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Endovascular γ-irradiation to prevent recurrent femoral in-stent restenosis
Cardiovascular Radiation Medicine 3 (2002) 7 – 11
Endovascular g-irradiation to prevent recurrent femoral in-stent restenosis A case report Karsten Kruegera,*, Mark Bendelb, Markus Zaehringera, Monika Nolteb, Guido Winnekendoka, Klaus Lacknera a
Department of Diagnostic Radiology, University of Cologne Medical School, Joseph-Stelzmann-Street, D 50924 Cologne, Germany b Department of Radiooncology, University of Cologne Medical School, Joseph-Stelzmann-Street, D 50924 Cologne, Germany Received 1 March 2002; accepted 13 May 2002
Abstract
We report about a patient with twice recurrence of femoral in-stent restenoses. Centered endoluminal g-irradiation with 192 iridium was performed immediately after the second stent recanalization. The irradiation dose was 14 Gy calculated at 2-mm depth of vessel wall. One-year follow-up demonstrates neither clinical nor angiographic evidence of restenosis. D 2002 Elsevier Science Inc. All rights reserved.
Keywords:
Arteries, femoral; Arteries, stenosis; Arteries, transluminal angioplasty; Restenosis; Brachytherapy, endovascular, stents; Radiation
1. Introduction Two main components contribute to the development of restenosis after percutaneous transluminal angioplasty (PTA). The first mechanism is the proliferation of smooth muscle cells and matrix formation resulting in neointima formation [1,2]. The second mechanism is the negative remodeling. This leads to constriction of the entire vessel [3]. Negative remodeling can be avoided by stent placement. However, stents will not reduce the occurrence of restenosis by intima hyperplasia as was demonstrated in femoropopliteal arteries [4,5]. Therefore, there are only limited indications for stent placement in femoropopliteal arteries, as for example severe dissection after angioplasty or hemodynamic significant stenosis after angioplasty. Catheter-based endovascular irradiation (brachytherapy) has shown promising results in animal experiments and clinical studies by reducing restenosis [6– 10]. It was shown in randomized clinical studies that endovascular irradiation reduces the rate of restenosis after treatment of in-stent restenosis in coronary arteries [7,9 – 14]. Limited data are available thus far on the efficacy of brachytherapy in preventing restenosis after treatment of in-
stent restenosis in femoropopliteal arteries [15,16]. In a recently published nonrandomized study, the restenosis rate 6 months after irradiation of new implanted stents was only 12% [17]. We report about a patient in whom in-stent restenosis occurred twice. After the second stent recanalisation, centered endovascular g-irradiation with 192 iridium was performed to prevent the development of a new in-stent restenosis. One-year follow-up is available now.
2. Case report In 1998, a 62-year-old femal patient was admitted at our hospital with Fontain grade II B claudication of her right leg. She was a smoker and had a history of hyperlipidemia without other cardiovascular risk factors. Intraarterial subtraction angiography revealed a high grade, excentric, 5-cm long stenosis of the superficial femoral artery and otherwise normal vessels. PTA was performed with 50% remaining stenosis. The balloon diameter1 was 6 mm (balloon length 6 cm). An additional artherectomy further reduced the degree of stenosis to about 30%. During the intervention 7500 units of herapin were administered by intravenous bolus. The ankle –brachial index (ABI) increased from 0.59
* Corresponding author. Tel.: +49-221-478-5060; fax: +49-221-4784213. E-mail address: [email protected] (K. Krueger). 1522-1865/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 1 5 2 2 - 1 8 6 5 ( 0 2 ) 0 0 1 3 2 - 4
1
Sailor PTA Catheter, Invatec, Concesio Brescia, Italy.
