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Figure 1. Flow of Patients Through the Sirolimus-Eluting Stent for In-Stent Restenosis (SISR) Trial
Image description not available.
Figure 2. Minimal Lumen Diameter and Diameter Stenosis at Baseline and 6 Months
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A, The mean (SD) minimal lumen diameter in the analysis segment at 6-month follow-up was 1.52 (0.63) mm with vascular brachytherapy vs 1.80 (0.63) mm with the sirolimus-eluting stent (P<.001). B, The mean (SD) percentage of the diameter stenosis in the analysis segment at 6-month follow-up was 40.97% (21.08%) with vascular brachytherapy vs 32.35% (20.62%) with the sirolimus-eluting stent (P<.001).

Figure 3. Target Vessel Failure
Image description not available.

The rate of target vessel failure was 21.6% (27/125) with vascular brachytherapy and 12.4% (32/259) with the sirolimus-eluting stent (relative risk, 1.7; 95% confidence interval, 1.1-2.8; P = .02). P = .02 by the Wilcoxon test and P = .01 by the log-rank test. Error bars indicate ±1.5 times the SE.

Table 1. Baseline Clinical and Angiographic Characteristics*
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Table 2. Procedural Outcomes and Preprocedural Quantitative Coronary Angiographic Measurements
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Table 3. Quantitative Coronary Angiography at Baseline, Postprocedure, and 6-Month Follow-up
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Table 4. Patterns of Restenotic Lesions at 6-Month Follow-up
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Table 5. Major Clinical Events to 270 Days
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Table 6. Fitted Hierarchical Regression Model*
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1.
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.  N Engl J Med. 1994;331:489-495PubMedArticle
2.
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.  N Engl J Med. 1994;331:496-501PubMedArticle
3.
Serruys PW, van Hout B, Bonnier H.  et al.  Randomised comparison of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease (Benestent II).  Lancet. 1998;352:673-681PubMedArticle
4.
Moses JW, Leon MB, Popma JJ.  et al.  Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery.  N Engl J Med. 2003;349:1315PubMedArticle
5.
Morice MC, Serruys PW, Sousa JE.  et al.  A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization.  N Engl J Med. 2002;346:1773-1780PubMedArticle
6.
Stone GW, Ellis SG, Cox DA.  et al.  A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease.  N Engl J Med. 2004;350:221-231PubMedArticle
7.
Holmes DR Jr, Leon MB, Moses JW.  et al.  Analysis of 1-year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis.  Circulation. 2004;109:634-640PubMedArticle
8.
Babapulle MN, Joseph L, Belise P, Brophy JM, Eisenberg MJ. A hierarchical Bayesian meta-analysis of randomized clinical trials of drug eluting stents.  Lancet. 2004;364:583-591PubMedArticle
9.
Stone GW, Ellis SG, Cox DA.  et al.  One year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS IV trial.  Circulation. 2004;109:1942-1947PubMedArticle
10.
Windecker S, Remondino A, Eberli FR.  et al.  Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization.  N Engl J Med. 2005;353:653-662PubMedArticle
11.
Dibra A, Kastrati A, Mehilli J.  et al.  Paclitaxel-eluting or siroliumus-eluting stents to prevent restenosis in diabetic patients.  N Engl J Med. 2005;353:663-670PubMedArticle
12.
Kastrati A, Dibra A, Eberle S.  et al.  Sirolimus-eluting stents vs paclitaxel-eluting stents in patients with coronary artey disease: meta-analysis of randomized trials.  JAMA. 2005;294:819-825PubMedArticle
13.
Goy JJ, Stauffer JC, Siegenthaler M.  et al.  A prospective randomized comparison between paclitaxel and sirolimus stents in the real world of interventional cardiology.  J Am Coll Cardiol. 2005;45:308-311PubMedArticle
14.
Tanabe K, Serruys PW, Grube E.  et al.  TAXUS III trial: in-stent restenosis treated with stent-based delivery of paclitaxel incorporated in a slow-release polymer formulation.  Circulation. 2003;107:559-564PubMedArticle
15.
Sousa JE, Costa MA, Sousa AG.  et al.  Two-year angiographic and intravascular ultrasound follow-up after implantation of sirolimus-eluting stents in human coronary arteries.  Circulation. 2003;107:381-383PubMedArticle
16.
Regar E, Serruys PW, Bode C.  et al.  Angiographic findings of the multicenter randomized study with the sirolimus-eluting bx velocity balloon-expandable stent (RAVEL): sirolimus-eluting stents inhibit restenosis irrespective of the vessel size.  Circulation. 2002;106:1949-1956PubMedArticle
17.
Waksman R, Ajani AE, White RL.  et al.  Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts.  N Engl J Med. 2002;346:1194-1199PubMedArticle
18.
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;359:551-557PubMedArticle
19.
Waksman R, White RL, Chan RC.  et al.  Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis.  Circulation. 2000;101:2165-2171PubMedArticle
20.
Teirstein PS, Massullo V, Jani S.  et al.  Catheter-based radiotherapy to inhibit restenosis after coronary stenting.  N Engl J Med. 1997;336:1697-1703PubMedArticle
21.
Teirstein PS, Massullo V, Jani S.  et al.  Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial.  Circulation. 2000;101:360-365PubMedArticle
22.
Leon MB, Teirstein PS, Moses J.  et al.  Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting.  N Engl J Med. 2001;344:250-256PubMedArticle
23.
Popma JJ, Suntharalingam M, Lansky AJ.  et al.  Randomized trial of 90Sr/90Y beta-radiation versus placebo control for treatment of in-stent restenosis.  Circulation. 2002;106:1090-1096PubMedArticle
24.
Pocock SJ. The combination of randomized and historical controls in clinical trials.  J Chronic Dis. 1976;29:175-188PubMedArticle
25.
Smith SC, Dove JT, Jacobs AK.  et al.  ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines)—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [endorsed by the Society for Cardiac Angiography and Interventions].  Circulation. 2001;103:3019-3041PubMedArticle
26.
Mehran R, Dangas G, Abizaid AS.  et al.  Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome.  Circulation. 1999;100:1872-1878PubMedArticle
27.
Ahmed JM, Mintz GS, Weissman NJ.  et al.  Mechanism of lumen enlargement during intracoronary stent implantation: an intravascular ultrasound study.  Circulation. 2000;102:7-10PubMedArticle
28.
Farb A, Sangiorgi G, Carter AJ.  et al.  Pathology of acute and chronic coronary stenting in humans.  Circulation. 1999;99:44-52PubMedArticle
29.
Kasaoka S, Tobis JM, Akiyama T.  et al.  Angiographic and intravascular ultrasound predictors of in-stent restenosis.  J Am Coll Cardiol. 1998;32:1630-1635PubMedArticle
30.
Virmani R, Farb A. Pathology of in-stent restenosis.  Curr Opin Lipidol. 1999;10:499-504PubMedArticle
31.
Waksman R, Ajani AE, White RL.  et al.  Five-year follow-up after intracoronary gamma radiation therapy for in-stent restenosis.  Circulation. 2004;109:340-344PubMedArticle
32.
Grise MA, Massullo V, Jani S.  et al.  Five-year clinical follow-up after intracoronary radiation: results of a randomized clinical trial.  Circulation. 2002;105:2737-2740PubMedArticle
33.
Sousa JE, Costa MA, 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;107:24-27PubMedArticle
34.
Degertekin M, Regar E, Tanabe K.  et al.  Sirolimus-eluting stent for treatment of complex in-stent restenosis.  J Am Coll Cardiol. 2003;41:184-189PubMedArticle
35.
Commeau P, Barragan PT. ISR II study: a long-term evaluation of sirolimun-eluting stent in the treatment of patients with in-stent restenotic native coronary artery lesions.  Catheter Cardiovasc Interv. 2005;66:158-162PubMedArticle
36.
Neumann F-J, Desmet W, Grube E.  et al.  Effectiveness and safety of sirolimus-eluting stents in the treatment of restenosis after coronary stent placement.  Circulation. 2005;111:2107-2111PubMedArticle
37.
Radke PW, Kobella S, Kaiser A.  et al.  Treatment of in-stent restenosis using a paclitaxel-eluting stent: acute results and long-term follow-up of a matched-pair comparison with intracoronary β-radiation therapy.  Eur Heart J. 2004;25:920-925PubMedArticle
38.
Saia F, Lemos PA, Hoye A.  et al.  Clinical outcomes for sirolimus-eluting stent implantation and vascular brachytherapy for the treatment of in-stent restenosis.  Catheter Cardiovasc Interv. 2004;62:283-288PubMedArticle
39.
Kastrati A, Mehilli J, von Beckerath N.  et al.  Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial.  JAMA. 2005;293:165-171PubMedArticle
Original Contribution
March 15, 2006

