Interventional Cardiology

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1 Interventional Cardiology Short- and Long-Term Outcomes With Drug-Eluting and Bare-Metal Coronary Stents A Mixed-Treatment Comparison Analysis of Patient-Years of Follow-Up From Randomized Trials Sripal Bangalore, MD, MHA; Sunil Kumar, MD; Mario Fusaro, MD; Nicholas Amoroso, MD; Michael J. Attubato, MD; Frederick Feit, MD; Deepak L. Bhatt, MD, MPH; James Slater, MD Downloaded from by guest on June 28, 2018 Background Drug-eluting stents (DES) have been in clinical use for nearly a decade; however, the relative short- and long-term efficacy and safety of DES compared with bare-metal stents (BMS) and among the DES types are less well defined. Methods and Results PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials, until March 2012, that compared any of the Food and Drug Administration approved durable stent and polymer DES (sirolimus-eluting stent [SES], paclitaxel-eluting stent [PES], everolimus-eluting stent [EES], zotarolimus-eluting stent [ZES], and ZES-Resolute [ZES-R]) with each other or against BMS for de novo coronary lesions, enrolling at least 100 patients and with follow-up of at least 6 months. Short-term ( 1 year) and long-term efficacy (target-vessel revascularization, target-lesion revascularization) and safety (death, myocardial infarction, stent thrombosis) outcomes were evaluated and trial-level data pooled by both mixed-treatment comparison and direct comparison analyses. From 76 randomized clinical trials with patient-years of follow-up, compared with BMS, each DES reduced long-term target-vessel revascularization (39% 61%), but the magnitude varied by DES type (EES SES ZES-R PES ZES BMS), with a 42% probability that EES had the lowest target-vessel revascularization rate. There was no increase in the risk of any long-term safety outcomes, including stent thrombosis, with any DES (versus BMS). In addition, there was reduction in myocardial infarction (all DES except PES versus BMS) and stent thrombosis (with EES versus BMS: Rate ratio, 0.51; 95% credibility interval, ). The safest DES appeared to be EES ( 86% probability), with reduction in myocardial infarction and stent thrombosis compared with BMS. Short-term outcomes were similar to long-term outcomes, with SES, ZES-R, and everolimus-eluting stent being the most efficacious and EES being the safest stent. Conclusions DES are highly efficacious at reducing the risk of target-vessel revascularization without an increase in any safety outcomes, including stent thrombosis. However, among the DES types, there were considerable differences, such that EES, SES, and ZES-R were the most efficacious and EES was the safest stent. (Circulation. 2012;125: ) Key Words: drug-eluting stents paclitaxel pannus formation sirolimus everolimus zotarolimus stents Drug-eluting stents (DES) are widely used for percutaneous coronary intervention in patients with coronary artery disease. These stents have the advantage of reducing the incidence of in-stent restenosis compared with bare-metal stents (BMS). However, DES are more expensive than BMS, and first-generation DES have been associated with an increased risk of late stent thrombosis when antiplatelet agents are withheld, and in some studies, very late stent thrombosis. 1,2 Since the introduction of sirolimus-eluting stents (SES), followed by paclitaxel-eluting stents (PES), there has been considerable debate on the long-term efficacy 3 and safety 2 of these stents. Newer DES have been developed that have claimed to be safer 4,5 and/or more efficacious 6,7 ; however, for safety outcomes, BMS is still considered the benchmark. Clinical Perspective on p 2891 The relative efficacy and safety of the currently Food and Drug Administration (FDA) approved DES (SES, PES, Received February 1, 2012; accepted April 30, From the New York University School of Medicine, New York, NY (S.B., M.F., N.A., M.J.A., F.F., J.S.); University of Nebraska, Omaha, NE (S.K.); and VA Boston Healthcare System, Brigham and Women s Hospital & Harvard Medical School, Boston, MA (D.L.B.). Guest Editor for this article was Alice K. Jacobs, MD. The online-only Data Supplement is available with this article at /-/DC1. Correspondence to Sripal Bangalore, MD, MHA, FACC, FSCAI, Director of Research, Cardiac Catheterization Laboratory, Director, Cardiovascular Outcomes Group, Assistant Professor of Medicine, New York University School of Medicine, The Leon H. Charney Division of Cardiology, New York, NY sripalbangalore@gmail.com 2012 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 2874 Circulation June 12, 2012 Downloaded from by guest on June 28, 2018 Figure 1. Study selection. RCT indicates randomized clinical trial; CABG, coronary artery bypass grafting. everolimus [EES], zotarolimus [ZES], and ZES-Resolute [ZES-R]) compared with BMS and against each other are not well defined. Recent studies and analyses have tended to compare one DES against a comparator encompassing all other DES, which makes a hierarchical comparison of the relative efficacy and safety of each of the DES problematic. Whether any one DES is measurably different in its efficacy and safety is a topic of great interest to physicians and patients. Although each of the DES has had claims of superior efficacy or safety, direct comparisons have been limited. The objective of the present analysis was to evaluate the relative efficacy and safety of the currently available DES versus BMS and against each other for both short- and long-term outcomes using mixed-treatment comparison (MTC) analyses. Methods Eligibility Criteria We conducted PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) searches for randomized clinical trials using the terms, drug-eluting stent and bare metal stent and using the names of individual drug-eluting stents (SES, PES, EES, ZES, and ZES-R) until March 2012 (Week 2). The MeSH terms are listed in online-only Data Supplement Table I. We checked the reference lists of review articles, meta-analyses, and original studies identified by the electronic searches to find other eligible trials. There was no language restriction for the search. In addition, we searched conference proceedings/abstracts of the following societies: American Heart Association, American College of Cardiology, Transcatheter Cardiovascular Therapeutics, Society of Cardiovascular Angiography and Intervention, European Society of Cardiology, and Euro-PCR. For studies that did not report outcomes of interest, we contacted the authors via . Additionally, we searched the FDA dockets, searching all documents submitted for device approval by hand, as well as the FDA meeting minutes, which are available on the FDA s Web site. Eligible trials had to fulfill the following criteria: (1) Randomized clinical trials comparing the above durable polymer and stent DES with BMS or against each other, in patients undergoing percutaneous coronary intervention of a de novo coronary lesion; (2) follow-up of at least 6 months; (3) enrollment of at least 100 patients; and (4) ability to report the outcomes of interest (below). Trials that used DES with an eluting drug other than those compared (as listed in the Methods), balloon angioplasty alone, or comparison with

3 Bangalore et al DES and Outcomes 2875 Figure 2. Network of stent type comparisons. The links between the stent types are trials representing either direct comparison (solid lines) or indirect comparison (dotted lines). The numbers along the links represent the number of trial arms that provided direct comparisons between the stent types. Downloaded from by guest on June 28, 2018 coronary artery bypass graft surgery were excluded. In addition, we excluded trials that tested 2 stents that eluted the same drug but differed in stent designs (PERSEUS [Prospective Evaluation in a Randomized Trial of the Safety and Efficacy of the Use of the TAXUS Element Paclitaxel-Eluting Coronary Stent System], 8 PIPA [Comparison of Paclitaxel-Eluting Coroflex Please Stent Versus Paclitaxel-Eluting Stent], 9 and the PLATINUM Clinical Trial to Assess the PROMUS Element Stent System for Treatment of De Novo Coronary Artery Lesions 10 ) because