8
K. Krueger et al. / Cardiovascular Radiation Medicine 3 (2002) 7–11
before to 1.0 after the intervention. Aspirin was given daily (100 mg). The patient was re-admitted 4 days later with acute rest pain of her right leg showing a total occlusion of the superficial femoral artery. Catheter-guided intraarterial thrombolysis was performed (Urokinase 100,000 units/hour, total dose 2.3 million units) successfully. The patient received intravenous heparin (partial thrombin time [PTT] 50 –80 s) during the thrombolysis. A Palmaz-Stent2 (diameter 6 mm) was placed into the superficial femoral artery, because the remaining stenosis of the dilated region was considered as the reason for thrombosis. The ABI was 1.0 after stenting. Oral medication was changed to aspirin (100 mg daily) plus clopidogrel (75 mg daily). In March 1999, 13 months after stent placement, the patient was admitted again for claudication symptoms. The walking distance was at the time less than 100 m. The ABI was decreased to 0.65 and color-coded duplex sonography and angiography revealed a high grade in-stent restenosis (Fig. 1). Atherectomy was performed and a new PalmazStent (diameter 6 mm) implanted into the distal part of the former stent lumen overlapping the distal edge with good result (Fig. 1). The ABI improved to 1.0 and the walking distance was unlimited. Only clopidogrel was prescribed because of an aspirin intolerability. In May 2000, the walking distance was again reduced to less than 200 m. At treadmill test (10 min, velocity 3 km/h, slope 12° according to recommendations by Rutherford et al. [18]), claudication symptoms began after 34 m. The ABI was 0.65. The maximum velocity index (intrastenotic divided by prestenotic maximum blood velocity) within the stenotic region was 3.95. Intraarterial angiography confirmed the high degree in-stent restenosis (Fig. 2). Angioplasty with a 6-mm balloon catheter1 (inflation pressure 10 atmospheres, inflation time twice 1.5 min) was performed in cross-over technique with good result (Fig. 2). During the intervention, 5000 units of heparin were administered by intravenous bolus. Immediately after angioplasty, a catheter with a 10-cm long segmented balloon3 for centering the radioactive source was inserted into the artery. The centering catheter was placed so that its segmented balloon (length 10 cm) overlapped the stent by approximately 1 cm at each end (Fig. 2). The diameter of the centering catheter (5 mm) was 1 mm smaller that than that of the PTA-balloon catheter to ensure residual blood flow during irradiation. Before the patient was transported to the brachytherapy unit, the exact position of the centering device was verified by radiography and the sheath with the centering catheter was taped to the skin. Endovascular irradiation was performed using an iridium-192 wire with a diameter of 0.9 mm4 after verifying
Fig. 1. Digital subtraction angiography of the superficial femoral artery 13 months after stent placement shows a high grade restenosis due to intimal hyperplasia within the stent lumen. The walking distance of the patient was limited to less than 200 m. The picture at right side shows the result of atherectomy and after new stent employment. All images are in posterior – anterior direction.
the correct position of the centering catheter once more. The centering balloon catheter was inflated at a pressure of four atmospheres. The irradiation dose was 14 Gy calculated in 2-mm depth of the vessel wall. The whole length of centering catheter was exposed to irradiation. The irradiation time was 307.2 s (current source strength 6.131 Ci). To reduce the risk of thromboembolic complications while the centering balloons were being inflated, irradiation was interrupted after 3 min for 120 s and the centering balloons deflated. Following the procedure in the brachytherapy unit, the centering catheter was removed and the patient was transported back to the catheter unit where a control angiography was performed to exclude thromboembolic or other complications. PTT was measured by a bed-site test5 before leaving to and after return (both > 150 s) from the Department of Radiooncology. Herapin therapy was continued for 24 h (7500 units subcutaneous twice daily). The ABI
2
Cordis, Roden, The Netherlands. PARIS, Centering Catheter System, Guidant, Tememla, CA, USA. 4 Nucletron (Micro) Selectron High Dose Rate Afterloader, Nucletron BV, Ve enendaal, Netherland. 3
5
CoaguChek Plus, Coagulation Monitor, Boehringer Mannheim, Germany.
K. Krueger et al. / Cardiovascular Radiation Medicine 3 (2002) 7–11
9
Fig. 2. Digital subtraction angiography of the right superficial femoral artery shows a high grade in-stent restenosis 14 months after successful recanalisation (far left). Vessel irregularities remained after angioplasty (second left). A catheter with a 10-cm long segmented balloon (PARIS, Centering Catheter System) was used to center the iridium gamma source in the artery (second right). The centering catheter overlapped the stent at both sides. The artery was exposed to 14 Gray calculated at 2-mm depth of the vessel wall. The intraarterial angiography 1 year after angioplasty and endovascular irradiation shows no evidence of restenosis. The walking distance of the patient is unlimited. All images are in posterior – anterior direction.
improved to 1.05 at the day after the intervention, the maximum velocity index on duplex sonography was 0.9. The follow-up is now 1 year. Color-coded duplex sonography, interviews and treadmill tests were performed after 3, 6 and 12 months. An intraarterial subtraction angiography was performed after 1 year. The walking distance remained unlimited. The patient did not complain about claudication symptoms during the treadmill tests. The ABI was 1.12 after 1 month, 1.0 after 6 and 12 months. The maximum velocity index at the proximal stent edge was 1.0, 0.87 and 1.03 after 3, 6 and 12 months, respectively (at distal stent edge: 0.76, 0.81, 0.70 and within the stented lumen 0.76, 0.68, 0.58). Control angiography 12 months after angioplasty and endovascular irradiation revealed a patent vessel lumen without restenosis (Fig. 2).
3. Discussion In a patient with twice recurrent femoral in-stent restenosis, the performance of endovascular g-irradiation immediately after the last intervention prevented the development of a new in-stent restenosis within a 1-year follow-up period.