Sirolimus-Eluting Stents vs Vascular Brachytherapy for In-Stent Restenosis Within Bare-Metal StentsThe SISR Randomized Trial

Author Affiliations
 

Author Affiliations: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn (Dr Holmes); Scripts Clinic, La Jolla, Calif (Dr Teirstein); Department of Cardiology, Washington Hospital Center, Washington, DC (Dr Satler); Department of Cardiology, Duke University Medical Center, Durham, NC (Dr Sketch); Department of Health Care Policy, Harvard Medical School, Boston, Mass (Dr O’Malley); Department of Cardiology, Brigham and Women's Hospital, Boston, Mass (Drs Popma and Kuntz); Department of Cardiology, Stanford University Medical Center, Stanford, Calif (Dr Fitzgerald); Cordis Corporation, Warren, NJ (Drs Wang and Cohen and Ms Caramanica); and Department of Cardiology, Hospital of the University of Pennsylvania, Philadelphia (Dr Cohen).

JAMA. 2006;295(11):1264-1273. doi:10.1001/jama.295.11.1264
Context

Context Although vascular brachytherapy is the only approved therapy for restenosis following bare-metal stent implantation, drug-eluting stents are now being used. Data on the relative merits of each are limited.

Objective To determine the safety and efficacy of the sirolimus-eluting stent compared with vascular brachytherapy for the treatment of patients with restenosis within a bare-metal stent.

Design, Setting, and Patients Prospective, multicenter, randomized trial of 384 patients with in-stent restenosis who were enrolled between February 2003 and July 2004 at 26 academic and community medical centers. Data presented represent all follow-up as of June 30, 2005.

Interventions Vascular brachytherapy (n = 125) or the sirolimus-eluting stent (n = 259).

Main Outcome Measure Target vessel failure (cardiac death, myocardial infarction, or target vessel revascularization) at 9 months postprocedure.

Results Baseline patient characteristics were well matched. Lesion length was similar between vascular brachytherapy and sirolimus-eluting stent patients (mean [SD], 16.76 [8.55] mm vs 17.22 [7.97] mm, respectively; P = .61). Procedural success was 99.2% (124/125) in the vascular brachytherapy group and 97.3% (250/257) in the sirolimus-eluting stent group (P = .28). The rate of target vessel failure was 21.6% (27/125) with vascular brachytherapy and 12.4% (32/259) with the sirolimus-eluting stent (relative risk [RR], 1.7; 95% confidence interval [CI], 1.1-2.8; P = .02). Target lesion revascularization was required in 19.2% (24/125) of the vascular brachytherapy group and 8.5% (22/259) of the sirolimus-eluting stent group (RR, 2.3 [95% CI, 1.3-3.9]; P = .004). At follow-up angiography, the rate of binary angiographic restenosis for the analysis segment was 29.5% (31/105) for the vascular brachytherapy group and 19.8% (45/227) for the sirolimus-eluting stent group (RR, 1.5 [95% CI, 1.0-2.2]; P = .07). Compared with the vascular brachytherapy group, minimal lumen diameter was larger in the sirolimus-eluting stent group at 6-month follow-up (mean [SD], 1.52 [0.63] mm vs 1.80 [0.63] mm; P<.001), reflecting greater net lumen gain in the analysis segment (0.68 [0.60] vs 1.0 [0.61] mm; P<.001) due to stenting and no edge restenosis.