these trials did not provide head-to-head comparisons of 2 different DES or DES versus BMS. 11,12 Selection and Quality Assessment Four authors (S.B., S.K., M.F., and N.A.) independently assessed trial eligibility and trial bias risk and extracted data. Disagreements were resolved by consensus. The bias risk of trials were assessed with the components recommended by the Cochrane Collaboration 13 : Sequence generation of the allocation; allocation concealment; blinding of participants, personnel, and outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias. Trials with high or unclear risk for bias for any 1 of the first 3 components were considered trials with high risk of bias. Otherwise, they were considered trials with low risk of bias. Data Extraction and Synthesis Short ( 1 year) and long-term ( 1 year) efficacy and safety outcomes were evaluated. Efficacy outcomes were target-vessel revascularization (TVR) and target-lesion revascularization (TLR). Safety outcomes were death, myocardial infarction (MI), and stent thrombosis. Three types of stent thrombosis were evaluated: Any stent thrombosis (based on trial stent thrombosis definition), Academic Research Consortium (ARC) defined definite or probable stent thrombosis, and ARC-defined definite stent thrombosis. For short-term outcomes, the outcomes closest to 1 year were abstracted. For long-term outcomes, the longest reported follow-up events, including short-term outcomes, were abstracted. Statistical Analyses Mixed-Treatment Comparisons Bayesian hierarchical random effects models 14 for MTC meta-analysis were used to compare the different stent types. 15 This was performed with WinBUGS code validated by the UK Medical Research Council Health Services Research Collaboration. 16 The MTC allows for comparisons of agents not directly addressed within any of the individual trials. In addition to analyzing the direct within-trial comparisons between 2 stents (such as stent A versus B), the MTC framework enabled us to incorporate the indirect comparisons constructed from 2 trials that had 1 stent type in common (such as comparison of stent A versus C using trials comparing A versus B and B versus C). This type of analysis has the advantage of maintaining the within-trial randomized treatment comparison of each trial while combining all available comparisons between treatments. The MTC analysis produces tighter credibility intervals (CrI, analogous to the confidence interval of frequentist methodology), which implies greater precision of the estimates than the direct comparison analysis. 17 For the purpose of analysis, the 6 stent types were defined: BMS, SES, PES, EES, ZES, and ZES-R. The primary analysis compared each individual DES to BMS, which was used as reference. For the short-term outcome analyses, outcomes at or within 1 year were evaluated. For the long-term analysis, given the variability in the length of follow-up for each of these trials, the analysis used the rate of efficacy and safety outcomes per 1000 person-years to obtain the log rate ratios of 1 stent relative to another. For long-term outcomes, a random-effects Poisson regression model was fitted, taking into account the correlation structure induced by the multiarm trials. 18 A randomeffects rather than a fixed-effect model was used because this was likely the most appropriate and conservative analysis to account for differences between trials. Rates, rather than number of events, were consid-

4 2876 Circulation June 12, 2012 Table 1. Baseline Characteristics of Included Trials Downloaded from by guest on June 28, 2018 Trial Year Total Sample Size, n Stent Comparisons Follow-Up, mo Mean Age, y Men, % BASKET SES/PES/BMS BASKET-PROVE* EES/BMS/SES COMPARE 30, / EES/PES CORPAL SES/PES C-SIRIUS SES/BMS CREST MI SES/ZES DEBATER SES/BMS DES-Diabetes* 36, / SES/PES DESSERT SES/BMS DiabeDES SES/PES DIABETES 40, / SES/BMS Diaz de la Llera et al SES/BMS Endeavor II 43, / ZES/BMS Endeavor III 4, / ZES/SES Endeavor IV 5, / ZES/PES Erglis et al PES/BMS E-SIRIUS SES/BMS ESSENCE-DIABETES EES/SES EXAMINATION EES/BMS EXCELLENT