Yttrium-90 Beta-Irradiation for the Treatment of In-Stent Coronary Restenosis

Three-Year Clinical Follow-Up After Strontium-90/Yttrium-90 Beta-Irradiation for the Treatment of In-Stent Coronary Restenosis Verena Baierl, MDa, Simone Baumgartner, MDa, Barbara Pöllinger, MDb, Marcus Leibig, MDa, Johannes Rieber, MDa, Andreas König, MDa, Florian Krötz, MDa, Hae-Young Sohn, MDa, Uwe Siebert, MDc, Wolfgang Haimerl, PhDb, Eckhart Dühmke, MDb, Karl Theisen, MDa, Volker Klauss, MDa, and Thomas M. Schiele, MDa,* Because late vessel failure has been speculated as a possible limitation of vascular brachytherapy, we conducted a prospective clinical evaluation at 6, 12, 24, and 36 months of follow-up after irradiation with strontium-90/yttrium-90 for in-stent restenosis, regardless of the patient’s symptomatic status. We report complete 3-year follow-up data for 106 consecutive patients. The cumulative rate of death at 6, 12, 24, and 36 months was 0.9%, 0.9%, 0.9%, and 1.9% respectively. The corresponding rates for acute ST-elevation myocardial infarction were 2.8%, 4.7%, 4.7%, and 4.7%, respectively. The cumulative rate of late thrombotic occlusion at 6, 12, 24, and 36 months was 3.8%, 4.7%, 4.7%, and 4.7%, respectively. The corresponding rates of target lesion revascularization and target vessel revascularization were 8.5% and 12.3% (p ⴝ 0.046), 14.2% (p ⴝ 0.157) and 18.0% (p ⴝ 0.046), 12.3% and 18.9% (p ⴝ 0.008), and 21.7% (p ⴝ 0.083) and 29.2% (p ⴝ 0.005), respectively. The cumulative rate of all major adverse cardiovascular events at 6, 12, 24, and 36 months was 16.1%, 24.5% (p ⴝ 0.003), 27.4% (p ⴝ 0.083), and 35.8% (p ⴝ 0.003), respectively. In conclusion, these results indicate a delayed and, even in the third year after the index procedure, continued restenotic process after ␤ irradiation of in-stent restenotic lesions. © 2005 Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96:1399 –1403)

Repeat restenosis limits percutaneous coronary intervention of in-stent restenosis (ISR). Its incidence averages 50% regardless of the therapeutic modality used.1– 4 Restenosis usually develops within 3 to 5 months after the index procedure. Restenosis after 6 months is very rarely observed.5,6 Vascular brachytherapy (VBT) has been proved to reduce the repeat ISR rate effectively in randomized controlled trials.7–11 However, the follow-up intervals have only been 6 or 9 months, which may be too short, because radiation could delay the vascular healing process. Systematic follow-up data for extended periods have been published only rarely.12–17 Most of these studies investigated either de novo stenosis or ISR or were limited by small sample sizes. A 2-year follow-up analysis of ␤-VBT for ISR with larger patient numbers covered partly incomplete clinical data of low-risk populations only and demonstrated conflicting data, with either

a Division of Cardiology, Department of Medicine, and bDepartment of Radiation Therapy and Radiation Oncology, Medizinische Klinik und Poliklinik, University Hospital Campus Innenstadt, Munich, Germany; and c Harvard Center for Risk Analysis, Harvard School of Public Health, Boston, Massachusetts. Manuscript received May 9, 2005; revised manuscript received and accepted June 28, 2005. *Corresponding author: Tel: 49-89-5160-2177; fax: 49-89-5160-2152. E-mail address: [email protected] (T.M. Schiele).