Conclusion Sirolimus-eluting stents result in superior clinical and angiographic outcomes compared with vascular brachytherapy for the treatment of restenosis within a bare-metal stent.

Trial Registration ClinicalTrials.gov Identifier: NCT00231257

Trial Registration Published online March 12, 2006 (doi:10.1001/jama.295.11.1264).

Coronary stents revolutionized interventional cardiology by greatly improving both initial procedural success and longer-term outcomes, reducing clinical and angiographic restenosis rates by 30% to 50% compared with conventional balloon angioplasty.13 While the introduction of drug-eluting stents further decreased in-stent restenosis, the absolute magnitude of this reduction depends on specific angiographic and clinical characteristics416; however, use of the drug-eluting stent remains constrained in some regions because of high cost. Vascular brachytherapy is currently the only approved therapy for restenosis within a bare-metal stent based on its documented superiority to balloon angioplasty and other treatment modalities.1723 The purpose of this trial was to compare the use of vascular brachytherapy with implantation of the sirolimus-eluting stent for the treatment of restenosis occurring within a previously placed bare-metal stent.

METHODS
Study Design and Eligibility

This prospective, randomized, multicenter trial complied with the provisions of the Declaration of Helsinki and was approved by the Food and Drug Administration and all institutional review boards. All patients gave written informed consent. This study was designed to compare the safety and the effectiveness of vascular brachytherapy (either β or γ) with the sirolimus-eluting stent for the treatment of in-stent restenosis following bare-metal stent placement.

Eligible patients had a history of stable or unstable angina or documented silent myocardial ischemia. The target lesion was an in-stent restenotic coronary arterial lesion between 15 mm and 40 mm in length and between 2.5 mm and 3.5 mm in diameter by visual estimate. The vessel 1 cm distal to the target lesion was required to be at least 2.5 mm in diameter to allow use of commercially available brachytherapy devices.

Major exclusion criteria included myocardial infarction (MI) within the preceding 24 hours, ejection fraction of less than 40%, prior thoracic radiation or intravascular brachytherapy, total occlusions, unprotected left main coronary artery disease with greater than 50% stenosis, or treatment of a nontarget lesion occurring within 30 days before or planned after the index study procedure. Patients with a serum creatinine level of 2 mg/dL or greater (≥176.8 μmol/L) were excluded as were patients who had undergone initial stent placement in the target lesion less than 4 weeks prior to the index study procedure.

To promote enrollment, patients were randomized in a ratio of 1 to 2 to treatment with either vascular brachytherapy or the sirolimus-eluting stent. Randomization was accomplished at each site using an interactive voice randomization system (Interactive Clinical Technologies Inc, Yardley, Pa). The procedure “PROC PLAN” (SAS software version 6.2, SAS Institute Inc, Cary, NC) was used to generate the randomization list using a block size of 6.

Procedural Performance

Prior to and following the index procedure, all patients received 325 mg/d of oral aspirin and either clopidogrel (loading dose of 300-375 mg followed by 75 mg/d) or ticlopidine (loading dose of 500 mg followed by 250 mg twice daily). During the procedure, intravenous heparin was administered to maintain an activated clotting time of greater than 300 seconds for patients in the vascular brachytherapy group and greater than 250 seconds for patients in the sirolimus-eluting stent group. Glycoprotein IIb/IIIa inhibitors were administered at the discretion of the physician.

Vascular brachytherapy and sirolimus-eluting stent implantation were performed according to conventional techniques. Predilatation was required in the sirolimus-eluting stent group. “Geographic miss” was defined as a mismatch between the length of the vessel treated with predilatation and the length of the vessel receiving the indicated treatment. In the vascular brachytherapy group, geographic miss was minimized by covering the damaged arterial segment with the radioactive source train extending at least 5 mm beyond each margin of the region treated with balloon dilatation. Placement of a new stent in the vascular brachytherapy group was discouraged.

Geographic miss was minimized in the sirolimus-eluting stent group by selecting a stent that extended more than 3 mm beyond both ends of the region of balloon angioplasty, ensuring stent coverage from the angiographically normal vessel proximal to distal. While it was required that the restenotic segment be fully covered, it was not required that the entire region initially covered by the bare-metal stent be restented.

Data Collection Follow-up and Core Laboratory Analysis

Data were submitted to the data coordinating center (Harvard Clinical Research Institute, Harvard Medical School, Boston, Mass). Clinical end points were adjudicated by an independent clinical events committee blinded to study group assignment. A separate data and safety monitoring board not affiliated with either the study sponsor or the investigators reviewed data periodically throughout the trial to identify potential safety issues and monitor study conduct. The data presented herein represent all angiographic and clinical follow-up data available as of June 30, 2005.