EES/SES Gao et al SES/BMS GISSOC II-GISE SES/BMS HAAMU-STENT PES/BMS Han et al SES/PES 19.5 NA NA Herdeg et al PES/BMS Hong et al SES/PES Horizons-AMI 57a,57b 2009/ PES/BMS ISAR-Diabetes SES/PES ISAR-Left-Main SES/PES ISAR-SMART III SES/PES ISAR-Test-2 27, / ZES/SES Juwana et al SES/PES Kamoi et al SES/PES Kim et al SES/PES KOMER 64a ZES/SES/PES Long-DES II SES/PES Long-DES III SES/EES MISSION 67, / SES/BMS MULTISTRATEGY 69, / SES/BMS NAPLES-Diabetes SES/ZES/PES Ortolani et al SES/BMS Pache et al SES/BMS Pan et al SES/PES PASEO 75, PES/BMS/SES PASSION 77, / PES/BMS Petronio et al SES/PES PRISON II 80, / SES/BMS PROSIT 82, / SES/PES RAVEL 84, / SES/BMS REALITY SES/PES RESET EES/SES (Continued)

5 Bangalore et al DES and Outcomes 2877 Table 1. Continued Downloaded from by guest on June 28, 2018 Trial Year Total Sample Size, n Stent Comparisons Follow-Up, mo Mean Age, y Men, % RESOLUTE All Comers 11, / ZES-R/EES SCANDSTENT 88, / SES/BMS SCORPIUS SES/BMS SEA-SIDE SES/EES SESAMI 92, / SES/BMS SES-SMART 94, / SES/BMS SIRIUS 96, / SES/BMS SIRTAX 98, / SES/PES SORT OUT II SES/PES SORT OUT III ZES/SES SORT OUT IV EES/SES Spirit II 103, / EES/PES Spirit III 6, / EES/PES Spirit IV 7, / EES/PES STRATEGY 107, / SES/BMS TAXI-LATE 109, / SES/PES TAXUS II 111, / PES/BMS TAXUS IV 113, / PES/BMS TAXUS V PES/BMS TAXUS VI 116, / PES/BMS TWENTE ZES-R/EES TYPHOON 119, / SES/BMS ZEST ZES/SES/PES Zest-AMI* ZES/SES/PES Zhang et al SES/PES BASKET indicates Basel Stent Kosten Effektivitäts Trial; SES, sirolimus-eluting stent; PES, paclitaxel-eluting stent; BMS, bare-metal stent; BASKET-PROVE, Basel Stent Kosten-Effektivitäts Trial Prospective Validation Examination; EES, everolimus-eluting stent; COMPARE, Comparison of the Everolimus Eluting XIENCE-V Stent With the Paclitaxel Eluting TAXUS LIBERTÉ Stent in All-Comers; C-SIRIUS, Canadian Study of the Sirolimus-Eluting Stent in the Treatment of Patients With Long De Novo Lesions in Small Native Coronary Arteries; CREST MI, Carotid Revascularization Endarterectomy Versus Stenting Trial Myocardial Infarction; ZES, zotarolimus-eluting stent; DEBATER, A Comparison of Drug Eluting Stents and Bare Metal Stents With or Without Abciximab in ST-Segment Elevation Myocardial Infarction, The Eindhoven Reperfusion Study; DES-Diabetes, Drug-Eluting Stent in Patients With Diabetes Mellitus; DESSERT, Diabetes Drug Eluting Sirolimus Stent Experience in Restenosis Trial; DiabeDES, The Diabetes and Drug-Eluting Stent (DiabeDES) Randomized Angiography Trial; DIABETES, DIABETes and sirolimus Eluting Stent; Endeavor, A Randomized Controlled Trial of the Medtronic Endeavor Drug ABT-578 Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions; E-SIRIUS, European multicenter, randomized, double-blind study of the SIRolImUS-coated Bx Velocity balloon expandable stent in the treatment of patients with de novo coronary artery lesions; ESSENCE-DIABETES, Everolimus-Eluting Stent Versus Sirolimus-Eluting Stent Implantation for De Novo Coronary Artery Disease in Patients With Diabetes Mellitus; EXAMINATION, a clinical Evaluation of Xience-V stent in Acute Myocardial INfArcTION; EXCELLENT, Efficacy of Xience/Promus vs Cypher to reduce Late Loss after stenting; GISSOC II-GISE, Gruppo Italiano di Studio sullo Stent nelle Occlusioni Coronariche, supported by GISE (Società Italiana di Cardiologia Invasiva); HAAMU-STENT, Helsinki Area Acute Myocardial Infarction Treatment Reevaluation; Horizons-AMI, Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction; ISAR-Diabetes, The Intracoronary Stenting and Angiographic Results: Do Diabetic Patients Derive Similar Benefit from Paclitaxel-Eluting and Sirolimus-Eluting Stents; ISAR-Left-Main, Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for Unprotected Coronary Left Main Lesions; ISAR-SMART III, Intracoronary Drug-Eluting Stenting to Abrogate Restenosis in Small Arteries III; KOMER, Korean Multicentre Endeavor; Long-DES, Percutaneous Treatment of LONG Native Coronary Lesions With Drug-Eluting Stent; MISSION, A Prospective Randomised Controlled Trial to Evaluate the Efficacy of Drug-Eluting Stents versus