0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.06.087

an almost doubled target revascularization rate or an almost preserved medical efficacy. Longer follow-up periods after ␤-VBT have not been published to date. Thus, the objective of this prospective study was to delineate complete 3-year clinical follow-up, irrespective of clinical status, after ␤-VBT with strontium-90/yttrium-90 for ISR in 106 consecutive patients at 6, 12, 24, and 36 months. Methods Study design and population: The study population consisted of 106 consecutive patients who underwent successful percutaneous coronary intervention for ISR and VBT using strontium-90/yttrium-90 and for whom we had prospective 3-year clinical follow-up data at 6, 12, 24, and 36 months, regardless of their symptomatic status. All patients gave written informed consent. Patients were eligible for inclusion in the study if they had angina pectoris or objective signs of myocardial ischemia and ISR of a native coronary artery with a diameter stenosis of 50% to 100% by visual assessment. The exclusion criteria were acute myocardial infarction within 3 months before the index procedure, a contraindication to antiplatelet therapy, a left ventricular ejection fraction ⬍30%, unprotected left main disease, the presence of thrombus or an intraluminal filling www.AJConline.org

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defect, anticipated difficulty with the follow-up procedures, an expected life expectancy of ⬍5 years, pregnancy, childbearing potential, and previous chest irradiation. Angioplasty and brachytherapy procedure: After the baseline coronary angiogram, percutaneous coronary intervention, predominantly with a cutting balloon (Boston Scientific, Natick, Massachusetts) or a conventional balloon, was performed according to standard practice using the femoral approach. A satisfactory initial acute result was a prerequisite for subsequent VBT using a monorail-type 5Fr delivery catheter (Novoste, Norcross, Georgia) to deliver hydraulically a source train of strontium-90/yttrium-90 seeds with a length of either 40 or 60 mm. A manual stepping maneuver was performed in 19 patients. The dose, prescribed at 2 mm from the longitudinal axis of the source train, varied according to the angiographically determined reference diameter (2.7 to 3.35 mm: 18.4 Gy; 3.35 to 4.0 mm: 23.0 Gy; and ⬎4.0 mm: 25.3 Gy). All balloon inflations and radiation sources were recorded. Meticulous care was taken to cover the injured vessel segment entirely by the radiation source to prevent overt geographic miss. Acetylsalicylic acid 100 mg/day was given indefinitely and clopidogrel 75 mg/day was administered for 6 months in all cases. Coronary angiography: Coronary angiography was performed after intracoronary administration of 0.25 mg of nitroglycerin in 2 orthogonal projections using identical projection angles and table height throughout the whole procedure at baseline and at follow-up. Quantitative coronary angiography was performed offline in a blinded fashion using the validated Philips Digital Cardiac Imaging system (Philips, Eindhoven, The Netherlands). The minimum lumen diameter was determined by edge detection; the reference diameter was automatically calculated by the interpolated method. The minimum lumen diameter was defined as the mean of the smallest lumen diameter determined in the respective vessel segment analyzed. The mean reference diameter was obtained from averaging an apparently healthy coronary segment proximal and distal to the analysis segment. The percentage of diameter stenosis of each analyzed segment was calculated. Acute gain was defined as the minimum lumen diameter after completion of the index procedure minus the minimum lumen diameter before percutaneous coronary intervention. Definitions: Overt geographic miss was considered present when the injured vessel segment obviously and unavoidably had not been fully covered by irradiation. Angiographic geographic miss was present when it had been detectable only while performing off-line quantitative coronary angiography after the index procedure. Technical success was considered present when ⱖ90% of the planned radiation dose had been delivered and the final residual stenosis was ⬍30%. Acute myocardial infarction was defined as a creatine-kinase increase higher than twice the