Coronary angiography was performed at baseline, at the completion of the procedure, and at 6-month follow-up; angiograms were analyzed with a quantitative computer-based system (Medis, Leesburg, Va) at the angiographic core laboratory (Brigham and Women's Angiographic Core Laboratory, Boston, Mass). Minimal lumen diameter was defined as the mean minimal lumen diameter derived from 2 orthogonal views by quantitative coronary artery angiography. Late lumen loss was defined as the difference between the minimal lumen diameter at the completion of the procedure and that measured at 6-month follow-up. Net gain was defined as the difference between preprocedure minimal lumen diameter and that measured at 6-month follow-up. Binary angiographic restenosis was defined as greater than 50% narrowing of the lumen diameter in the target lesion. Quantitative angiographic assessment of the target lesion included measurements corresponding to the analysis segment (defined as all portions of the vessel that received treatment within the radiation or stent zones including the proximal and distal 5-mm margins) and the injury segment (defined as the region of vessel injured during treatment by balloon dilatation or stent placement). A subset of 100 patients was asked to undergo intravascular ultrasound assessment.

Study End Points

The primary end point of this study was target vessel failure defined as cardiac death, MI, or target vessel revascularization at 9 months postprocedure. Secondary angiographic end points included postprocedure in-stent and in-lesion minimal lumen diameter and percentage of diameter stenosis as well as 6-month in-stent and in-lesion binary restenosis and late loss by quantitative angiography. Secondary clinical end points included target lesion and target vessel revascularization at 6 and 9 months and the composite of major adverse cardiac event rates (defined as death, either Q-wave or non–Q-wave MI, emergent coronary artery bypass graft surgery, or repeat target lesion revascularization) at 30 days, at 6, 9, and 12 months, and at 2, 3, 4, and 5 years after the procedure. Non–Q-wave MI was defined as elevation of postprocedure creatine kinase levels to greater than 2 times the upper limit of normal with creatine kinase-MB fraction elevated above normal. Target lesion and target vessel revascularization procedures were required to be “clinically driven”7 as adjudicated by the clinical events committee. Measurements of stent lumen and stent volume obstruction were obtained with intravascular ultrasound. Economic data were obtained for cost-effectiveness analysis.

Statistical Analysis

This study was designed to demonstrate the noninferiority or superiority of the sirolimus-eluting stent (Cordis, Warren, NJ) compared with intracoronary vascular brachytherapy. Noninferiority was expected based on documented safety and efficacy with both approaches. Superiority was expected due to significant reduction in target vessel failure and improvement in analysis segment net gain and late lumen loss in previous studies with the sirolimus-eluting stent.

Bayesian statistical methods were used for trial design and to perform the formal analysis of the primary end point. Bayesian methods use a modeling approach that allows a reduction in the sample size of the vascular brachytherapy group (control group) by “borrowing” data from previous studies in which individual patient-specific data are available (the Cordis-sponsored GAMMA I22 and GAMMA II [D.R.H., unpublished data, 2006] studies). Angiographic follow-up at 6 months and clinical follow-up at 9 months were obtained in the current trial to match the time of follow-up in the GAMMA trials.

Because Bayesian methods do not provide initial sample size estimates, the original sample size calculation was based on standard statistical methods. Using methods based on Pocock,24 heterogeneity between the current and previous (historical) trials was accounted for in a revised power calculation that reflected the Bayesian analysis planned for these data. It was assumed that the analysis data set would contain 117 patients in the vascular brachytherapy group and 233 patients in the sirolimus-eluting stent group, and an additional 256 control patients from the historical trials. The assumed target vessel failure rates were 30.5% for the historical control groups and 15.3% for the sirolimus-eluting stent group. The assumed amount of variation in the target vessel failure rate for vascular brachytherapy across the trials ranged from 1.5% to 10.0%. The significance level for rejecting the null hypothesis was .05. In all scenarios, the trial had a power level greater than 80% for both noninferiority and superiority.

A Bayesian regression model was used to analyze target vessel failure at 270 days using the concurrent and historical data. The model accounted for unobserved heterogeneity between the trials by accounting for the clustering of observations within trials and controlled for the following observed variables: reference vessel diameter, lesion length, sex, history of diabetes, left anterior descending artery disease, and the number of diseased vessels. To test for noninferiority, the posterior probability that the target vessel failure rate for the sirolimus-eluting stent group was less than the sum of the target vessel failure rate for the vascular brachytherapy group was calculated; the “Δ” corresponded to 7.5% on the probability scale. To test for superiority, the posterior probability that the target vessel failure rate for the sirolimus-eluting stent group was less than the target vessel failure rate for the vascular brachytherapy group was computed. If the posterior probability exceeded 0.95 (required for significance at the .05 level), the null hypothesis was rejected in favor of the alternative (noninferiority or superiority).

The effectiveness analysis and safety evaluation were performed on the intent-to-treat study population. Unless otherwise specified, all frequentist (ie, non-Bayesian) statistical tests and/or 95% confidence intervals (CIs) were performed with a 2-sided α level of .05. Treatment group comparisons on continuous measures were performed using the 2-sample t test. The 95% CI of the mean difference between groups was calculated. Treatment group comparisons on categorical measures were performed using the Fisher exact test and excluded the “unknown” category. The 95% CIs of the difference in percentages are presented for each treatment group using the normal approximation to the binomial distribution. The relative risks (RRs) between the treatment groups and the 95% CIs of the risks were also calculated.

Computations for all frequentist results were performed using SAS version 8.2 (SAS Institute Inc). For Bayesian analysis, the BUGS (Bayesian Inference Using Gibbs Sampling) software was used: WinBUGS version 1.4.1 (MRC Biostatistical Unit, Cambridge, England).

RESULTS

From February 12, 2003, through July 27, 2004, 384 patients were enrolled and randomized to treatment with vascular brachytherapy (n = 125) or the sirolimus-eluting stent (n = 259) (Figure 1). Follow-up continued until June 30, 2005.

Clinical characteristics did not differ between the 2 groups except for chronic renal insufficiency, which was more prevalent in the sirolimus-eluting stent group (Table 1). Overall, mean (SD) age was 62.9 (11.1) years, 67.4% (258/383) were male, 47.1% (173/367) had a history of prior MI, and 48.3% (154/319) had unstable angina. Treated lesions were predominantly type B2 (33.5% [128/382]) or type C (41.4% [158/382]) using the modified lesion classification system of the American Heart Association and the American College of Cardiology25 and most often were located in the left anterior descending artery (46.9% [179/382]). Compared with the vascular brachytherapy group, total occlusion of the lesion was more common in the sirolimus-eluting stent group (1.6% [2/125] vs 6.7% [17/255]; P = .04).

Procedural outcomes were excellent (Table 2) with no significant differences in in-hospital complications between the groups. The mean (SD) radiation length in the vascular brachytherapy group was 39.7 (11.0) mm. Final mean (SD) stent length in the sirolimus-eluting stent group was 32.49 (12.3) mm while the total stent length to lesion length ratio was 1.9 (0.8).

Baseline dimensions including lesion length, minimal lumen diameter, diameter stenosis, and reference vessel diameter were similar between the 2 groups (Table 2). However, compared with the vascular brachytherapy group, the postprocedure analysis segment minimal lumen diameter (mean [SD], 1.87 [0.39] vs 2.06 [0.48] mm) and diameter stenosis (28.91% [10.44%] vs 23.53% [12.09%]) favored the sirolimus-eluting stent group (both P<.001) and resulted in a significant improvement in acute gain in vessel diameter (Table 3).

At follow-up angiography, despite no significant difference in late loss between the 2 groups, minimal lumen diameter, percentage of diameter stenosis, and net gain were significantly better in the sirolimus-eluting stent group (Table 3 and Figure 2). At the 6-month follow-up, the mean (SD) minimal lumen diameter in the analysis segment was 1.52 (0.63) mm in the vascular brachytherapy group and 1.80 (0.63) mm in the sirolimus-eluting stent group (P<.001) while the net gain was 0.68 (0.60) mm and 1.00 (0.61) mm, respectively (P<.001). For the injured segment, the net gain was 0.96 (0.68) mm in the vascular brachytherapy group and 1.29 (0.70) mm in the sirolimus-eluting stent group (P<.001). The binary angiographic restenosis rate was 29.5% (31/105) for the vascular brachytherapy group and 19.8% (45/227) for the sirolimus-eluting stent group (RR, 1.5; 95% CI, 1.0-2.2; P = .07).

Edge restenosis, defined as greater than 50% narrowing in the 5 mm immediately proximal or distal to the treated region, was apparent in the vascular brachytherapy group, with numerically greater late loss in the proximal edge and significantly greater late loss in the distal edge. This observation is supported by the distinct patterns of restenosis observed in both groups at follow-up (Table 4).26 Lesions treated with vascular brachy therapy demonstrate several morphological characteristics of restenosis predominantly involving the margins of the stent including type 1b (margin restenosis), type 1c (focal restenosis), type 2 (restenosis extending to the stent margin), and type 3 (diffuse restenosis extending outside of the stent margins), while the pattern of restenosis for lesions treated with the sirolimus-eluting stent were predominantly type 1c (21/45 [46.7%]).

Clinical Outcomes

There were 4 major in-hospital adverse clinical events in the sirolimus-eluting stent group (Table 5). Major adverse cardiac events in or out of the hospital were markedly different at 270 days (19.2% [24/125] for the vascular brachytherapy group vs 10.0% [26/259] for the sirolimus-eluting stent group; RR, 1.9; 95% CI, 1.1-3.2; P = .02). There were no deaths in the entire trial and only 6 patients had an MI; all 6 patients were in the sirolimus-eluting stent group and 4 occurred while the patients were in the hospital. Of the 4 in-hospital MIs, 1 was symptomatic and the other 3 were serum marker elevations only. Thus, the significant difference was predominantly due to a difference in the rate of target lesion revascularization (19.2% [24/125] in the vascular brachytherapy group vs 8.5% [22/259] in the sirolimus-eluting stent group; RR, 2.3; 95% CI, 1.3-3.9; P = .004). There also was a significant difference in the primary trial end point of target vessel failure (21.6% [27/125] in the vascular brachytherapy group vs 12.4% [32/259] in the sirolimus-eluting stent group; RR, 1.7; 95% CI, 1.1-2.8; P = .02) (Table 5 and Figure 3). Only 2 patients experienced stent thrombosis; both patients were in the sirolimus-eluting stent group and the thrombosis occurred after 30 days (P > .99).

Bayesian Analysis

Bayesian regression models were used to analyze the primary outcome (target vessel failure at 270 days). The primary analysis used data from the 3 trials (SISR, GAMMA I,22 and GAMMA II) but excluded minimal luminal diameter. The 95% CIs for the parameter estimates for the sirolimus-eluting stent group are below 0, indicating that the sirolimus-eluting stent has a target vessel failure rate that is significantly less than that of vascular brachytherapy (Table 6). The inclusion of minimal lumen diameter in the model has minimal effect on the results, suggesting that little of the effect was due to the mechanical properties of the stent. The posterior probabilities of both hypotheses (noninferiority and superiority) were both highly significant indicating that the sirolimus-eluting stent is superior to vascular brachytherapy.

To support the conclusion of superiority, a sensitivity analysis was performed. When only the data generated from patients treated in the Sirolimus-Eluting Stent for In-Stent Restenosis (SISR) trial were analyzed, the posterior probabilities were further from 1 but were still significant (at the .01 level for noninferiority and at the .05 level for superiority). Therefore, the results remain the same regardless of whether the historical control trials were used in the analysis.

