46% (12 of 26). There was no significant change of the reference diameter. Including both target lesion restenoses and newly developed edge stenoses at the end of the irradiation zone, the mean late lumen loss was mm and mean late loss index was (Table). Repeat PTCA was performed in a total of 6 (23%) patients: 1 patient with target lesion restenosis and in 5 patients with edge stenoses. A low restenosis rate was observed in proximal lesions (11%, 1 of 9) and in stented de novo stenoses (21%, 3 of 14). High restenosis rates were seen in the small groups of previously occluded (75%, 3 of 4) or restenosed (50%, 2 of 4) vessels. To gain further insights into the mechanisms of edge stenoses, we analyzed the ratio of the length of the irradiation balloon to the length of the lesion, that is, the extent to which the irradiation balloon exceeded the stenosed area. The restenosis rate was significantly lower in patients in whom this ratio exceeded 2 compared with those with a ratio below 2 (Figure 4). Discussion Local irradiation from different sources has been shown to inhibit neointima formation in animal experiments. 2 4 Thus far, 4 human studies of intracoronary brachytherapy have been reported. 5 8,15 Condado et al 5 and Teirstein et al 6,7 showed a reduction of late lumen loss and a lower restenosis rate at 6 months and during 2 to 3 years of follow-up with -irradiation from a 192 Ir source. Verin et al 15 demonstrated the technical feasibility of intracoronary -irradiation with an 18-Gy inner arterial surface dose applied from a centered 90 Y wire but did not find an obviously reduced restenosis rate at the treated site (6 of 15, 40%). Recently, King et al 8 showed a low restenosis rate of 15% (3 of 20) of the target lesion after intracoronary -irradiation with 12 to 16 Gy at 2-mm distance from the center of a 90 Y source. In addition, they found some positive remodeling of the treated segments in 9 of the 20 patients but no aneurysms. This study is the first report the use of a liquid Re-filled balloon catheter for intracoronary irradiation in humans. We Quantitative Coronary Angiography Before Angioplasty After Angioplasty Follow-Up Minimal lumen diameter, mm Reference diameter, mm Diameter stenosis, % Angiographic measurements at follow-up are taken from the most severe narrowing within the whole treated segment including both the target lesion and newly developed edge stenoses. Figure 4. Stenosis rate after 6 months was significantly lower in patients in whom length of irradiation balloon was at least twice the length of primary lesion. In 2 patients with total occlusions, lesion length could not be measured.

5 Höher et al Coronary Irradiation With Liquid Re 2359 demonstrated the technical feasibility (100%) and the safety of this new technique. With the use of standard PTCA technology, coronary Re brachytherapy could be performed with low additional technical efforts. Like other high-energy -emitters, Re allows us to apply a high focal radiation dose over a short period of time. Because of its low penetration depth, the use of -radiation reduces the ionizing exposure of the patient and the operator and requires less effort for radioprotection in the catheterization laboratory compared with -sources. Features of Re, facilitating intracoronary application, are the high -energy, its liquid form, and the short half-life of 17 hours with daily availability from the W/ Re generator. Filling a conventional balloon catheter with liquid Re results in a self-centering irradiation source independent from bending of the artery, cardiac motion, and stenosis morphology. When the size of the radiation balloon is matched to the diameter of the artery, there is direct contact between the radiation source and the inner vessel wall. This results in equal and predefined radiation doses at equidistant points from the luminal surface of the vessel independent from the vessel size. The Refilled balloon therefore avoids the problem of centering a thin radioactive wire within the vessel. However, it does not affect the characteristic fast radial dose decrease of -radiation in contrast with -radiation, resulting in a significantly lower dose at the deeper adventitial layers compared with the luminal surface. The dose prescribed in this initial feasibility trial of liquid Re was chosen from the following considerations: Teirstein et al 6 showed a significant effect with Gy at a distance of mm from the ribbon source to the target lesion. This corresponds to our dose of 30 Gy at the balloon surface in contact with the luminal vessel side. Compared with the pilot study of Verin et al 15 that found no impressive effect with 18 Gy at the inner vessel side, our dose was chosen 50% higher. In this first feasibility trial with Re, we took care to avoid radiation induced pseudoaneurysms that previously had been described by Condado et al 5 with a recalculated dose of 38.5 Gy delivered at a distance of 1.5 mm from the radioactive wire. Although the risk for developing pseudoaneurysms might be much less with lowpenetrating -radiation and the fact that Condado et al considered it likely that the treated site received up to 92 Gy, we decided to stay below the limit of 38 Gy at the balloon surface. With regard to the fast dose decrease of -radiation, we accepted a low, potentially inadequate dose in the deeper, adventitial layers. Prior