Table 1 Clinical and angiographic baseline characteristics of study population (n ⫽ 106) Age (yrs) Men Body mass index Unstable angina pectoris Cardiovascular risk factors Family history of ischemic heart disease Hypercholesterolemia Mean cholesterol level (mg/dl) Statin in medication Diabetes mellitus Systemic arterial hypertension Smoking Renal insufficiency (serum creatinine ⬎1.2 mg/dl) Patients on hemodialysis Extent of coronary artery disease (lesions with diameter stenosis ⬎50%) 1 Vessel 2 Vessel 3 Vessel Left ventricular ejection fraction (%) No. of restenoses First Second Third Fourth Location of target lesion Left anterior descending coronary artery Left circumflex coronary artery Right coronary artery Lesion characteristics Ostial Total occlusion Reference lumen diameter ⬍2.5 mm Transplant vasculopathy Stent length ⬎10 mm Length of stent segment (mm) Length of injured segment (mm) Length of irradiated segment (mm) Length of analysis segment (mm)

64.0 ⫾ 10 87 (82%) 26.8 ⫾ 4 23 (22%) 59 (56%) 93 (88%) 181.4 ⫾ 37 99 (93%) 34 (32%) 92 (87%) 53 (50%) 45 (42%) 6 (6%)

35 (33%) 23 (22%) 48 (45%) 61.5 ⫾ 11 1.4 ⫾ 1 80 (75%) 13 (12%) 5 (5%) 6 (6%) 45 (42%) 18 (17%) 43 (41%) 13 (12%) 4 (4%) 15 (14%) 5 (5%) 100 (94%) 32.4 ⫾ 18 39.1 ⫾ 21 52.9 ⫾ 39 60.7 ⫾ 48

upper limit of normal and/or new Q waves on the electrocardiogram. Deaths were classified as cardiac or noncardiac. Deaths of undetermined cause were deemed to have been cardiac. A major adverse cardiac event (MACE) was considered to have occurred if any of the following were documented: death, myocardial infarction, and target vessel revascularization (TVR). Target lesion revascularization (TLR) was defined as coronary angioplasty or surgical bypass to treat symptomatic restenosis of the stented segment. TVR comprised all revascularization procedures of the entire vessel and thus included stenotic segments attributable to edge effect. Statistical analysis: Clinical and quantitative coronary angiographic data were collected in a computerized database (Filemaker Pro, version 5.0, FileMaker, Santa Clara, California). Statistical analysis was performed by a dedicated software package (Statistical Package for Social Sci-

Coronary Artery Disease/Three-Year Follow-Up After Beta-Irradiation Table 2 Characteristics of angioplasty and irradiation procedures (n ⫽ 106) Angioplasty device used Cutting balloon Conventional balloon High-speed rotational angioplasty Balloon diameter (mm) Balloon length (mm) Balloon artery ratio No. of balloon inflations Maximum inflation pressure (atm) Prescribed radiation dose (Gy) Pullback maneuver performed Fractionation necessary Overt geographic miss Angiographic geographic miss

84 (79%) 21 (20%) 1 (1%) 3.2 ⫾ 1 12.7 ⫾ 5 1.19 ⫾ 1.1 3.3 ⫾ 2 13.2 ⫾ 5 21.4 ⫾ 2 19 (18%) 2 (2%) 3 (3%) 7 (7%)

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animal experiments.18 –21 Clinically, regarding ␥-VBT, data from the randomized controlled Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting (SCRIPPS) trial revealed an 85.0% event-free survival rate at 6 months after VBT.7 However, it had decreased to 76.9% at 3 years of follow-up.12 At 5 years of follow-up, the event-free survival rate had decreased further to 61.5%.13 In the randomized controlled ␥ Washington Radiation for In-stent Restenosis (␥-WRIST), the 6-month event-free survival rate was 70.8%,8 but had decreased to 53.8% after 5 years.15 The documented loss of efficacy was in part a result of an almost doubled rate of TLR, indicating an ongoing restenotic process after VBT. This phenomenon could not be demon-

ences for Windows, version 10.0.7, SPSS, Chicago, Illinois). All variables are presented as the percentage of frequencies or as means ⫾ SDs. A p value ⬍0.05 was considered significant.

Results Baseline clinical and angiographic characteristics: The baseline clinical and angiographic characteristics of the study population are listed in Table 1. Patients revealed a high prevalence of cardiovascular risk factors, unstable angina pectoris, and renal insufficiency. The prevalence of multivessel disease and the lesion length were higher than average. Details of the angioplasty and brachytherapy procedure are listed in Table 2. Most of the ISRs were treated moderately aggressively with the cutting balloon; pull-back maneuvers were performed in 1/5 of cases. Geographic miss was rare. Clinical follow-up data were obtained for all patients. Table 3 lists the incidence of clinical events during the entire follow-up period. Only 2 patients died; 1 patient with significant co-morbidity died of terminal kidney failure, and 1 patient died of fatal gastrointestinal bleeding while the patient was on clopidogrel and acetylsalicylic acid. The occurrence of acute myocardial infarctions and late thrombotic occlusions was confined to the first year after the index procedure. The incidence of TLR, TVR, and total MACEs showed a statistically significant increase during the first year, a trend during the second year, and a repeated significant increase during the third year (Figure 1). The event-free survival rates for TLR, TVR, and total MACEs are depicted in Figure 2.

Discussion Because of its proven superiority over balloon angioplasty, VBT represents the gold standard for the treatment of ISR.7–11 However, despite an impressive relative risk reduction of 50% at 6 to 9 months after the index procedure, the durability of these results have been the subject of ongoing concern, due to theoretical considerations and findings from

Figure 1. Comparison of cumulative incidence of (A) TLR, (B) TVR, and (C) combined MACEs at 6, 12, 24, and 36 months after index procedure.

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Table 3 Clinical events at follow-up Event

6 mo Per Interval

Clinical follow-up Death Acute myocardial infarction Late total occlusion TLR TVR MACEs

Cumulative

106 (100%) 1 (0.9%) 1 (0.9%) 3 (2.8%) 3 (2.8%) 4 (3.8%) 4 (3.8%) 9 (8.5%) 9 (8.5%) 13 (12.3%) 13 (12.3%) 17 (16.1%) 17 (16.1%)

12 mo Per Interval

24 mo

Cumulative

105 (100%) 0 (0%) 1 (0.9%) 2 (1.9%) 5 (4.7%) 1 (0.9%) 5 (4.7%) 4 (3.8%) 13 (12.3%) 7 (6.6%) 20 (18.9%) 9 (8.5%) 26 (24.5%)

Figure 2. Kaplan-Meier curves for event-free survival from (A) TLR, (B) TVR, and combined (C) MACEs during the 3-year observation period.

Per Interval

Cumulative

105 (100%) 0 (0%) 1 (0.9%) 0 (0%) 5 (4.7%) 0 (0%) 5 (4.7%) 2 (1.9%) 15 (14.2%) 3 (2.8%) 23 (21.7%) 3 (2.8%) 29 (27.4%)

36 mo Per Interval

Cumulative

104 (100%) 1 (0.9%) 2 (1.9%) 0 (0%) 5 (4.7%) 0 (0%) 5 (4.7%) 4 (3.8%) 19 (18.0%) 8 (7.5%) 31 (29.2%) 9 (8.5%) 38 (35.8%)

strated in the respective placebo groups. For ␤-VBT, only scarce, yet conflicting, data exist. In the largest study on ␤-VBT for ISR, the randomized controlled Stents and Radiation Therapy (START) trial, the event-free survival rate was 71.3% after 8 months,11 with only a minimal reduction to 68.0% at 2 years.16 In contrast, the ␤-WRIST registry showed rate of freedom from MACEs of 66.0% after 6 months,10 with a pronounced loss of efficacy at 2 years of follow-up with freedom from MACEs in only 54%.14 As in the ␥-VBT trials, the increased incidence of MACEs predominantly was the result of additional revascularization procedures, especially of the target lesion and, to a minor extent, of the target vessel, as an indicator of the protractedly evolving restenosis process after ␤-VBT. Systematic prospective serial angiographic studies to delineate this phenomenon have only been rarely performed. A continuous, gradually declining late lumen loss could be documented during a 2-year follow-up period.17 No data exist for observation intervals of ⬎2 years. In our study, in absolute terms, we demonstrated event rates at 3 years of follow-up that were closely comparable with the START data at 2 years of follow-up. Although according to systematic angiographic analyses, an eventual conclusion of the restenotic process might have been conjectured as explanatory, our findings showed an ongoing increase of TLR, TVR, and MACE rates during the third year of follow-up. Several mechanisms may be involved to explain the observed findings. First, complete inhibition of restenosis would require eradication of proliferative properties or death of the entire cell population. However, it has been previously demonstrated that the radiation doses currently applied would not be sufficient to accomplish this. In a contemporary clinical setting, approximately 10% of irradiated clonogenic cells will survive and maintain their integrity and ability to divide and migrate.21 Complete inhibition of restenosis has not been shown in any of the clinical VBT trials.7–11 Second, it has been proposed that the proliferative properties and time kinetics of the surviving fraction of clonogenic smooth muscle cells might be comparable to those of nonirradiated cells. Consequently, restenosis after VBT would probably follow a qualitative pattern comparable to that of nonirriadiated tissue, yet taking its origin from a smaller number of proliferating cells. This would result in

Coronary Artery Disease/Three-Year Follow-Up After Beta-Irradiation

a regularly timed process of restenosis with a reduced absolute amount of neointimal hyperplasia.21 Some points limiting the findings of our study deserve attention. Because the population studied was prone to a high rate of restenosis and MACEs, the results of our study should not be generalized quantitatively. In particular, regarding the length of the vessel segment analyzed and the high prevalence of cardiovascular risk factors and co-morbidities, the cohort might not be representative. Most of the ISRs were treated with the cutting balloon, but conventional balloon angioplasty was also used frequently. Whether the angioplasty device used has specific consequences for the acute and late outcomes after VBT has not been prospectively investigated. Currently, it is believed that the use of the cutting balloon might improve the procedural result without having an influence on the effects of radiation itself.22 In our study, no significant differences could be demonstrated with the use of the cutting versus conventional balloons (data not shown). The radiation dose applied, depending on the angiographically determined reference diameter, was 18.4, 23.0, or 25.3 Gy. The dose prescriptions were made according to the recommendations of the manufacturer and have been derived from experimental and clinical data in an empiric fashion only. Thus, in light of the limited evidence regarding the actual target tissue and correct absolute dose, the radiation doses applied might have been suboptimal. The natural progression of the underlying coronary artery disease might have influenced the evolution of the angiographic restenosis rate and late loss. We did not systematically investigate this topic by analyzing the remaining coronary arteries. However, because the reference lumen diameter did not show any changes, the potential influence might have been negligible. 1. Bauters C, Banos JL, Van Belle E, McFadden EP, Lablanche JM, Bertrand ME. Six-month angiographic outcome after successful repeat percutaneous intervention for in-stent restenosis. Circulation 1998;97:318–321. 2. Mahdi NA, Pathan AZ, Harrell L, Leon MN, Lopez J, Butte A, Ferrell M, Gold HK, Palacios IF. Directional coronary atherectomy for the treatment of Palmaz-Schatz in-stent restenosis. Am J Cardiol 1998;82:1345–1351. 3. Mehran R, Dangas G, Mintz GS, Waksman R, Abizaid A, Satler LF, Pichard AD, Kent KM, Lansky AJ, Stone GW, Leon MB. Treatment of in-stent restenosis with excimer laser coronary angioplasty versus rotational atherectomy: comparative mechanisms and results. Circulation 2000;101:2484 –2489. 4. Dietz U, Rupprecht H, de Belder M, Wijns W, Quarles van Ufford MA, Klues HG, vom Dahl J. 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. 5. Serruys PW, Luijten HE, Beatt KJ, Geuskens R, de Feyter PJ, van den Brand M, Reiber JH, Ten Katen HJ, van Es GA, Hugenholtz PG. Incidence of restenosis after successful coronary angioplasty: a timerelated phenomenon. A quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months. Circulation 1988;77:361–371. 6. Nobuyoshi M, Kimura T, Nosaka H, Mioka S, Ueno K, Yokoi H, Hamasaki N, Horiuchi H, Ohishi H. Restenosis after successful percutaneous transluminal coronary angioplasty: serial angiographic follow-up of 229 patients. J Am Coll Cardiol 1988;12:616 – 623.

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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;336:1697–1703. 8. Waksman R, White RL, Chan RC, Bass BG, Geirlach L, Mintz GS, Satler LF, Mehran R, Serruys PW, Lansky AJ, et al. Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165–2171. 9. 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 Engl J Med 2001;344:250 –256. 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;101:1895–1898. 11. Popma JJ, Suntharalingam M, Lansky AJ, Heuser RR, Speiser B, Teirstein PS, Massullo V, Bass T, Henderson R, Silber S, et al, for the 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. 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. Circulation 2000;101:360 –365. 13. Grise MA, Massullo V, Jani S, Popma JJ, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Cloutier DA, Leon MB, Tripuraneni P, Teirstein PS. Five-year clinical follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation 2002;105:2737–2740. 14. Waksman R, Ajani AE, White RL, Pinnow E, Mehran R, Bui AB, Deible R, Gruberg L, Mintz GS, Satler LF, et al. Two-year follow-up after beta and gamma intracoronary radiation therapy for patients with diffuse in-stent restenosis. Am J Cardiol 2001;88:425– 428. 15. Waksman R, Ajani AE, White RL, Chan R, Bass B, Pichard AD, Satler LF, Kent KM, Torguson R, Deible R, Pinnow E, Lindsay J. Five-year follow-up after intracoronary gamma radiation therapy for in-stent restenosis. Circulation 2004;109:340 –344. 16. Silber S, Popma JJ, Sunthalaringam M, Lansky AJ, Heuser RR, Speiser B, Teirstein PS, Bass T, O’Neill W, Lasala J, et al, for the START Investigators. Two-year clinical follow-up of 90Sr/90Y betaradiation versus placebo control for the treatment of in-stent restenosis. Am Heart J 2005;149:689 – 694. 17. Schiele TM, Pollinger B, Kantlehner R, Rieber J, Konig A, Seelig V, Krotz F, Sohn HY, Siebert U, Duhmke E, Theisen K, Klauss V. Evolution of angiographic restenosis rate and late lumen loss after intracoronary beta radiation for in-stent restenotic lesions. Am J Cardiol 2004;93:836 – 842. 18. Waksman R, Robinson KA, Crocker IR, Wang C, Gravanis MB, Cipolla GD, Hillstead RA, King SB III. Intracoronary low-dose betairradiation inhibits neointima formation after coronary artery balloon injury in the swine restenosis model. Circulation 1995;92:3025–3031. 19. Carter AJ, Scott D, Bailey L, Hoopes T, Jones R, Virmani R. Doseresponse effects of 32P radioactive stents in an atherosclerotic porcine coronary model. Circulation 1999;100:1548 –1554. 20. Coussement PK, de Leon H, Ueno T, Salame MY, King SB III, Chronos NA, Robinson KA. Intracoronary beta-radiation exacerbates long-term neointima formation in balloon-injured pig coronary arteries. Circulation 2001;104:2459 –2464. 21. Wiedermann JG, Marboe C, Amols H, Schwartz A, Weinberger J. Intracoronary irradiation markedly reduces restenosis after balloon angioplasty in a porcine model. J Am Coll Cardiol 1994;23:1491–1498. 22. Bonan R. The role of brachytherapy and cutting balloon angioplasty in the current treatment of stent restenosis. Coron Artery Dis 2004;15:319 –325.