In principle, primary stent placement is not indicated in femoropopliteal arteries as was stated by the TransAtlantic InterSociety Consensus Working Group [19]. This recommendations based on disappointing results of randomized trials. The 12 months patency rate was only 62% in the group with primary stent placement compared to 85% in the PTA group [4]. In a study by Cejna et al. [5], the cumulative 1-year patency rate was 63% in both groups. The reason for the high rate of in-stent restenosis in coronary and femoropopliteal arteries is the formation of a significant amount of neointima. Catheter-based endoluminal radiation (brachytherapy) has shown promising results in animal experiments and clinical studies aimed at reducing restenoses subsequent to stent application or angioplasty for recurrent stenoses [7,9,10,13,14]. The consequence of these promising results was the approval of endovascular irradiation for intracoronary in-stent restenoses by the Food and Drug Administration (FDA) on November 3, 2000. So far, the efficacy of endoluminal irradiation in femoropopliteal arteries was investigated in a limited number of trials. A patency rate of 84% up to 7.5 years posttreatment demonstrated a study on recurrent stenoses of femoropopliteal arteries initiated in 1990 [16]. Endovascular g
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K. Krueger et al. / Cardiovascular Radiation Medicine 3 (2002) 7–11
irradiation was administered at a dose of 12 Gy calculated 3 mm from the source center and was delivered into a noncentered catheter after different interventional procedures (angioplasty, directional atherectomy or stent placement). The same irradiation protocol was used in a nonrandomized [20] and a randomized trial [21] on angioplasty of long-distance lesions of femoropopliteal arteries. The restenosis rate decreased from 53.7% to 28.3% at 6 months post-PTA. Recently, the results of the nonrandomised feasibility part of the Peripheral Arteries Radiation Investigational Study (PARIS-trial) were reported [22]. The angiographic restenosis rate 6 months after PTA of de-novo femoropopliteal stenoses was 17.2% in 35 patients. A centering catheter was used to deliver a dose of 14 Gy 2 mm into the vessel wall. A major concern of in-stent endovascular irradiation is the high rate of late thrombosis [23 –26]. A review of both randomized and nonrandomized studies found that 9% of patients receiving irradiation had late thrombosis compared to less than 2% of the controls [25]. In a recently published trial [17] on endovascular irradiation of new implanted stents in femoropopliteal arteries was the rate of thrombosis higher (7/33) than the rate of stenosis (4/33). In our case, an endothelialized stent was exposed to irradiation and during the follow-up of 1 year thrombosis did not occur. In coronary studies, late thrombosis occurred mainly if irradiation was performed after deployment of a new stent [27] and has been attributed to a pronounced delay in endothelialization. Anticoagulation with clopidogrel in our patient might be another reason. In a recent published trail on coronary in-stent restenosis by Leon et al. [27], late thrombosis occurred in irradiated patients after the discontinuation of oral antiplatelet therapy with ticlopidine or clopidogrel. Longer follow-up will show whether the short-term benefit of endovascular g-irradiation to prevent in-stent restenosis will last in our patient. Furthermore, randomized clinical studies will have to prove the significance of our observation.
References [1] Kuntz RE, Gibson CM, Nobuyoshi M, Baim DS. Generalized model of restenosis after conventional balloon angioplasty, stenting and directional atherectomy. J Am Coll Cardiol 1993;21:15 – 25. [2] Mintz GS, Popma JJ, Pichard AD, Kent KM, Satler LF, Wong C, Hong MK, Kovach JA, Leon MB. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation 1996;94:35 – 43. [3] Luo H, Nishioka T, Eigler NL, Forrester JS, Fishbein MC, Berglund H, Siegel RJ. Coronary artery restenosis after balloon angioplasty is humans in associated with circumferential coronary constriction. Arterioscler Thromb Vasc Biol 1996;16:1393 – 8. [4] Vroegindeweij D, Vos LD, Tielbeek AV, Buth J, vd Bosch HC. Balloon angioplasty combined with primary stenting versus balloon angioplasty alone in femoropopliteal obstructions: a comparative randomized study. Cardiovasc Interv Radiol 1997;20:420 – 5.