animal studies from Waksman et al 16 showed that with a dosage of 14 Gy at 2 mm from the radiation source, the effect of - and -radiation on the suppression of neointima formation was comparable. However, when delivering radiation from a centered wire source, the artery is not expanded to 3.0 mm and therefore the tissue dose at a 2-mm radius from the source center is probably higher at least in some portions of the arterial wall compared with the 15 Gy dose in 0.5-mm tissue depth of this study. Our 6-month angiographic results after Re irradiation were characterized by 2 aspects: The target lesion restenosis rate was only 12%, which is comparable to the results from the BERT feasibility trial, 8 showing a 15% restenosis rate at the target lesion. However, a disappointing finding of this feasibility study was the high incidence (35%) of new edge stenoses, increasing the overall restenosis rate to 46%. Including these edge stenoses, late lumen loss was 0.57 in this trial and comparable to the results from Verin et al 15 ( 0.50). Such edge stenoses could be due to a low irradiation dose within a traumatized vessel segment. A proliferative tissue response has been described with low dose 192 Ir irradiation of 10 Gy applied before balloon overdilation in a pig model 4 and after external x-ray application. 17 However, edge stenoses have not been described from the BERT trial, 8,9,18 although the authors applied very similar -irradiation doses. Recently Sabaté etal 19 analyzed the volumetric changes after irradiation according to the BERT trial with the use of 3D ultrasound. They also found a reduced effect at the edges with a decrease in luminal volume due to an increase in plaque volume and no net change in external elastic membrane volume, but only 1 of 21 lesions showed an angiographic edge stenosis. Our data indicate that the occurrence of edge stenoses is significantly influenced by the extent to which the irradiated segment is longer than the dilated lesion. In this study, the Re balloon had the same length as the dilation balloon. With a mean balloon length of mm (range 20 to 40 mm), the irradiated segment was shorter than in the BERT trial, in which a 30-mm delivery system was used. Mean lesion length was slightly longer (11 mm) in this study compared with BERT (9 mm). Possibly, a decreasing dose at the ends of the balloon applied in an already traumatized tissue segment triggers a proliferative response. In this study, a mean of balloon inflations were performed during angioplasty before irradiation. Because of slight shifts of the angioplasty balloon, the traumatized segment can be expected to be even longer than the simple length of the dilation balloon. There are some other factors that potentially reduce the effective tissue dose. Two thirds of the patients received coronary stents before irradiation. Experimental studies indicate that stents reduce the radiation dose by 4% to 14%, depending on the stent type. 20 We did not correct the irradiation dose with and without stenting. However, assuming a maximum dose reduction of 14%, the remaining dose of 12.9 Gy would still have been in the dose range applied in the BERT trial. Furthermore, -radiation is shielded by calcium. Although there were no heavily calcified lesions in this study, it should be mentioned that angiography has a limited sensitivity for inhomogeneous, focal calcific deposits. 21 As a safety and a feasibility study, this trial was not restricted to certain lesion types. Although the case numbers were small, restenoses were frequent (5 of 8) in previously restenosed and occluded lesions. Because of the fast dose decrease of -radiation within the vessel wall, it cannot be excluded that in lesions with a high plaque burden the effective dose to the proliferating tissue elements might have been too low. Study Limitations The number of patients in this feasibility trial was limited. The study did not include a control group and thus was not randomized. Because of the lack of the control group, we

6 2360 Circulation May 23, 2000 could not prove the efficacy of Re irradiation, and it remains open whether the low target lesion restenosis rate is indeed due to the irradiation procedure. Concerning the safety of this new method, our study is limited to the procedural results and 6-month follow-up. Because of the geometry of the Re-filled balloon, the dose was homogenous at the inner vessel surface. However, we did not use intravascular ultrasound to evaluate plaque burden and did not adapt the prescribed -irradiation dose to vessel wall thickness. Hypoxia reduces the biological effect of radiation in malignant tissue. 22 This raises the question whether radiation delivered from an inflated balloon is less effective than irradiation from a nonoccluding device caused by compression of the vessel wall and compromise of the vasa vasorum. However, our previous animal studies with the Re-filled balloon showed a significant reduction of neointimal hyperplasia with 7.5 Gy in 0.5-mm tissue depths, which is comparable to the data from nonoccluding -emitting catheters. 2 Furthermore, it is unclear which degree of hypoxia is reached in the vessel wall and whether oxygen concentration in the target cells is low enough (0.02%) to diminish radiation-induced formation of DNA strand breaks, 22 taking into account the short duration of balloon inflations (mean seconds), the low inflation pressure (3 to 4 atm), and the anatomy of vasa vasorum in the adventitia. 