Predictors of Treatment Effects

Predictors of target lesion revascularization to 270 days were assessed in the entire cohort using univariable and multivariable techniques. Nine factors were found to be significant on univariable analysis. However, only 3 of these remained significant with multiple logistic regression analysis: modified American Heart Association and the American College of Cardiology lesion classification score, diameter stenosis postprocedure within the injured segment, and specific treatment group.

COMMENT

The SISR trial enrolled patients with one of the most challenging conditions in interventional cardiology, namely, restenosis following previous implantation of a bare-metal stent. Placement of bare-metal stents is associated with improved acute gain in luminal diameter but neointimal hyperplasia produces in-stent restenosis in 30% to 50% of patients who may be recalcitrant to treatment.2730

Vascular brachytherapy is currently the only approved treatment for in-stent restenosis. β and γ radiation appear to achieve similar reductions in restenosis in comparable lesions.1723 The widespread application of vascular brachytherapy has been limited due to logistic challenges, radiation safety concerns, and evidence of both edge restenosis and late loss of efficacy (late restenosis) after 3 years.31,32 Because of the significant reduction in restenosis rates in de novo lesions with drug-eluting stents, there has been an interest in their application for the treatment of in-stent restenosis.

Initial nonrandomized studies of the use of the sirolimus-eluting stent and the paclitaxel-eluting stent for in-stent restenosis appeared favorable.3338 Both angiographic and clinical indices of restenosis compare well with historical controls, reporting 6-month to 12-month in-lesion late loss values of 0.08 to 0.36 mm and binary angiographic restenosis rates of 0% to 9.7% for sirolimus-eluting stents and 0.42 to 0.54 mm and 16% to 20% for paclitaxel-eluting stents.

Superiority of drug-eluting stents over balloon angioplasty was demonstrated in the ISAR-DESIRE (Intracoronary Stenting and Angiographic Results: Drug-eluting Stents for In-Stent Restenosis) study39 in which 300 patients were randomized to balloon angioplasty, the paclitaxel-eluting stent, or the sirolimus-eluting stent. Net gain at 6 months was 0.41 mm for patients randomized to balloon angioplasty, 1.02 mm for patients randomized to the paclitaxel-eluting stent, and 1.12 mm for patients randomized to the sirolimus-eluting stent; 6-month binary angiographic restenosis occurred in 44.6%, 21.7% (P = .001 vs balloon angioplasty), and 14.3% of patients (P<.001 vs balloon angioplasty), respectively. Target vessel revascularization was 33.0%, 19.0%, and 8.0% for the 3 groups, respectively, favoring the sirolimus-eluting stent vs both balloon angioplasty (P<.001) and the paclitaxel-eluting stent (P = .02).

The current trial demonstrates a marked reduction in target vessel failure with the sirolimus-eluting stent driven predominantly by a reduction in the rate of target vessel revascularization. We found similar results using both Bayesian and classic frequentist analytical approaches. Angiographic findings in the current investigation provide a clear mechanistic explanation for the superiority of the sirolimus-eluting stent: (1) acute gain was markedly improved by the use of a stent compared with balloon angioplasty; (2) late loss was similar in both the vascular brachytherapy group and the sirolimus-eluting stent group; and (3) margin restenosis or edge effect was observed on angiography in the vascular brachytherapy group.

No evidence of late catch-up in restenosis has been observed when the sirolimus-eluting stent is used to treat de novo lesions. Longer-term follow-up of patients in this trial is critical to document rates of late thrombosis and whether late catch-up of restenosis occurs as has been observed with long-term follow-up of vascular brachytherapy trials. While the trial was not formally powered for safety outcomes, the safety outcomes and the event rate trends are consistent with the findings in the other trials that studied the sirolimus-eluting stent.4,5,1013

Asymmetric randomization was used to promote enrollment in this study. During the course of the study, enrollment slowed due to a reduction in both the occurrence of in-stent restenosis and a decrease in the number of sites performing vascular brachytherapy. Trial participation bias cannot be controlled for but is thought unlikely due to the similarity of patient clinical and angiographic characteristics with other reported restenosis trials.3338

In conclusion, in-stent restenosis following bare-metal stent placement remains a significant clinical problem. While vascular brachytherapy remains the only approved therapy for this condition, the results of this study indicate that the sirolimus-eluting stent is superior to vascular brachytherapy at 9 months. Angiographic measurements indicate that while both methods are effective at suppressing neointimal hyperplasia, the sirolimus-eluting stent yields greater benefits from acute gain due to the stent component of the device and from the absence of edge restenosis. This study suggests that the sirolimus-eluting stent is a safe and effective treatment for in-stent restenosis occurring within bare-metal stents.

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Article Information

Corresponding Author: David R. Holmes, Jr, MD, Mayo Clinic, Division of Cardiovascular Diseases, 200 First St SW, Rochester, MN 55905 (holmes.david@mayo.edu).

Published Online: March 12, 2006 (doi:10.1001/jama.295.11.1264).

Author Contributions: Dr Holmes had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Holmes, Popma, Kuntz, Cohen.

Acquisition of data: Holmes, Teirstein, Satler, Sketch, Popma, Fitzgerald, Caramanica, Cohen.

Analysis and interpretation of data: Holmes, Sketch, O’Malley, Popma, Kuntz, Fitzgerald, Wang, Cohen.

Drafting of the manuscript: Holmes, O’Malley, Cohen.

Critical revision of the manuscript for important intellectual content: Teirstein, Satler, Sketch, O’Malley, Popma, Kuntz, Fitzgerald, Wang, Caramanica, Cohen.

Statistical analysis: Holmes, O’Malley, Kuntz, Fitzgerald, Wang.

Obtained funding: Cohen.

Administrative, technical, or material support: Holmes, Popma, Fitzgerald, Caramanica, Cohen.

Study supervision: Holmes, Satler, Sketch, Popma, Cohen.

Financial Disclosures: Dr Teirstein has received research grants and royalties from Johnson & Johnson. Dr Pompa has received research grants from the Cordis Corporation. Dr Kuntz is an employee of Medtronic Corporation, which was not involved in this study. None of the other authors reported disclosures.

Funding/Support: Funding for this study was provided by the Cordis Corporation (Warren, NJ), a Johnson & Johnson Company.

Role of the Sponsor: Dr Holmes, the Harvard Clinical Research Institute, Dr O’Malley, and the Cordis Corporation were responsible for the study design and the execution of the study. Dr Holmes, the Harvard Clinical Research Institute (supervised by Dr Kuntz), and the angiographic core laboratory (supervised by Dr Popma) were responsible for all of the statistical analyses.

Data and Safety Monitoring Board: Robert Bonow, MD (Northwestern University, Chicago, Ill); Michael Farkouh, MD (New York University School of Medicine, New York, NY); Bernard Gersh, MD (Mayo Clinic, Rochester, Minn); Gary Mintz, MD (Cardiovascular Research Foundation, Washington, DC); John Orav, MD (Brigham and Women's Hospital, Boston, Mass); Allan Schwartz, MD (Columbia Presbyterian Medical Center, New York, NY).

Clinical Events Committee: Julian Aroesty, MD (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass); Manish Chauhan, MD (Texas Cardiovascular Consultants, Austin, Tex); Laurence Epstein, MD (Brigham and Women's Hospital, Harvard Medical School, Boston, Mass); David Gossman, MD (Lahey Medical Center, Burlington, Mass); Joseph Kannam, MD (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass); Carey Kimmelstiel, MD (New England Medical Center, Boston, Mass); Warren Manning, MD, John Markis, MD, and Peter Oettgen, MD (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass); Sergio Waxman, MD (Lahey Medical Center, Burlington, Mass).

SISR Investigators: David R. Holmes, MD, principal investigator (Mayo Clinic, Rochester, Minn); Joseph Carrozza, MD (Beth Israel Deaconess Medical Center, Boston, Mass); Stephen Ellis, MD (Cleveland Clinic Foundation, Cleveland, Ohio); Sriram Iyer, MD (Lenox Hill Hospital Center, New York, NY); Paul Teirstein, MD (Scripps Institute, La Jolla, Calif); Emerson Perin, MD (Texas Heart Institute, Houston); Lowell Satler, MD (Washington Hospital Center, Washington, DC); Victor Corrigan, MD (St Joseph's Research Institute, Atlanta, Ga); Michael Sketch, MD (Duke University Medical Center, Durham, NC); Theodore Schreiber, MD (William Beaumont Hospital, Royal Oak, Mich); David Roberts, MD (Sutter Memorial General Hospital, Sacramento, Calif); David R. Holmes, MD (St Mary's Hospital, Rochester, Minn); Tim Fischell, MD (Borgess Medical Center, Kalamazoo, Mich); Todd Caulfield, MD (St Vincent's Hospital, Portland, Ore); Barry Rutherford, MD (St Luke's Hospital, Kansas City, Mo); Richard Shlofmitz, MD (St Francis Medical Center Hospital, Roslyn, NY); Thomas Eagan, MD (Baptist Hospital, Birmingham, Ala); Wesley Pederson, MD (Abbott Northwestern Hospital, Minneapolis, Minn); Louis McKeever, MD (Midwest Heart Research Foundation, Lombard, Ill); John Lasala, MD (Barnes Jewish Hospital, St Louis, Mo); Hooman Madyoon, MD (St Joseph's Medical Center, Stockton, Calif); Jay Midwall, MD (JFK Memorial Hospital, Atlantis, Fla); Richard Reisman, MD (Swedish Heart Hospital, Seattle, Wash); Michael Williamson, MD (Morton Plant Hospital, Clearwater, Fla); James Ritter, MD (Christiana Hospital, Newark, Del); Marc Unterman, MD (Atlanta Heart and Vascular Research Institute, Atlanta, Ga); Michel Joyal, MD (Montreal Heart, Montreal, Quebec).

Acknowledgment: We appreciate the editorial review of this article by Brian Firth, MD, PhD (employee of Cordis Corporation), who did not receive special compensation for his review.

REFERENCES
1.
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.  N Engl J Med. 1994;331:489-495PubMedArticle
2.
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.  N Engl J Med. 1994;331:496-501PubMedArticle
3.
Serruys PW, van Hout B, Bonnier H.  et al.  Randomised comparison of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease (Benestent II).  Lancet. 1998;352:673-681PubMedArticle
4.
Moses JW, Leon MB, Popma JJ.  et al.  Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery.  N Engl J Med. 2003;349:1315PubMedArticle
5.
Morice MC, Serruys PW, Sousa JE.  et al.  A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization.  N Engl J Med. 2002;346:1773-1780PubMedArticle
6.
Stone GW, Ellis SG, Cox DA.  et al.  A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease.  N Engl J Med. 2004;350:221-231PubMedArticle
7.
Holmes DR Jr, Leon MB, Moses JW.  et al.  Analysis of 1-year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis.  Circulation. 2004;109:634-640PubMedArticle
8.
Babapulle MN, Joseph L, Belise P, Brophy JM, Eisenberg MJ. A hierarchical Bayesian meta-analysis of randomized clinical trials of drug eluting stents.  Lancet. 2004;364:583-591PubMedArticle
9.
Stone GW, Ellis SG, Cox DA.  et al.  One year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS IV trial.  Circulation. 2004;109:1942-1947PubMedArticle
10.
Windecker S, Remondino A, Eberli FR.  et al.  Sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization.  N Engl J Med. 2005;353:653-662PubMedArticle
11.
Dibra A, Kastrati A, Mehilli J.  et al.  Paclitaxel-eluting or siroliumus-eluting stents to prevent restenosis in diabetic patients.  N Engl J Med. 2005;353:663-670PubMedArticle
12.
Kastrati A, Dibra A, Eberle S.  et al.  Sirolimus-eluting stents vs paclitaxel-eluting stents in patients with coronary artey disease: meta-analysis of randomized trials.  JAMA. 2005;294:819-825PubMedArticle
13.
Goy JJ, Stauffer JC, Siegenthaler M.  et al.  A prospective randomized comparison between paclitaxel and sirolimus stents in the real world of interventional cardiology.  J Am Coll Cardiol. 2005;45:308-311PubMedArticle
14.
Tanabe K, Serruys PW, Grube E.  et al.  TAXUS III trial: in-stent restenosis treated with stent-based delivery of paclitaxel incorporated in a slow-release polymer formulation.  Circulation. 2003;107:559-564PubMedArticle
15.
Sousa JE, Costa MA, Sousa AG.  et al.  Two-year angiographic and intravascular ultrasound follow-up after implantation of sirolimus-eluting stents in human coronary arteries.  Circulation. 2003;107:381-383PubMedArticle
16.
Regar E, Serruys PW, Bode C.  et al.  Angiographic findings of the multicenter randomized study with the sirolimus-eluting bx velocity balloon-expandable stent (RAVEL): sirolimus-eluting stents inhibit restenosis irrespective of the vessel size.  Circulation. 2002;106:1949-1956PubMedArticle
17.
Waksman R, Ajani AE, White RL.  et al.  Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts.  N Engl J Med. 2002;346:1194-1199PubMedArticle
18.
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;359:551-557PubMedArticle
19.
Waksman R, White RL, Chan RC.  et al.  Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis.  Circulation. 2000;101:2165-2171PubMedArticle
20.
Teirstein PS, Massullo V, Jani S.  et al.  Catheter-based radiotherapy to inhibit restenosis after coronary stenting.  N Engl J Med. 1997;336:1697-1703PubMedArticle
21.
Teirstein PS, Massullo V, Jani S.  et al.  Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial.  Circulation. 2000;101:360-365PubMedArticle
22.
Leon MB, Teirstein PS, Moses J.  et al.  Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting.  N Engl J Med. 2001;344:250-256PubMedArticle
23.
Popma JJ, Suntharalingam M, Lansky AJ.  et al.  Randomized trial of 90Sr/90Y beta-radiation versus placebo control for treatment of in-stent restenosis.  Circulation. 2002;106:1090-1096PubMedArticle
24.
Pocock SJ. The combination of randomized and historical controls in clinical trials.  J Chronic Dis. 1976;29:175-188PubMedArticle
25.
Smith SC, Dove JT, Jacobs AK.  et al.  ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines)—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [endorsed by the Society for Cardiac Angiography and Interventions].  Circulation. 2001;103:3019-3041PubMedArticle
26.
Mehran R, Dangas G, Abizaid AS.  et al.  Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome.  Circulation. 1999;100:1872-1878PubMedArticle
27.
Ahmed JM, Mintz GS, Weissman NJ.  et al.  Mechanism of lumen enlargement during intracoronary stent implantation: an intravascular ultrasound study.  Circulation. 2000;102:7-10PubMedArticle
28.
Farb A, Sangiorgi G, Carter AJ.  et al.  Pathology of acute and chronic coronary stenting in humans.  Circulation. 1999;99:44-52PubMedArticle
29.
Kasaoka S, Tobis JM, Akiyama T.  et al.  Angiographic and intravascular ultrasound predictors of in-stent restenosis.  J Am Coll Cardiol. 1998;32:1630-1635PubMedArticle
30.
Virmani R, Farb A. Pathology of in-stent restenosis.  Curr Opin Lipidol. 1999;10:499-504PubMedArticle
31.
Waksman R, Ajani AE, White RL.  et al.  Five-year follow-up after intracoronary gamma radiation therapy for in-stent restenosis.  Circulation. 2004;109:340-344PubMedArticle
32.
Grise MA, Massullo V, Jani S.  et al.  Five-year clinical follow-up after intracoronary radiation: results of a randomized clinical trial.  Circulation. 2002;105:2737-2740PubMedArticle
33.
Sousa JE, Costa MA, 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;107:24-27PubMedArticle
34.
Degertekin M, Regar E, Tanabe K.  et al.  Sirolimus-eluting stent for treatment of complex in-stent restenosis.  J Am Coll Cardiol. 2003;41:184-189PubMedArticle
35.
Commeau P, Barragan PT. ISR II study: a long-term evaluation of sirolimun-eluting stent in the treatment of patients with in-stent restenotic native coronary artery lesions.  Catheter Cardiovasc Interv. 2005;66:158-162PubMedArticle
36.
Neumann F-J, Desmet W, Grube E.  et al.  Effectiveness and safety of sirolimus-eluting stents in the treatment of restenosis after coronary stent placement.  Circulation. 2005;111:2107-2111PubMedArticle
37.
Radke PW, Kobella S, Kaiser A.  et al.  Treatment of in-stent restenosis using a paclitaxel-eluting stent: acute results and long-term follow-up of a matched-pair comparison with intracoronary β-radiation therapy.  Eur Heart J. 2004;25:920-925PubMedArticle
38.
Saia F, Lemos PA, Hoye A.  et al.  Clinical outcomes for sirolimus-eluting stent implantation and vascular brachytherapy for the treatment of in-stent restenosis.  Catheter Cardiovasc Interv. 2004;62:283-288PubMedArticle
39.
Kastrati A, Mehilli J, von Beckerath N.  et al.  Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial.  JAMA. 2005;293:165-171PubMedArticle
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