[5] Cejna M, Thurnher S, Illiasch H, Horvath W, Waldenberger P, Hornik K, Lammer J. PTA versus Palmaz stent placement in femoropopliteal artery obstructions: a multicenter prospective randomized study. J Vasc Interv Radiol 2001;12:23 – 31. [6] Waksman R. Vascular brachytherapy: update on clinical trials. J Invasive Cardiol 2000;12:18A – 28A. [7] Teirstein PS, Massullo V, Jani S, Popma JJ, Mintz GS, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Morris NB, Leon MB, Tripuraneni P. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997;336:1697 – 703. [8] Diamond DA, Vesely TM. The role of radiation therapy in the management of vascular restenosis: Part II. Radiation techniques and results. J Vasc Interv Radiol 1998;9:389 – 400. [9] Waksman R, White RL, Chan RC, Bass BG, Geirlach L, Mintz GS, Satler LF, Mehran R, Serruys PW, Lansky AJ, Fitzgerald P, Bhargava B, Kent KM, Pichard AD, Leon MB. Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165 – 71. [10] Waksman R, Bhargava B, White L, Chan RC, Mehran R, Lansky AJ, Mintz GS, Satler LF, Pichard AD, Leon MB, Kent KK. Intracoronary beta-radiation therapy inhibits recurrence of in-stent restenosis. Circulation 2000;101:1895 – 8. [11] Teirstein PS, Massullo V, Jani S, Russo RJ, Cloutier DA, Schatz RA, Guarneri EM, Steuterman S, Sirkin K, Norman S, Tripuraneni P. Two year follow-up after catheter-based radiotherapy to inhibit coronary restenosis. Circulation 1999;99:243 – 7. [12] Teirstein PS, Massullo V, Jani S, Popma JJ, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Sirkin K, Cloutier DA, Leon MB, Tripuraneni P. Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial [see comments]. Circulation 2000;101:360 – 5. [13] Raizner AE, Oesterle SN, Waksman R, Serruys PW, Colombo A, Lim YL, Yeung AC, van der Giessen WJ, Vandertie L, Chiu JK, White LR, Fitzgerald PJ, Kaluza GL, Ali NM. Inhibition of restenosis with beta-emitting radiotherapy: report of the Proliferation Reduction with Vascular Energy Trial (PREVENT). Circulation 2000;102:951 – 8. [14] Verin V, Popowski Y, de Bruyne B, Baumgart D, Sauerwein W, Lins M, Kovacs G, Thomas M, Calman F, Disco C, Serruys PW, Wijns W, Piessens M, Kurtz J, Simon R, Delafontaine P, Erbel R, Group ftD-FS. Endoluminal beta-radiation therapy for the prevention of coronary restenosis after balloon angioplasty. N Engl J Med 2001;344:243 – 9. [15] Bottcher HD, Schopohl B, Liermann D, Kollath J, Adamietz IA. Endovascular irradiation — a new method to avoid recurrent stenosis after stent implantation in peripheral arteries: technique and preliminary results. Int J Radiat Oncol Biol Phys 1994;29:183 – 6. [16] Liermann DD, Bauernsachs R, Schopohl B, Bottcher HD. Five year follow-up after brachytherapy for restenosis in peripheral arteries. Semin Interv Cardiol 1997;2:133 – 7. [17] Wolfram R, Pokrajac B, Ahmadi R, Fellner C, Gyoengyoesi M, Haumer M, Bucek R, Poetter R, Minar E. Endovascular brachytherapy for prophylaxis against restenosis after long-segment femoropopliteal placement of stents: initial results. Radiology 2001;220: 724 – 9. [18] Rutherford RB, Flanigan DP, Gupta SK, Johnston KW, Karmody A, Whittemore AD, Baker JD, Ernst CB. Suggested standards for reports dealing with lower extremity ischemia. J Vasc Surg 1986;4: 80 – 94. [19] Dormandy JA, Rutherforde RB. Management of peripheral arterial disease (PAD): TASC Working Group — TransAtlantic Inter-Society Consensus (TASC). J Vasc Surg 2000;31(1 Pt. 2):S1 – 296. [20] Minar E, Pokrajac B, Ahmadi R, Maca T, Seitz W, Stumpflen A, Potter R, Ehringer H. Brachytherapy for prophylaxis of restenosis after long-segment femoropopliteal angioplasty: pilot study. Radiology 1998;208:173 – 9. [21] Minar E, Pokrajac B, Maca T, Ahmadi R, Fellner C, Mittlbock M, Seitz W, Wolfram R, Potter R. Endovascular brachytherapy for pro-
K. Krueger et al. / Cardiovascular Radiation Medicine 3 (2002) 7–11 phylaxis of restenosis after femoropopliteal angioplasty: results of a prospective randomized study. Circulation 2000;102:2694 – 9. [22] Waksman R, Laird JR, Jurkovitz CT, Lansky AJ, Gerrits F, Kosinski AS, Murrah N, Weintraub WS. Intravascular radiation therapy after balloon angioplasty of narrowed femoropopliteal arteries to prevent restenosis: results of the paris feasibility clinical trail. J Vasc Interv Radiol 2001;12:915 – 21. [23] Costa MA, Sabat M, van der Giessen WJ, Kay IP, Cervinka P, Ligthart JM, Serrano P, Coen VL, Levendag PC, Serruys PW. Late coronary occlusion after intracoronary brachytherapy. Circulation 1999;100: 789 – 92. [24] Waksman R, Bhargava B, Leon MB. Late thrombosis following
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intracoronary brachytherapy. Catheter Cardiovasc Interv 2000;49: 344 – 7. [25] Waksman R, Bhargava B, Mintz GS, Mehran R, Lansky AJ, Satler LF, Pichard AD, Kent KM, Leon MB. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol 2000;36:65 – 8. [26] Waksman R. Late thrombosis after radiation. Sitting on a time bomb. Circulation 1999;100:780 – 2. [27] Leon MB, Teirstein PS, Moses JW, Tripuraneni P, Lansky AJ, Jani S, Wong SC, Fish D, Ellis S, Holmes DR, Kerieakes D, Kuntz RE. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Eng J Med 2001;344:250.
Endovascular g-irradiation to prevent recurrent femoral in-stent restenosis A case report Karsten Kruegera,*, Mark Bendelb, Markus Zaehringera, Monika Nolteb, Guido Winnekendoka, Klaus Lacknera a
Department of Diagnostic Radiology, University of Cologne Medical School, Joseph-Stelzmann-Street, D 50924 Cologne, Germany b Department of Radiooncology, University of Cologne Medical School, Joseph-Stelzmann-Street, D 50924 Cologne, Germany Received 1 March 2002; accepted 13 May 2002
Abstract
We report about a patient with twice recurrence of femoral in-stent restenoses. Centered endoluminal g-irradiation with 192 iridium was performed immediately after the second stent recanalization. The irradiation dose was 14 Gy calculated at 2-mm depth of vessel wall. One-year follow-up demonstrates neither clinical nor angiographic evidence of restenosis. D 2002 Elsevier Science Inc. All rights reserved.
Keywords:
Arteries, femoral; Arteries, stenosis; Arteries, transluminal angioplasty; Restenosis; Brachytherapy, endovascular, stents; Radiation
1. Introduction Two main components contribute to the development of restenosis after percutaneous transluminal angioplasty (PTA). The first mechanism is the proliferation of smooth muscle cells and matrix formation resulting in neointima formation [1,2]. The second mechanism is the negative remodeling. This leads to constriction of the entire vessel [3]. Negative remodeling can be avoided by stent placement. However, stents will not reduce the occurrence of restenosis by intima hyperplasia as was demonstrated in femoropopliteal arteries [4,5]. Therefore, there are only limited indications for stent placement in femoropopliteal arteries, as for example severe dissection after angioplasty or hemodynamic significant stenosis after angioplasty. Catheter-based endovascular irradiation (brachytherapy) has shown promising results in animal experiments and clinical studies by reducing restenosis [6– 10]. It was shown in randomized clinical studies that endovascular irradiation reduces the rate of restenosis after treatment of in-stent restenosis in coronary arteries [7,9 – 14]. Limited data are available thus far on the efficacy of brachytherapy in preventing restenosis after treatment of in-
stent restenosis in femoropopliteal arteries [15,16]. In a recently published nonrandomized study, the restenosis rate 6 months after irradiation of new implanted stents was only 12% [17]. We report about a patient in whom in-stent restenosis occurred twice. After the second stent recanalisation, centered endovascular g-irradiation with 192 iridium was performed to prevent the development of a new in-stent restenosis. One-year follow-up is available now.
2. Case report In 1998, a 62-year-old femal patient was admitted at our hospital with Fontain grade II B claudication of her right leg. She was a smoker and had a history of hyperlipidemia without other cardiovascular risk factors. Intraarterial subtraction angiography revealed a high grade, excentric, 5-cm long stenosis of the superficial femoral artery and otherwise normal vessels. PTA was performed with 50% remaining stenosis. The balloon diameter1 was 6 mm (balloon length 6 cm). An additional artherectomy further reduced the degree of stenosis to about 30%. During the intervention 7500 units of herapin were administered by intravenous bolus. The ankle –brachial index (ABI) increased from 0.59
* Corresponding author. Tel.: +49-221-478-5060; fax: +49-221-4784213. E-mail address: [email protected] (K. Krueger). 1522-1865/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 1 5 2 2 - 1 8 6 5 ( 0 2 ) 0 0 1 3 2 - 4
1
Sailor PTA Catheter, Invatec, Concesio Brescia, Italy.
8
K. Krueger et al. / Cardiovascular Radiation Medicine 3 (2002) 7–11
before to 1.0 after the intervention. Aspirin was given daily (100 mg). The patient was re-admitted 4 days later with acute rest pain of her right leg showing a total occlusion of the superficial femoral artery. Catheter-guided intraarterial thrombolysis was performed (Urokinase 100,000 units/hour, total dose 2.3 million units) successfully. The patient received intravenous heparin (partial thrombin time [PTT] 50 –80 s) during the thrombolysis. A Palmaz-Stent2 (diameter 6 mm) was placed into the superficial femoral artery, because the remaining stenosis of the dilated region was considered as the reason for thrombosis. The ABI was 1.0 after stenting. Oral medication was changed to aspirin (100 mg daily) plus clopidogrel (75 mg daily). In March 1999, 13 months after stent placement, the patient was admitted again for claudication symptoms. The walking distance was at the time less than 100 m. The ABI was decreased to 0.65 and color-coded duplex sonography and angiography revealed a high grade in-stent restenosis (Fig. 1). Atherectomy was performed and a new PalmazStent (diameter 6 mm) implanted into the distal part of the former stent lumen overlapping the distal edge with good result (Fig. 1). The ABI improved to 1.0 and the walking distance was unlimited. Only clopidogrel was prescribed because of an aspirin intolerability. In May 2000, the walking distance was again reduced to less than 200 m. At treadmill test (10 min, velocity 3 km/h, slope 12° according to recommendations by Rutherford et al. [18]), claudication symptoms began after 34 m. The ABI was 0.65. The maximum velocity index (intrastenotic divided by prestenotic maximum blood velocity) within the stenotic region was 3.95. Intraarterial angiography confirmed the high degree in-stent restenosis (Fig. 2). Angioplasty with a 6-mm balloon catheter1 (inflation pressure 10 atmospheres, inflation time twice 1.5 min) was performed in cross-over technique with good result (Fig. 2). During the intervention, 5000 units of heparin were administered by intravenous bolus. Immediately after angioplasty, a catheter with a 10-cm long segmented balloon3 for centering the radioactive source was inserted into the artery. The centering catheter was placed so that its segmented balloon (length 10 cm) overlapped the stent by approximately 1 cm at each end (Fig. 2). The diameter of the centering catheter (5 mm) was 1 mm smaller that than that of the PTA-balloon catheter to ensure residual blood flow during irradiation. Before the patient was transported to the brachytherapy unit, the exact position of the centering device was verified by radiography and the sheath with the centering catheter was taped to the skin. Endovascular irradiation was performed using an iridium-192 wire with a diameter of 0.9 mm4 after verifying
Fig. 1. Digital subtraction angiography of the superficial femoral artery 13 months after stent placement shows a high grade restenosis due to intimal hyperplasia within the stent lumen. The walking distance of the patient was limited to less than 200 m. The picture at right side shows the result of atherectomy and after new stent employment. All images are in posterior – anterior direction.
the correct position of the centering catheter once more. The centering balloon catheter was inflated at a pressure of four atmospheres. The irradiation dose was 14 Gy calculated in 2-mm depth of the vessel wall. The whole length of centering catheter was exposed to irradiation. The irradiation time was 307.2 s (current source strength 6.131 Ci). To reduce the risk of thromboembolic complications while the centering balloons were being inflated, irradiation was interrupted after 3 min for 120 s and the centering balloons deflated. Following the procedure in the brachytherapy unit, the centering catheter was removed and the patient was transported back to the catheter unit where a control angiography was performed to exclude thromboembolic or other complications. PTT was measured by a bed-site test5 before leaving to and after return (both > 150 s) from the Department of Radiooncology. Herapin therapy was continued for 24 h (7500 units subcutaneous twice daily). The ABI
2
Cordis, Roden, The Netherlands. PARIS, Centering Catheter System, Guidant, Tememla, CA, USA. 4 Nucletron (Micro) Selectron High Dose Rate Afterloader, Nucletron BV, Ve enendaal, Netherland. 3
5
CoaguChek Plus, Coagulation Monitor, Boehringer Mannheim, Germany.
K. Krueger et al. / Cardiovascular Radiation Medicine 3 (2002) 7–11
9
Fig. 2. Digital subtraction angiography of the right superficial femoral artery shows a high grade in-stent restenosis 14 months after successful recanalisation (far left). Vessel irregularities remained after angioplasty (second left). A catheter with a 10-cm long segmented balloon (PARIS, Centering Catheter System) was used to center the iridium gamma source in the artery (second right). The centering catheter overlapped the stent at both sides. The artery was exposed to 14 Gray calculated at 2-mm depth of the vessel wall. The intraarterial angiography 1 year after angioplasty and endovascular irradiation shows no evidence of restenosis. The walking distance of the patient is unlimited. All images are in posterior – anterior direction.
improved to 1.05 at the day after the intervention, the maximum velocity index on duplex sonography was 0.9. The follow-up is now 1 year. Color-coded duplex sonography, interviews and treadmill tests were performed after 3, 6 and 12 months. An intraarterial subtraction angiography was performed after 1 year. The walking distance remained unlimited. The patient did not complain about claudication symptoms during the treadmill tests. The ABI was 1.12 after 1 month, 1.0 after 6 and 12 months. The maximum velocity index at the proximal stent edge was 1.0, 0.87 and 1.03 after 3, 6 and 12 months, respectively (at distal stent edge: 0.76, 0.81, 0.70 and within the stented lumen 0.76, 0.68, 0.58). Control angiography 12 months after angioplasty and endovascular irradiation revealed a patent vessel lumen without restenosis (Fig. 2).
3. Discussion In a patient with twice recurrent femoral in-stent restenosis, the performance of endovascular g-irradiation immediately after the last intervention prevented the development of a new in-stent restenosis within a 1-year follow-up period.
In principle, primary stent placement is not indicated in femoropopliteal arteries as was stated by the TransAtlantic InterSociety Consensus Working Group [19]. This recommendations based on disappointing results of randomized trials. The 12 months patency rate was only 62% in the group with primary stent placement compared to 85% in the PTA group [4]. In a study by Cejna et al. [5], the cumulative 1-year patency rate was 63% in both groups. The reason for the high rate of in-stent restenosis in coronary and femoropopliteal arteries is the formation of a significant amount of neointima. Catheter-based endoluminal radiation (brachytherapy) has shown promising results in animal experiments and clinical studies aimed at reducing restenoses subsequent to stent application or angioplasty for recurrent stenoses [7,9,10,13,14]. The consequence of these promising results was the approval of endovascular irradiation for intracoronary in-stent restenoses by the Food and Drug Administration (FDA) on November 3, 2000. So far, the efficacy of endoluminal irradiation in femoropopliteal arteries was investigated in a limited number of trials. A patency rate of 84% up to 7.5 years posttreatment demonstrated a study on recurrent stenoses of femoropopliteal arteries initiated in 1990 [16]. Endovascular g
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K. Krueger et al. / Cardiovascular Radiation Medicine 3 (2002) 7–11
irradiation was administered at a dose of 12 Gy calculated 3 mm from the source center and was delivered into a noncentered catheter after different interventional procedures (angioplasty, directional atherectomy or stent placement). The same irradiation protocol was used in a nonrandomized [20] and a randomized trial [21] on angioplasty of long-distance lesions of femoropopliteal arteries. The restenosis rate decreased from 53.7% to 28.3% at 6 months post-PTA. Recently, the results of the nonrandomised feasibility part of the Peripheral Arteries Radiation Investigational Study (PARIS-trial) were reported [22]. The angiographic restenosis rate 6 months after PTA of de-novo femoropopliteal stenoses was 17.2% in 35 patients. A centering catheter was used to deliver a dose of 14 Gy 2 mm into the vessel wall. A major concern of in-stent endovascular irradiation is the high rate of late thrombosis [23 –26]. A review of both randomized and nonrandomized studies found that 9% of patients receiving irradiation had late thrombosis compared to less than 2% of the controls [25]. In a recently published trial [17] on endovascular irradiation of new implanted stents in femoropopliteal arteries was the rate of thrombosis higher (7/33) than the rate of stenosis (4/33). In our case, an endothelialized stent was exposed to irradiation and during the follow-up of 1 year thrombosis did not occur. In coronary studies, late thrombosis occurred mainly if irradiation was performed after deployment of a new stent [27] and has been attributed to a pronounced delay in endothelialization. Anticoagulation with clopidogrel in our patient might be another reason. In a recent published trail on coronary in-stent restenosis by Leon et al. [27], late thrombosis occurred in irradiated patients after the discontinuation of oral antiplatelet therapy with ticlopidine or clopidogrel. Longer follow-up will show whether the short-term benefit of endovascular g-irradiation to prevent in-stent restenosis will last in our patient. Furthermore, randomized clinical studies will have to prove the significance of our observation.
References [1] Kuntz RE, Gibson CM, Nobuyoshi M, Baim DS. Generalized model of restenosis after conventional balloon angioplasty, stenting and directional atherectomy. J Am Coll Cardiol 1993;21:15 – 25. [2] Mintz GS, Popma JJ, Pichard AD, Kent KM, Satler LF, Wong C, Hong MK, Kovach JA, Leon MB. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation 1996;94:35 – 43. [3] Luo H, Nishioka T, Eigler NL, Forrester JS, Fishbein MC, Berglund H, Siegel RJ. Coronary artery restenosis after balloon angioplasty is humans in associated with circumferential coronary constriction. Arterioscler Thromb Vasc Biol 1996;16:1393 – 8. [4] Vroegindeweij D, Vos LD, Tielbeek AV, Buth J, vd Bosch HC. Balloon angioplasty combined with primary stenting versus balloon angioplasty alone in femoropopliteal obstructions: a comparative randomized study. Cardiovasc Interv Radiol 1997;20:420 – 5.
[5] Cejna M, Thurnher S, Illiasch H, Horvath W, Waldenberger P, Hornik K, Lammer J. PTA versus Palmaz stent placement in femoropopliteal artery obstructions: a multicenter prospective randomized study. J Vasc Interv Radiol 2001;12:23 – 31. [6] Waksman R. Vascular brachytherapy: update on clinical trials. J Invasive Cardiol 2000;12:18A – 28A. [7] Teirstein PS, Massullo V, Jani S, Popma JJ, Mintz GS, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Morris NB, Leon MB, Tripuraneni P. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997;336:1697 – 703. [8] Diamond DA, Vesely TM. The role of radiation therapy in the management of vascular restenosis: Part II. Radiation techniques and results. J Vasc Interv Radiol 1998;9:389 – 400. [9] Waksman R, White RL, Chan RC, Bass BG, Geirlach L, Mintz GS, Satler LF, Mehran R, Serruys PW, Lansky AJ, Fitzgerald P, Bhargava B, Kent KM, Pichard AD, Leon MB. Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165 – 71. [10] Waksman R, Bhargava B, White L, Chan RC, Mehran R, Lansky AJ, Mintz GS, Satler LF, Pichard AD, Leon MB, Kent KK. Intracoronary beta-radiation therapy inhibits recurrence of in-stent restenosis. Circulation 2000;101:1895 – 8. [11] Teirstein PS, Massullo V, Jani S, Russo RJ, Cloutier DA, Schatz RA, Guarneri EM, Steuterman S, Sirkin K, Norman S, Tripuraneni P. Two year follow-up after catheter-based radiotherapy to inhibit coronary restenosis. Circulation 1999;99:243 – 7. [12] Teirstein PS, Massullo V, Jani S, Popma JJ, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Sirkin K, Cloutier DA, Leon MB, Tripuraneni P. Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial [see comments]. Circulation 2000;101:360 – 5. [13] Raizner AE, Oesterle SN, Waksman R, Serruys PW, Colombo A, Lim YL, Yeung AC, van der Giessen WJ, Vandertie L, Chiu JK, White LR, Fitzgerald PJ, Kaluza GL, Ali NM. Inhibition of restenosis with beta-emitting radiotherapy: report of the Proliferation Reduction with Vascular Energy Trial (PREVENT). Circulation 2000;102:951 – 8. [14] Verin V, Popowski Y, de Bruyne B, Baumgart D, Sauerwein W, Lins M, Kovacs G, Thomas M, Calman F, Disco C, Serruys PW, Wijns W, Piessens M, Kurtz J, Simon R, Delafontaine P, Erbel R, Group ftD-FS. Endoluminal beta-radiation therapy for the prevention of coronary restenosis after balloon angioplasty. N Engl J Med 2001;344:243 – 9. [15] Bottcher HD, Schopohl B, Liermann D, Kollath J, Adamietz IA. Endovascular irradiation — a new method to avoid recurrent stenosis after stent implantation in peripheral arteries: technique and preliminary results. Int J Radiat Oncol Biol Phys 1994;29:183 – 6. [16] Liermann DD, Bauernsachs R, Schopohl B, Bottcher HD. Five year follow-up after brachytherapy for restenosis in peripheral arteries. Semin Interv Cardiol 1997;2:133 – 7. [17] Wolfram R, Pokrajac B, Ahmadi R, Fellner C, Gyoengyoesi M, Haumer M, Bucek R, Poetter R, Minar E. Endovascular brachytherapy for prophylaxis against restenosis after long-segment femoropopliteal placement of stents: initial results. Radiology 2001;220: 724 – 9. [18] Rutherford RB, Flanigan DP, Gupta SK, Johnston KW, Karmody A, Whittemore AD, Baker JD, Ernst CB. Suggested standards for reports dealing with lower extremity ischemia. J Vasc Surg 1986;4: 80 – 94. [19] Dormandy JA, Rutherforde RB. Management of peripheral arterial disease (PAD): TASC Working Group — TransAtlantic Inter-Society Consensus (TASC). J Vasc Surg 2000;31(1 Pt. 2):S1 – 296. [20] Minar E, Pokrajac B, Ahmadi R, Maca T, Seitz W, Stumpflen A, Potter R, Ehringer H. Brachytherapy for prophylaxis of restenosis after long-segment femoropopliteal angioplasty: pilot study. Radiology 1998;208:173 – 9. [21] Minar E, Pokrajac B, Maca T, Ahmadi R, Fellner C, Mittlbock M, Seitz W, Wolfram R, Potter R. Endovascular brachytherapy for pro-
K. Krueger et al. / Cardiovascular Radiation Medicine 3 (2002) 7–11 phylaxis of restenosis after femoropopliteal angioplasty: results of a prospective randomized study. Circulation 2000;102:2694 – 9. [22] Waksman R, Laird JR, Jurkovitz CT, Lansky AJ, Gerrits F, Kosinski AS, Murrah N, Weintraub WS. Intravascular radiation therapy after balloon angioplasty of narrowed femoropopliteal arteries to prevent restenosis: results of the paris feasibility clinical trail. J Vasc Interv Radiol 2001;12:915 – 21. [23] Costa MA, Sabat M, van der Giessen WJ, Kay IP, Cervinka P, Ligthart JM, Serrano P, Coen VL, Levendag PC, Serruys PW. Late coronary occlusion after intracoronary brachytherapy. Circulation 1999;100: 789 – 92. [24] Waksman R, Bhargava B, Leon MB. Late thrombosis following
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intracoronary brachytherapy. Catheter Cardiovasc Interv 2000;49: 344 – 7. [25] Waksman R, Bhargava B, Mintz GS, Mehran R, Lansky AJ, Satler LF, Pichard AD, Kent KM, Leon MB. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol 2000;36:65 – 8. [26] Waksman R. Late thrombosis after radiation. Sitting on a time bomb. Circulation 1999;100:780 – 2. [27] Leon MB, Teirstein PS, Moses JW, Tripuraneni P, Lansky AJ, Jani S, Wong SC, Fish D, Ellis S, Holmes DR, Kerieakes D, Kuntz RE. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Eng J Med 2001;344:250.