Sirolimus-Eluting Stents vs Vascular Brachytherapy for In-Stent Restenosis Within Bare-Metal Stents JAMA. 2006;295:

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1 ORIGINAL CONTRIBUTION JAMA-EXPRESS s vs Vascular for In- Restenosis Within Bare-Metal s The SISR Randomized Trial David R. Holmes, Jr, MD Paul Teirstein, MD Lowell Satler, MD Michael Sketch, MD James O Malley, PhD Jeffery J. Popma, MD Richard E. Kuntz, MD, MSc Peter J. Fitzgerald, MD, PhD Hong Wang, MD, MPH Eileen Caramanica, BA, MS Sidney A. Cohen, MD, PhD for the SISR Investigators 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. 1-3 While the introduction of drug-eluting stents further decreased in-stent restenosis, the absolute magnitude of this reduction depends on specific angiographic and clinical characteristics 4-16 ; 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 See also pp 1253 and 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, 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], [8.55] mm vs [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 sirolimuseluting 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], ; 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, ]; 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, ]; P=.07). Compared with the vascular brachytherapy group, minimal lumen diameter was larger in the sirolimuseluting 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: NCT JAMA. 2006;295: to balloon angioplasty and other treatment modalities The purpose of this trial was to compare the use of vascular brachytherapy with implanta- wwww.jama.com Author Affiliations and the SISR Investigators are listed at the end of this article. Corresponding Author: David R. Holmes, Jr, MD, Mayo Clinic, Division of Cardiovascular Diseases, 200 First St SW, Rochester, MN (holmes.david@mayo.edu) JAMA, March 15, 2006 Vol 295, No. 11 (Reprinted) 2006 American Medical Association. All rights reserved.

2 tion 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 or ) with the sirolimuseluting stent for the treatment of instent 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 ( 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 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, 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 American Medical Association. All rights reserved. (Reprinted) JAMA, March 15, 2006 Vol 295, No

3 Figure 1. Flow of Patients Through the for In- Restenosis (SISR) Trial 125 Assigned to Receive Vascular 121 Received Intervention as Assigned 4 Did Not Receive Intervention as Assigned 0 Lost to Follow-up 4 Withdrew Consent 2243 Patients Assessed for Eligibility 384 Randomized 1859 Excluded (Did Not Meet Inclusion/Met Exclusion Criteria) 259 Assigned to Receive 250 Received Intervention as Assigned 9 Did Not Receive Intervention as Assigned 0 Lost to Follow-up 4 Withdrew Consent 125 Included in Analysis 259 Included in Analysis 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 patientspecific data are available (the Cordissponsored GAMMA I 22 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 sirolimuseluting 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 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 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 1266 JAMA, March 15, 2006 Vol 295, No. 11 (Reprinted) 2006 American Medical Association. All rights reserved.

4 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 (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, Clinical characteristics did not differ between the 2 groups except for chronic renal insufficiency, which was more prevalent in the sirolimuseluting 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 Table 1. Baseline Clinical and Angiographic Characteristics* Vascular (n = 125) Cardiology 25 and most often were located in the left anterior descending artery (46.9% [179/382]). Compared with the vascular brachytherapy group, total (n = 259) P Value Age, mean (SD), y 63.5 (11.7) 62.7 (10.7).49 Male sex 82 (65.6) 176 (68.2).64 Medical history Hypertension 104 (83.2) 208 (80.6).59 Hyperlipidemia 111 (88.8) 235 (91.5).46 History of smoking 81 (66.4) 170 (66.9).99 Diabetes 37 (29.6) 86 (33.3).49 Prior myocardial infarction 62 (53.0) 111 (44.4).15 Prior CABG surgery 16 (12.8) 39 (15.1).64 Congestive heart failure 12 (9.7) 22 (8.6).71 Unstable angina 54 (50.9) 100 (46.9).55 Renal insufficiency 4 (3.2) 24 (9.3).04 History of allergies 52 (41.6) 113 (43.8).74 Ejection fraction, mean (SD), % 55.3 (8.5) 56.8 (9.0).13 Coronary arteries 50% stenosis Single 62 (49.6) 146 (56.6).23 Double 40 (32.0) 73 (28.3).48 Triple 23 (18.4) 39 (15.1).46 Target lesion location Left anterior descending artery 56 (44.8) 123 (47.9).59 Circumflex coronary artery 24 (19.2) 49 (19.1).99 Right coronary artery 45 (36.0) 85 (33.1).57 Lesion length, mean (SD), mm (8.55) (7.97).61 Total occlusion 2 (1.6) 17 (6.7).04 Bifurcation lesion 43 (34.7) 72 (28.2).23 use 25 (20.0) 250 (96.5) NA Abbreviations: CABG, coronary artery bypass graft; NA, statistical comparison not appropriate. *Values are expresed as number (percentage) unless otherwise indicated. Table 2. Procedural Outcomes and Preprocedural Quantitative Coronary Angiographic Measurements Vascular (n = 125) (n = 259) Difference (95% CI) P Value Lesion success, No. (%)* 124 (99.2) 254 (98.8) 0.4% ( 3.3% to 2.7%).99 Device success, No. (%) 121 (96.8) 249 (96.5) 0.3% ( 4.7% to 3.9%).99 Procedural success, No. (%) 124 (99.2) 250 (97.3) 1.9% ( 1.9% to 4.8%).28 Preprocedure diameter, mean (SD), mm Reference vessel 2.62 (0.43) 2.64 (0.44) 0.02 ( 0.11 to 0.07).66 Minimal lumen 0.86 (0.35) 0.78 (0.51) 0.07 ( to 0.15).06 Preprocedure diameter stenosis, mean (SD), % (11.82) (12.89) 2.90 ( 5.59 to 0.21).04 Lesion length, mean (SD), mm (8.55) (7.97) 0.46 ( 2.22 to 1.29).61 Radiation length, mean (SD), mm 39.7 (11.0) Final stent length, mean (SD), mm (7.58) (12.32) ( to 10.78) NA Lesion length ratio 1.9 (0.8) Abbreviations: CI, confidence interval; NA, statistical comparison not appropriate. *Defined as attainment of less than 50% residual stenosis by quantitative coronary angiography using any percutaneous method. Defined as achievement of a final residual stenosis of less than 50% by quantitative coronary angiography using the assigned device only. Defined as achievement of a final residual stenosis of less than 50% by quantitative coronary angiography without the occurrence of death, myocardial infarction, or repeat revascularization of the target lesion during the hospital stay. Based on all 125 brachytherapy patients. Based on the 25 brachytherapy patients who received a stent American Medical Association. All rights reserved. (Reprinted) JAMA, March 15, 2006 Vol 295, No

5 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 (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, ; 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- Table 3. Quantitative Coronary Angiography at Baseline, Postprocedure, and 6-Month Follow-up Vascular (n = 125) (n = 259) Difference (95% CI) P Value Minimal lumen diameter, mean (SD), mm Analysis segment* Preprocedure 0.86 (0.35) 0.78 (0.37) 0.07 ( to 0.15).06 Postprocedure 1.87 (0.39) 2.06 (0.48) 0.19 ( 0.29 to 0.10).001 Follow-up at 6 mo 1.52 (0.63) 1.80 (0.63) 0.27 ( 0.42 to 0.12).001 Injured segment Postprocedure 2.04 (0.44) 2.43 (0.40) 0.39 ( 0.48 to 0.30).001 Follow-up at 6 mo 1.80 (0.69) 2.08 (0.74) 0.28 ( 0.45 to 0.11).001 Diameter stenosis, mean (SD), % Analysis segment* Preprocedure (11.82) (12.89) 2.90 ( 5.59 to 0.21).04 Postprocedure (10.44) (12.09) 5.38 (2.89 to 7.88).001 Follow-up at 6 mo (21.08) (20.62) 8.63 (3.81 to 13.45).001 Injured segment Postprocedure (15.52) 9.24 (11.19) (10.16 to 15.67).001 Follow-up at 6 mo (24.23) (25.88) 8.60 (2.71 to 14.49).004 Acute gain, mean (SD), mm Analysis segment* 1.02 (0.40) 1.27 (0.48) 0.26 ( 0.36 to 0.16).001 Injured segment 1.18 (0.46) 1.64 (0.44) 0.45 ( 0.55 to 0.36).001 Net gain, mean (SD), mm Analysis segment* 0.68 (0.60) 1.00 (0.61) 0.32 ( 0.46 to 0.18).001 Injured segment 0.96 (0.68) 1.29 (0.70) 0.33 ( 0.49 to 0.17).001 Late loss, mean (SD), mm Analysis segment* 0.33 (0.54) 0.27 (0.55) 0.06 ( 0.06 to 0.19).33 Injured segment 0.23 (0.63) 0.33 (0.66) 0.11 ( 0.26 to 0.04).17 (n = 105) (n = 227) Binary angiographic restenosis, No. (%) Analysis segment* 31 (29.5) 45 (19.8) 9.7% ( 0.5% to 19.9%).07 Injured segment 18 (17.1) 41 (18.1) 0.9% ( 9.7% to 7.9%).88 Abbreviation: CI, confidence interval. *Defined as all portions of the vessel within the radiation or stent zones including the proximal and distal 5-mm margins. Defined as the region of vessel injured with balloon dilatation or stent placement JAMA, March 15, 2006 Vol 295, No. 11 (Reprinted) 2006 American Medical Association. All rights reserved.

6 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 sirolimuseluting stent were predominantly type 1c (21/45 [46.7%]). Clinical Outcomes There were 4 major in-hospital adverse clinical events in the sirolimuseluting 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, ; 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 inhospital 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 sirolimuseluting stent group; RR, 2.3; 95% CI, ; 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, ; 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 lu- Figure 2. Minimal Lumen Diameter and Diameter Stenosis at Baseline and 6 Months A B Cumulative Frequency, % Preintervention 6-mo Follow-up Postintervention Vascular Cumulative Frequency, % Postintervention 6-mo Follow-up Preintervention Minimal Lumen Diameter, mm Diameter Stenosis, % 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). Table 4. Patterns of Restenotic Lesions at 6-Month Follow-up Explanation of Restenosis Pattern* Vascular (n = 31) (n = 45) Difference (95% CI) P Value In-stent restenosis type, No. (%) 1a Articulation of gap between stents b Margin 9 (29.0) 7 (15.6) 13.5% ( 5.7% to 32.6%).25 1c Focal 6 (19.4) 21 (46.7) 27.3% ( 47.5% to 7.2%).02 1d Multifocal pattern within the stent 0 4 (8.9) 8.9% ( 17.2% to 0.6%) mm; Extending to the margins of the stent 8 (25.8) 6 (13.3) 12.5% ( 5.9% to 30.8%).23 3 Diffuse; extending outside of the stent margins 6 (19.4) 4 (8.9) 10.5% ( 5.7% to 26.7%).30 4 Total occlusion 2 (6.5) 3 (6.7) 0.2% ( 11.5% to 11.1%).99 (n = 29) (n = 43) In-stent restenosis length, mean (SD), mm (6.29) (6.52) 1.37 ( 1.71 to 4.45).38 *Based on Mehran et al American Medical Association. All rights reserved. (Reprinted) JAMA, March 15, 2006 Vol 295, No

7 Table 5. Major Clinical Events to 270 Days No. (%) of Patients Vascular (n = 125) (n = 259) In Hospital Difference (95% CI), % RR (95% CI) P Value Major adverse clinical event 0 4 (1.5) 1.5 ( 3.9 to 1.6).31 Death Myocardial infarction Q-wave Non Q-wave 0 4 (1.5) 1.5 ( 3.9 to 1.6).31 Emergent CABG surgery Target lesion revascularization Target lesion CABG surgery Target lesion PTCA Target vessel revascularization Target vessel failure 0 4 (1.5) 1.5 ( 3.9 to 1.6).31 Late stent thrombosis In and Out of Hospital to 270 d Major adverse clinical event 24 (19.2) 26 (10.0) 9.2 (1.8 to 17.5) 1.9 (1.1 to 3.2).02 Death Myocardial infarction Q-wave 0 1 (0.4).04 ( 2.2 to 2.6).99 Non Q-wave* 0 6 (2.3) 2.3 ( 5.0 to 0.9).18 Emergent CABG surgery Target lesion revascularization 24 (19.2) 22 (8.5) 10.7 (3.5 to 19.0) 2.3 (1.3 to 3.9).004 Target lesion CABG surgery 6 (4.8) 1 (0.4) 4.4 (1.3 to 9.7) 12.4 (1.5 to 102.2).006 Target lesion PTCA 20 (16.0) 21 (8.1) 7.9 (1.2 to 15.8) 2.0 (1.1 to 3.5).02 Target vessel revascularization 27 (21.6) 28 (10.8) 10.8 (3.1 to 19.4) 2.0 (1.2 to 3.2).008 Target vessel failure 27 (21.6) 32 (12.4) 9.2 (1.5 to 18.0) 1.7 (1.1 to 2.8).02 thrombosis Late stent thrombosis 0 2 (0.8) 0.8 ( 2.8 to 2.3).99 Abbreviations: CABG, coronary artery bypass graft; CI, confidence interval; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; RR, relative risk. *One of the MIs was a Q-wave MI. Could not calculate due to zero values. Figure 3. Target Vessel Failure Cumulative Incidence, % No. at Risk Vascular Time After Initial Procedure, d Vascular 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, ; P=.02). P=.02 by the Wilcoxon test and P=.01 by the log-rank test. Error bars indicate ±1.5 times the SE minal diameter. The 95% CIs for the parameter estimates for the sirolimuseluting 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 sirolimuseluting stent is superior to vascular brachytherapy. To support the conclusion of superiority, a sensitivity analysis was performed. When only the data generated 1270 JAMA, March 15, 2006 Vol 295, No. 11 (Reprinted) 2006 American Medical Association. All rights reserved.

8 from patients treated in the Sirolimus- Eluting for In- 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 instent restenosis in 30% to 50% of patients who may be recalcitrant to treatment Vascular brachytherapy is currently the only approved treatment for instent restenosis. and radiation appear to achieve similar reductions in restenosis in comparable lesions 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 instent restenosis. Table 6. Fitted Hierarchical Regression Model* Term Posterior Mean (SD) Median (95% CI) Trial indicators SISR 1.54 (0.21) 1.50 ( 2.09 to 1.24) GAMMA I 1.27 (0.31) 1.34 ( 1.68 to 0.45) GAMMA II 1.29 (0.30) 1.36 ( 1.71 to 0.47) Level 2 mean parameter 1.37 (0.51) 1.40 ( 1.95 to 0.51) Level 2 variance parameter 0.71 (7.36) 0.02 (0.001 to 3.72) Fixed effects 0.91 (0.31) 0.92 ( 1.51 to 0.30) Reference vessel diameter 0.29 (0.23) 0.29 ( 0.74 to 0.16) Lesion length 0.02 (0.01) 0.02 (0.002 to 0.05) Male sex 0.02 (0.23) 0.02 ( 0.43 to 0.47) Diabetes mellitus 0.07 (0.23) 0.07 ( 0.51 to 0.36) Left anterior descending artery diseased 0.35 (0.21) 0.35 ( 0.07 to 0.76) 2 Diseased vessels 0.26 (0.24) 0.26 ( 0.21 to 0.72) 3 Diseased vessels 0.01 (0.31) ( 0.63 to 0.59) Abbreviation: SISR, for In- Restenosis. *Model excludes minimal lumen diameter. Initial nonrandomized studies of the use of the sirolimus-eluting stent and the paclitaxel-eluting stent for in-stent restenosis appeared favorable 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 ing and Angiographic Results: Drug-eluting s for In- Restenosis) study 39 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 sirolimuseluting 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 paclitaxeleluting 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 sirolimuseluting 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 2006 American Medical Association. All rights reserved. (Reprinted) JAMA, March 15, 2006 Vol 295, No

9 event rate trends are consistent with the findings in the other trials that studied the sirolimus-eluting stent. 4,5,10-13 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 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 sirolimuseluting stent is a safe and effective treatment for in-stent restenosis occurring within bare-metal stents. Published Online: March 12, 2006 (doi: / jama ). 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). 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). 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