23 With the use of a liquid- filled, radioactive balloon, there is always a decreasing irradiation dose at the edges of the balloon. From our data, delivery of such a decreasing dose in a diseased segment traumatized by angioplasty predisposes for the development of edge stenosis. Usage of longer radioactive balloons exceeding the traumatized segment should limit the occurrence of edges stenosis, shifting the dose decrease at the edge of the balloon into nontraumatized segments. Low-pressure inflation of the radioactive balloon alone will not cause new vessel trauma, as we know from vessel occlusion during angioscopy. 24 Conclusions Coronary irradiation with a Re-filled balloon is technically feasible and safe. The target lesion restenosis rate was low. The observed edge stenoses appear to be avoidable by increasing the length of the irradiated segment. A randomized trial is warranted to evaluate the efficacy of Re brachytherapy. Acknowledgment This study was supported by the Deutsche Forschungsgemeinschaft (SFB 451-B6). References 1. Bauters C, Isner JM. The biology of restenosis. Prog Cardiovasc Dis. 1997;40: Waksman R, Robinson KA, Crocker IR, et al. Intracoronary low-dose -irradiation inhibits neointima formation after coronary artery balloon injury in the swine restenosis model. Circulation. 1995;92: Wiedermann JG, Marboe C, Amols H, et al. Intracoronary irradiation markedly reduces neointimal proliferation after balloon angioplasty in swine: persistent benefit at 6-month follow-up. J Am Coll Cardiol. 1995; 25: Weinberger J, Amols H, Ennis RD, et al. Intracoronary irradiation: dose response for the prevention of restenosis in swine. Int J Radiat Oncol Biol Phys. 1996;36: Condado JA, Waksman R, Gurdiel O, et al. Long-term angiographic and clinical outcome after percutaneous transluminal coronary angioplasty and intracoronary radiation therapy in humans. Circulation. 1997;96: Teirstein PS, Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med. 1997;336: Teirstein PS, Massullo V, Jani S, et al. Two-year follow-up after catheter-based radiotherapy to inhibit coronary restenosis. Circulation. 1999;99: King SB, Williams DO, Chougule P, et al. Endovascular beta-radiation to reduce restenosis after coronary balloon angioplasty: Results of the Beta Energy Restenosis Trial (BERT). Circulation. 1998;97: Meerkin D, Tardif JC, Crocker IR, et al. Effects of intracoronary -radiation therapy after coronary angioplasty: an intravascular ultrasound study. Circulation. 1999;99: Kotzerke J, Rentschler M, Glatting G, et al. Dosimetric fundamentals of endovascular therapy using Re- for the prevention of restenosis after angioplasty. Nuklearmedizin. 1998;37: Simpkin DJ, Mackie TR. EGS4 Monte Carlo determination of the beta dose kernel in water. Med Phys. 1990;17: Fox RA. Dosimetry of beta emitting radionuclides for use in balloon angioplasty. Australas Phys Eng Sci Med. 1997;20: Knapp FF Jr, Beets AL, Guhlke S, et al. Availability of rhenium- from the alumina-based tungsten-/rhenium- generator for preparation of rhenium--labeled radiopharmaceuticals for cancer treatment. Anticancer Res. 1997;17: Kotzerke J, Fenchel S, Guhlmann A, et al. Pharmacokinetics of Tc-99 m-pertechnetate and Re--perrhenate after oral application of perchlorate: option of subsequent care using liquid Re- in a balloon catheter. Nucl Med Commun. 1998;19: Verin V, Urban P, Popowski Y, et al. Feasibility of intracoronary -irradiation to reduce restenosis after balloon angioplasty: a clinical pilot study. Circulation. 1997;95: Waksman R, Robinson KA, Crocker IR, et al. Endovascular low-dose irradiation inhibits neointima formation after coronary artery balloon injury in swine: a possible role for radiation therapy in restenosis prevention. Circulation. 1995;91: Schwartz RS, Koval TM, Edwards WD, et al. Effect of external beam irradiation on neointimal hyperplasia after experimental coronary artery injury. J Am Coll Cardiol. 1992;19: Meerkin D, Bonan R, Crocker IR, et al. Efficacy of beta radiation in prevention of post-angioplasty restenosis: an interim report from the beta energy restenosis trial. Herz. 1998;23: Sabate M, Serruys PW, van der Giessen WJ, et al. Geometric vascular remodeling after balloon angioplasty and beta- radiation therapy: a 3-dimensional intravascular ultrasound study. Circulation. 1999;100: Amols HI, Trichter F, Weinberger J. Intracoronary radiation for prevention of restenosis: dose perturbations caused by stents. Circulation. 1998;98: Höher M, Bogun F, Kochs M, et al. Local calcification as a determinant of the outcome of excimer laser coronary angioplasty an in vitro study. Coron Artery Dis. 1993;4: Zhang H, Koch CJ, Wallen CA, et al. Radiation-induced DNA damage in tumors and normal tissues, III: oxygen dependence of the formation of strand breaks and DNA-protein crosslinks. Radiat Res. 1995;142: Kwon HM, Sangiorgi G, Ritman EL, et al. Adventitial vasa vasorum in balloon-injured coronary arteries: visualization and quantitation by a microscopic 3-dimensional computed tomography technique. J Am Coll Cardiol. 1998;32: Hamon M, Lablanche JM, Bauters C, et al. Effect of balloon inflation in angiographically normal coronary segments during coronary angioscopy: a quantitative angiographic study. Cathet Cardiovasc Diagn. 1994;31: