Intracoronary Brachytherapy for In-Stent Restenosis Using Long Sources Reduces Restenosis

Treatment of in-stent restenosis (ISR) remains a major challenge in modern interventional cardiology. Intracoronary stenting (ICS) is a major device in percutaneous coronary interventions (PCI).¹ Despite advances in ICS techniques and adjunct pharmacotherapy, the incidence of initial ISR remains up to 30% and is dependent upon patient characteristics, lesion morphology, and procedural technique.² The incidence of recurrent ISR varies among reported series and approaches 50%, regardless of treatment modalities, including percutaneous transluminal coronary angioplasty (PTCA), rotational atherectomy (RA), excimer laser ablation, and restenting.^3,4 Cutting balloon angioplasty is a novel technique that combines the features of conventional balloon angioplasty with multiple microtome-sharp atherotomes (microsurgical blades)⁵ and has shown to be more effective than other percutaneous techniques for the treatment of ISR.^6,7 Trials using ICBT have shown this technique to be effective in reducing recurrent ISR after PCI, even in complex coronary lesions.^8–12 A major limitation of ICBT has been the development of edge restenosis, otherwise called the “candy wrapper or edge effect,” as well as late stent thrombosis, especially if repeat stenting is involved. By definition, edge effect means stenosis on angiographic follow-up occurring after ICBT that is less than 5 mm proximal or distal to the tip of the radiation source.¹³ Observational studies show that the pathophysiology of this entity has been attributed to a combination of: a) “geographical miss,” which is the failure to deliver full radiation to the injured segment due to dose fall-off or dose lack along the edges of the injured segment, and b) stimulatory effect of low-dose radiation on smooth muscle cell proliferation. The relationships between edge effect and inadequate coverage of the injured segment by the radiation source were, however, never tested prospectively. The optimal margin coverage necessary to reduce the edge effect, and its consequences on non-stented segments on the late outcome are unknown. In current day practice, there is limited, well-established data depicting the incidence of recurrent restenosis with the use of a longer ICBT source and “stepping” technique, with minimal overlap in the treatment of ISR after the use of lesion modification techniques such as RA3 and/or CB.¹⁴ The aim of this study was to evaluate the short- and long-term benefits of using long ICBT sources after the use of concomitant lesion modification devices, along with prolonged dual antiplatelet therapy in the treatment of all in-stent restenosis patients in real-life setting. Methods Patients. We analyzed 226 consecutive patients with angiographically documented ISR (240 vessels and 264 lesions) who underwent ICBT between February 2001 and February 2003. Baseline characteristics of these patients appear in Table 1. All patients had clinical or laboratory evidence of myocardial ischemia. Demographic and clinical characteristics were recorded on standard forms. Angiographic and procedural data were recorded by trained cardiac catheterization laboratory personnel. Procedural characteristics. Lesion modification was performed in over 98% of cases (71.2% CB alone and 27.7% RA ± CB); CB angioplasty was performed using the device manufactured by Boston Scientific Corporation (San Diego, California). CB length used was 6, 10 or 15 mm and the diameter ranged from 2.0 to 4.0 mm, depending on lesion length and original stent size. For long lesions, tandem balloon inflations were performed. Maximum inflation pressure was 10 mmHg. RA was performed using the Rotablator^® (Scimed, Boston Scientific Corp., Maple Grove, Minnesota) and the burr size was chosen according to an average burr-to-artery ratio of 0.6. All lesions were then dilated with an appropriate sized balloon (1:1 ratio) to achieve optimal angiographic results. The use of glycoprotein IIb/IIIa inhibitor adjunct therapy was discretional. Re-stenting the lesion was strongly discouraged to avoid the risk of stent thrombosis. Pre- and post-intervention stenotic vessel and minimal lumen diameter (MLD) were assessed by quantitative coronary angiography (QCA). After obtaining optimal angiographic results, intracoronary b-radiation was delivered by the Beta-Cath™ System (Novoste Corporation, Norcross, Georgia). A fixed-dose delivery of b-radiation (18.4 Gy at 2.0 mm for reference vessel diameter = 3.36 mm) was used, as it has been shown to be effective in the prevention of neointimal proliferation.¹⁵ The length of the b-radiation source used was 30 mm and 40 mm. For longer lesions, a step-up technique with minimal (one-seed) overlap was performed. Due to a high incidence of late thrombotic occlusion following ICBT,^16,17 all patients were treated with long-term antiplatelet therapy with clopidogrel and aspirin for a one-year period. Definitions and clinical endpoints. Post-procedural and clinical endpoints were monitored and recorded using standard protocols. Angiographic success was defined as residual stenosis 5 times the upper limit of normal), cerebrovascular accident, and urgent revascularization, including coronary artery bypass surgery on the day of PCI. Major adverse cardiac events (MACE) included death from any cause, myocardial infarction manifesting as prolonged chest pain associated with CK-MB > 5 times normal, or the appearance of new Q-waves, TVR, including percutaneous intervention or surgical revascularization, and disabling stroke. MACE was recorded at hospital discharge and at 30 days. Procedural events were defined as transient or persistent vessel closure during PCI; angiographic residual dissection (based on National Heart Lung and Blood Institute classification types A–F); sidebranch closure ( 1.5 mm diameter with normal pre-procedure flow); visible distal thromboembolism, slow flow (less than TIMI 3 flow in the absence of proximal dissection or spasm, or distal embolization at any time during PCI); distal embolization; dye extravasations; frank vessel perforation; and persistent chest pain lasting > 30 minutes post-procedure. Follow-up. Follow-up information was collected primarily through telephone contact or review of medical records during out-patient visits and hospitalizations. Queries regarding the patients’ clinical status and any hospitalizations or procedures occurring since the ICBT procedure were made. If needed, the patients’ primary medical physicians were consulted and relevant medical records were obtained from them. Patient deaths were confirmed either by telephone calls to their home, or using the social security death index on the worldwide web. Routine angiographic follow-up was not performed. Statistical analysis. Baseline characteristics and continuous data are represented as mean ± SD, or number and dichotomous data as percentages. Rank sum statistics were used to compare differences between continuous variables. Contingency table analysis was performed for comparison of categorical variables. Inter-group differences were analyzed using the log-rank measure. A p-value of 3 times the normal elevation, and 1 patient with > 5 times the normal elevation. The average length of stay was 2.0 ± 3.0 days. Follow-up was obtained for all 226 patients in-hospital, at 30 days, and at one year. The mean duration of follow-up was 12 ± 2 months. At 30-day follow-up, MACE was 5%. Two patients died while in the hospital due to non-cardiac causes (one renal failure and the other related to sepsis). There was no delayed acute closure or subacute stent thrombosis during the follow-up period. The rate of clinical TVR at one year was 9.7% (TLR 7.1% and non-TLR 2.6%), which was managed by repeat PCI in 91% and surgical revascularization in 9% of patients. The incidence of edge restenosis in this study group was 2%. Multivariate predictors of clinical TLR were age > 70 years (OR 2.0; 95% CI 1.1–5.3, p = 0.006) and diabetes mellitus (OR 1.8; 95% CI 1.1–3.9, p 18–20 Despite the advantages of ICS, the development of ISR and its management has been the leading challenge to the interventionalist. The incidence of ISR has been reported to range between 5–30%.^18–20 By histologic analysis, ISR has been shown to be the result of inflammation of vascular media and subsequent smooth muscle proliferation, leading to neointimal tissue formation. Trials focused on the treatment of ISR using various techniques such as PTCA,^21,22 repeat ICS,23 PRCA,^24,25 directional atherectomy,²⁶ and excimer laser,²⁷ have reported similar long-term outcomes. The use of CB alone in the treatment of ISR has been studied also and has shown favorable results in a non-randomized setting, but no benefit over PTCA was observed in the randomized trials.^28,29 The main advantage of CB is the reduced chance of “watermelon seeding” and low re-stent usage due to the reduced incidence of dissection. Favorable clinical data supporting ICBT employing both g and b-radiation have been published, establishing this technique as the sole approved therapy for the treatment of ISR.^8–12 The limiting factor in the use of ICBT, however, is the development of edge restenosis or the “candy wrapper effect.”^35,36 Intravascular and pathologic studies showed that abnormal neointimal proliferation outside the stent margins predominantly contributed to the edge effect phenomenon. The increased tissue at the edge consists of proliferating smooth muscle cells and abundant extracellular matrix.³⁷ Although the exact cause of edge effect is not completely understood, observational studies have shown that its occurrence is most likely due to geographical miss, which reflects the failure to deliver full radiation to the injured segment due to dose fall-off or dose absence along the edges of the injured segment.³⁸ The reduced radiation does not inhibit the intimal proliferation triggered by stent injury; in fact, it interacts with injured segments of the vessel and may promote proliferative response. The benefits shown in our study are most likely due to a combination of larger post-procedure MLD, lesser dissection, and use of a longer ICBT source to cover ISR lesions from healthy-to-healthy segments. Compared to bare metal stents, where stent thrombosis usually occurs in 30 days after PCI has been another major adverse clinical consequence of intracoronary brachytherapy.^30,31 Waksman et al. published data on the higher incidence of late total occlusion in a group of patients who underwent repeat stenting (stent sandwich) after brachytherapy for ISR.^32,33 This propensity for late stent thrombosis has been attributed to excessive inhibition of neointimal formation, resulting in continued intravascular exposure of the bare prothrombotic collagen or bare metal stent.³⁴ We used long-term dual antiplatelet therapy for all patients and strongly discouraged the use of repeat stenting, which might have resulted in the absence of late coronary thrombosis. The results of our study demonstrate that the combination of ICBT with lesion modification techniques (CB and/or RA) produces better results than what has thus far been reported in the literature. These favorable results can be attributed to our hypothesis of confining the vessel injury with the use of CB, a larger post-debulking MLD, and full coverage of the area of injury by using a longer source of ICBT, thus reducing the phenomenon of edge restenosis (“longer is better” strategy). The very low rate of repeat stenting is most likely attributed to the lower incidence of dissection. Despite RA, the ablated vessel segment is longer than the irradiated segment, thus the low-pressure vessel injury from rotational atherectomy did not trigger subsequent intimal hyperplasia, as evidenced by the very low incidence of clinical restenosis (14 which used a pull-back strategy for ICBT in longer lesions following CB PCI. Currently, drug-eluting stents (DES) are being increasingly utilized for the treatment of bare metal stent ISR, with mixed results.^40,41 Head-to-head randomized trials evaluating DES versus ICBT have been completed and results will be available in one year (TAXUS V and CSAR trials). Study limitations. The main limitation of this study derives from its non-randomized and retrospective nature. Instead, a consecutive group of patients was studied. Angiographic follow-up was not available on all patients and an intravascular ultrasound analysis was not routinely performed. The 60 mm Beta Cath source that is now available was not available for use when data for this study were being gathered. Randomized trials are needed to confirm the findings of synergism of lesion modification and brachytherapy, as noted in our study. Conclusions To reduce the edge effect, the primary objective of an effective treatment strategy is to confine the vessel injury, achieve the optimal MLD at the lesion segment, and extend the radiation coverage 5–10 mm beyond the injured segment. Discouraging re-stenting and the use of long-term antiplatelet therapy reduces the incidence of late thrombotic occlusion and provides acceptable long-term results. This strategy for the treatment of ISR appears to yield low rates of recurrent TVR and MACE at mid-term, although long-term data (> 1 year) will be needed to establish the long-term utility of this strategy for the treatment of ISR.

1. American Heart Association, Heart Disease and Stroke Statistics – 2003 Update. American Heart Association, Dallas, Texas, 2002. 2. Bauters C, Hubert E, Prat A, et al. Predictors of restenosis after coronary stent implantation. J Am Coll Cardiol 1998;31:1291–1298. 3. Park SW, Hong MK, Moon DH, et al. Treatment of diffuse in-stent restenosis with rotational atherectomy followed by radiation therapy with a rhenium-188-mercaptoacetyltriglycine-filled balloon. J Am Coll Cardiol 2001;38:631–637. 4. Sharma SK, Kini A, Mehran R, et al. Randomized trial of Rotational Atherectomy Versus Balloon Angioplasty for Diffuse In-stent Restenosis (ROSTER). Am Heart J 2004;147:16–22. 5. Barath P, Fishbein MC, Vari S, Forrester JS. Cutting balloon: A novel approach to percutaneous angioplasty. Am J Cardiol 1991;68:1249–1252. 6. Adamian M, Colombo A, Briguori C, et al. Cutting balloon angioplasty for the treatment of in-stent restenosis: A matched comparison with rotational atherectomy, additional stent implantation and balloon angioplasty. J Am Coll Cardiol 2001;38:672–679. 7. Muramatsu T, Tsukahara R, Ho M, et al. Efficacy of cutting balloon angioplasty for in-stent restenosis: An intravascular ultrasound evaluation. J Invasive Cardiol 2001;13:439–44. 8. Lansky AJ, Popma JJ, Massullo V, et al. Quantitative angiographic analysis of stent restenosis in the Scripps Coronary Radiation to Inhibit Intimal Proliferation Post Stenting (SCRIPPS) Trial. Am J Cardiol 1999;84:410–14. 9. Waksman R, White RL, Chan RC, et al. Intracoronary gamma radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165–2171. 10. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001;344:250–256. 11. Waksman R, Raizner AE, Yeung AC, et al. Use of localised intracoronary beta radiation in treatment of in-stent restenosis: The INHIBIT randomised controlled trial. Lancet 2002;359:551–557. 12. Popma JJ, Suntharalingam M, Lansky AJ, et al. STents And Radiation Therapy (START) Investigators. Randomized trial of 90Sr/90Y beta-radiation versus placebo control for treatment of in-stent restenosis. Circulation 2002;106:1090–1096. 13. Kim HS, Waksman R, Cottin Y, et al. Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis. J Am Coll Cardiol 2001;37:1026–1030. 14. Moustapha A, Salloum J, Saikia S, et al. Combined cutting balloon angioplasty and intracoronary beta radiation for treatment of in-stent restenosis: clinical outcomes and effect of pullback radiation for long lesions. Catheter Cardiovasc Interv 2002;57:325–329. 15. Morino Y, Kaneda H, Fox T, et al. Delivered dose and vascular response after beta-radiation for in-stent restenosis: Retrospective dosimetry and volumetric intravascular ultrasound analysis. Circulation 2002;106:2334–2339. 16. Waksman R, Bhargava B, Mintz GS, et al. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol 2000;36:65–68. 17. Waksman R, Ajani AE, White RL, et al. Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary gamma-radiation in patients with in-stent restenosis: Washington Radiation for In-Stent Restenosis Trial plus 6 months of clopidogrel (WRIST PLUS). Circulation 2001;103:2332–2335. 18. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. BENESTENT Study Group. N Engl J Med 1994;331:489–495. 19. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994;331:496–501. 20. Versaci F, Gaspardone A, Tomai F, et al. A comparison of coronary-artery stenting with angioplasty for isolated stenosis of the proximal left anterior descending coronary artery. N Engl J Med 1997;336:817–822. 21. Eltchaninoff H, Koning R, Tron C, et al. Balloon angioplasty for the treatment of coronary in-stent restenosis: immediate results and 6-month angiographic recurrent restenosis rate. J Am Coll Cardiol 1998;32:980–984. 22. Bauters C, Banos JL, Van Belle E, et al. Six-month angiographic outcome after successful repeat percutaneous intervention for in-stent restenosis. Circulation. 1998;97:318–321. 23. Al-Sergani HS, Ho PC, Nesto RW, et al. Stenting for in-stent restenosis: A long-term clinical follow-up. Catheter Cardiovasc Interv 1999;48:143–148. 24. Sharma SK, Duvvuri S, Dangas G, et al. Rotational atherectomy for in-stent restenosis: acute and long-term results of the first 100 cases. J Am Coll Cardiol 1998;32:1358–1365. 25. Dietz U, Rupprecht HJ, de Belder MA, et al. Angiographic analysis of the angioplasty versus rotational atherectomy for the treatment of diffuse in-stent restenosis trial (ARTIST). Am J Cardiol 2002;90:843–847. 26. Strauss BH, Umans VA, van Suylen RJ, et al. Directional atherectomy for treatment of restenosis within coronary stents: Clinical, angiographic and histologic results. J Am Coll Cardiol 1992;20:1465–1473. 27. Mehran R, Mintz GS, Satler LF, et al. Treatment of in-stent restenosis with excimer laser coronary angioplasty: Mechanisms and results compared with PTCA alone. Circulation 1997;96:2183–2189. 28. Albiero R, Silber S, Di Mario C, et al. and the RESCUT Investigators. Cutting balloon versus conventional balloon angioplasty for the treatment of in-stent restenosis: Results of the restenosis cutting balloon evaluation trial (RESCUT). J Am Coll Cardiol 2004;43:943–949. 29. Suzuki T. Restenosis Reduction by Cutting Balloon Evaluation (REDUCE) II Trial. Transcatheter Cardiovascular Therapeutics, 2003. 30. Waksman R. Late thrombosis after radiation. Sitting on a time bomb. Circulation 1999;100:780–782. 31. Costa MA, Sabat M, van der Giessen WJ, et al. Late coronary occlusion after intracoronary brachytherapy. Circulation 1999;100:789–792. 32. Cheneau E, Wu Z, Leborgne L, et al. Additional stenting promotes intimal proliferation and compromises the results of intravascular radiation therapy: An intravascular ultrasound study. Am Heart J 2003;146:142–145. 33. Cha DH, Malik IA, Cheneau E, et al. Use of restenting should be minimized with intracoronary radiation therapy for in-stent restenosis. Catheter Cardiovasc Interv 2003;59:1–5. 34. Waksman R, Ajani AE, Pinnow E, et al. Twelve versus six months of clopidogrel to reduce major cardiac events in patients undergoing gamma-radiation therapy for in-stent restenosis: Washington Radiation for In-Stent restenosis Trial (WRIST) 12 versus WRIST PLUS. Circulation 2002;106:776–778. 35. Albiero R, Adamian M, Kobayashi N, et al. Short- and intermediate-term results of 32P radioactive beta-emitting stent implantation in patients with coronary artery disease: The MILAN dose-response study. Circulation 2000;101:18–26. 36. Sabate M, Costa MA, Kozuma K, et al. Geographic miss: a cause of treatment failure in radio oncology applied to intracoronary radiation therapy. Circulation 2000;101:2467–2471. 37. Kim H-S, Waksman R, Kollum M, et al. Edge stenosis after intracoronary radiotherapy: Angiographic, intravascular, and histological findings. Circulation 2001;103:2219–2220. 38. Sianos G, Kay IP, Costa MA, et al. Geographical miss during catheter-based intracoronary beta-radiation: Incidence and implications in the BRIE study. Beta-Radiation In Europe. J Am Coll Cardiol 2001;38:415–420. 39. Cheneaus E, Waksman R, Yazdi H, et al. How to fix the edge effect of catheter-based radiation therapy in stented arteries. Circulation 2002;106:2271–2277. 40. Degertekin M, Regar E, Tanabe K, et al. Sirolimus-eluting stent for treatment of complex in-stent restenosis. The first clinical experience. J Am Coll Cardiol 2003;41:184–189. 41. Sousa E, Costa M, Abizaid A, et al. Sirolimus-eluting stent for the treatment of in-stent restenosis: A quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2003;107:24–27.1. American Heart Association, Heart Disease and Stroke Statistics – 2003 Update. American Heart Association, Dallas, Texas, 2002. 2. Bauters C, Hubert E, Prat A, et al. Predictors of restenosis after coronary stent implantation. J Am Coll Cardiol 1998;31:1291–1298. 3. Park SW, Hong MK, Moon DH, et al. Treatment of diffuse in-stent restenosis with rotational atherectomy followed by radiation therapy with a rhenium-188-mercaptoacetyltriglycine-filled balloon. J Am Coll Cardiol 2001;38:631–637. 4. Sharma SK, Kini A, Mehran R, et al. Randomized trial of Rotational Atherectomy Versus Balloon Angioplasty for Diffuse In-stent Restenosis (ROSTER). Am Heart J 2004;147:16–22. 5. Barath P, Fishbein MC, Vari S, Forrester JS. Cutting balloon: A novel approach to percutaneous angioplasty. Am J Cardiol 1991;68:1249–1252. 6. Adamian M, Colombo A, Briguori C, et al. Cutting balloon angioplasty for the treatment of in-stent restenosis: A matched comparison with rotational atherectomy, additional stent implantation and balloon angioplasty. J Am Coll Cardiol 2001;38:672–679. 7. Muramatsu T, Tsukahara R, Ho M, et al. Efficacy of cutting balloon angioplasty for in-stent restenosis: An intravascular ultrasound evaluation. J Invasive Cardiol 2001;13:439–44. 8. Lansky AJ, Popma JJ, Massullo V, et al. Quantitative angiographic analysis of stent restenosis in the Scripps Coronary Radiation to Inhibit Intimal Proliferation Post Stenting (SCRIPPS) Trial. Am J Cardiol 1999;84:410–14. 9. Waksman R, White RL, Chan RC, et al. Intracoronary gamma radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165–2171. 10. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001;344:250–256. 11. Waksman R, Raizner AE, Yeung AC, et al. Use of localised intracoronary beta radiation in treatment of in-stent restenosis: The INHIBIT randomised controlled trial. Lancet 2002;359:551–557. 12. Popma JJ, Suntharalingam M, Lansky AJ, et al. STents And Radiation Therapy (START) Investigators. Randomized trial of 90Sr/90Y beta-radiation versus placebo control for treatment of in-stent restenosis. Circulation 2002;106:1090–1096. 13. Kim HS, Waksman R, Cottin Y, et al. Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis. J Am Coll Cardiol 2001;37:1026–1030. 14. Moustapha A, Salloum J, Saikia S, et al. Combined cutting balloon angioplasty and intracoronary beta radiation for treatment of in-stent restenosis: clinical outcomes and effect of pullback radiation for long lesions. Catheter Cardiovasc Interv 2002;57:325–329. 15. Morino Y, Kaneda H, Fox T, et al. Delivered dose and vascular response after beta-radiation for in-stent restenosis: Retrospective dosimetry and volumetric intravascular ultrasound analysis. Circulation 2002;106:2334–2339. 16. Waksman R, Bhargava B, Mintz GS, et al. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol 2000;36:65–68. 17. Waksman R, Ajani AE, White RL, et al. Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary gamma-radiation in patients with in-stent restenosis: Washington Radiation for In-Stent Restenosis Trial plus 6 months of clopidogrel (WRIST PLUS). Circulation 2001;103:2332–2335. 18. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. BENESTENT Study Group. N Engl J Med 1994;331:489–495. 19. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med 1994;331:496–501. 20. Versaci F, Gaspardone A, Tomai F, et al. A comparison of coronary-artery stenting with angioplasty for isolated stenosis of the proximal left anterior descending coronary artery. N Engl J Med 1997;336:817–822. 21. Eltchaninoff H, Koning R, Tron C, et al. Balloon angioplasty for the treatment of coronary in-stent restenosis: immediate results and 6-month angiographic recurrent restenosis rate. J Am Coll Cardiol 1998;32:980–984. 22. Bauters C, Banos JL, Van Belle E, et al. Six-month angiographic outcome after successful repeat percutaneous intervention for in-stent restenosis. Circulation. 1998;97:318–321. 23. Al-Sergani HS, Ho PC, Nesto RW, et al. Stenting for in-stent restenosis: A long-term clinical follow-up. Catheter Cardiovasc Interv 1999;48:143–148. 24. Sharma SK, Duvvuri S, Dangas G, et al. Rotational atherectomy for in-stent restenosis: acute and long-term results of the first 100 cases. J Am Coll Cardiol 1998;32:1358–1365. 25. Dietz U, Rupprecht HJ, de Belder MA, et al. Angiographic analysis of the angioplasty versus rotational atherectomy for the treatment of diffuse in-stent restenosis trial (ARTIST). Am J Cardiol 2002;90:843–847. 26. Strauss BH, Umans VA, van Suylen RJ, et al. Directional atherectomy for treatment of restenosis within coronary stents: Clinical, angiographic and histologic results. J Am Coll Cardiol 1992;20:1465–1473. 27. Mehran R, Mintz GS, Satler LF, et al. Treatment of in-stent restenosis with excimer laser coronary angioplasty: Mechanisms and results compared with PTCA alone. Circulation 1997;96:2183–2189. 28. Albiero R, Silber S, Di Mario C, et al. and the RESCUT Investigators. Cutting balloon versus conventional balloon angioplasty for the treatment of in-stent restenosis: Results of the restenosis cutting balloon evaluation trial (RESCUT). J Am Coll Cardiol 2004;43:943–949. 29. Suzuki T. Restenosis Reduction by Cutting Balloon Evaluation (REDUCE) II Trial. Transcatheter Cardiovascular Therapeutics, 2003. 30. Waksman R. Late thrombosis after radiation. Sitting on a time bomb. Circulation 1999;100:780–782. 31. Costa MA, Sabat M, van der Giessen WJ, et al. Late coronary occlusion after intracoronary brachytherapy. Circulation 1999;100:789–792. 32. Cheneau E, Wu Z, Leborgne L, et al. Additional stenting promotes intimal proliferation and compromises the results of intravascular radiation therapy: An intravascular ultrasound study. Am Heart J 2003;146:142–145. 33. Cha DH, Malik IA, Cheneau E, et al. Use of restenting should be minimized with intracoronary radiation therapy for in-stent restenosis. Catheter Cardiovasc Interv 2003;59:1–5. 34. Waksman R, Ajani AE, Pinnow E, et al. Twelve versus six months of clopidogrel to reduce major cardiac events in patients undergoing gamma-radiation therapy for in-stent restenosis: Washington Radiation for In-Stent restenosis Trial (WRIST) 12 versus WRIST PLUS. Circulation 2002;106:776–778. 35. Albiero R, Adamian M, Kobayashi N, et al. Short- and intermediate-term results of 32P radioactive beta-emitting stent implantation in patients with coronary artery disease: The MILAN dose-response study. Circulation 2000;101:18–26. 36. Sabate M, Costa MA, Kozuma K, et al. Geographic miss: a cause of treatment failure in radio oncology applied to intracoronary radiation therapy. Circulation 2000;101:2467–2471. 37. Kim H-S, Waksman R, Kollum M, et al. Edge stenosis after intracoronary radiotherapy: Angiographic, intravascular, and histological findings. Circulation 2001;103:2219–2220. 38. Sianos G, Kay IP, Costa MA, et al. Geographical miss during catheter-based intracoronary beta-radiation: Incidence and implications in the BRIE study. Beta-Radiation In Europe. J Am Coll Cardiol 2001;38:415–420. 39. Cheneaus E, Waksman R, Yazdi H, et al. How to fix the edge effect of catheter-based radiation therapy in stented arteries. Circulation 2002;106:2271–2277. 40. Degertekin M, Regar E, Tanabe K, et al. Sirolimus-eluting stent for treatment of complex in-stent restenosis. The first clinical experience. J Am Coll Cardiol 2003;41:184–189. 41. Sousa E, Costa M, Abizaid A, et al. Sirolimus-eluting stent for the treatment of in-stent restenosis: A quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2003;107:24–27.