Bare-Metal Stents for the Treatment of Acute Myocardial Infarction; MULTISTRATEGY, Multicentre Evaluation of Single High-Dose Bolus Tirofiban vs Abciximab With Sirolimus-Eluting Stent or Bare Metal Stent in Acute Myocardial Infarction; NAPLES-Diabetes, Novel Approaches for Preventing or Limiting Events in Diabetic Patients; PASEO, Paclitaxel or Sirolimus-Eluting Stent vs Bare Metal Stent in Primary Angioplasty; PASSION, Paclitaxel-Eluting Stent vs Conventional Stent in Myocardial Infarction With ST-Segment Elevation; PRISON II, Primary Stenting of Totally Occluded Native Coronary Arteries II; PROSIT, Prospective Randomized comparison of SIrolimus- vs paclitaxel-eluting stents for the treatment of acute STEMI; RAVEL, Randomized Study With the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients With De Novo Native Coronary Artery Lesions; RESET, Randomized Evaluation of Sirolimus-eluting stent vs Everolimus-eluting stent Trial; SCANDSTENT, Stenting Coronary Arteries in Non-stress/Benestent Disease; SCORPIUS, German Multicenter Randomized Single Blind Study of the CYPHER Sirolimus-Eluting Stent in the Treatment of Diabetic Patients With De Novo Native Coronary Artery; SEA-SIDE, Sirolimus Versus Everolimus-Eluting Stent Randomized Assessment in Bifurcated Lesions and Clinical Significance of Residual Side-Branch Stenosis; SESAMI, Sirolimus-Eluting Stent Versus Bare-Metal Stent in Acute Myocardial Infarction; SES-SMART, Sirolimus-Eluting vs Uncoated Stents for Prevention of Restenosis in Small Coronary Arteries; SIRIUS, Sirolimus-Eluting Stent in De Novo Native Coronary Lesions; SIRTAX, SIRolimus-eluting stent compared with paclitaxel-eluting stent for coronary revascularization; SORT OUT, Scandinavian Organization for Randomized Trials With Clinical Outcome; STRATEGY, Single High-Dose Bolus Tirofiban and Sirolimus Eluting Stent Versus Abciximab and Bare Metal Stent in Acute Myocardial Infarction; TAXI-LATE, A Prospective Randomized Comparison Between Paclitaxel and Sirolimus Eluting Stents in the Real World of Interventional Cardiology; TWENTE, The Real-World Endeavor Resolute Versus XIENCE V Drug-Eluting Stent Study in Twente; TYPHOON, Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated With Balloon Angioplasty; ZES-R, zotarolimus eluting stent-resolute; ZEST, Comparison of the Efficacy and Safety of Zotarolimus-Eluting Stent With Sirolimus-Eluting and Paclitaxel-Eluting Stent for Coronary Lesions; and ZEST-AMI, Comparison of the Efficacy and Safety of Zotarolimus-Eluting Stent vs Sirolimus-Eluting Stent vs Paclitaxel-Eluting Stent for Acute Myocardial Infarction Patients. *Data from author communication.

6 2878 Circulation June 12, 2012 Table 2. Selected Characteristics of Included Trials Downloaded from by guest on June 28, 2018 Trial Clopidogrel Duration 6 mo Funding Source (Industry vs Nonindustry) BASKET 28 Yes Nonindustry BASKET-PROVE* 29 Yes Nonindustry COMPARE 30,31 Yes Industry CORPAL 32 NR NR C-SIRIUS 33 No Industry CREST MI 34 NR NR DEBATER 35 NR NR DES-Diabetes 36,37 Yes Nonindustry DESSERT 38 Yes Industry DiabeDES 39 Yes Nonindustry DIABETES 40,41 Yes Nonindustry Diaz de la Llera et al 42 Yes NR Endeavor II 43,44 No Industry Endeavor III 4,45 No Industry Endeavor IV 5,46 Yes Industry Erglis et al 47 NR NR E-SIRIUS 48 No Industry ESSENCE-DIABETES 49 Yes Nonindustry EXAMINATION 50 Yes Nonindustry EXCELLENT 51 Yes Both industry and nonindustry Gao et al 52 Yes NR GISSOC II-GISE 53 Yes Industry HAAMU-STENT 54 NR NR Han et al 55 Yes NR Herdeg et al 56 Yes Nonindustry Hong et al 57 Yes Nonindustry Horizons-AMI 57a,57b Yes Industry and nonindustry ISAR-Diabetes 58 Yes Nonindustry ISAR-Left-Main 59 Yes Nonindustry ISAR-SMART III 60 Yes Nonindustry ISAR-Test-2 27,61 Yes Nonindustry Juwana et al 62 Yes NR Kamoi et al 63 Yes Nonindustry Kim et al 64 Yes NR KOMER 64a Yes Industry Long-DES II 65 Yes Nonindustry Long-DES III 66 Yes Industry and nonindustry MISSION 67,68 Yes Industry and nonindustry MULTISTRATEGY 69,70 No Industry and nonindustry NAPLES-Diabetes 71 Yes None Ortolani et al 72 No Nonindustry Pache et al 73 Yes NR Pan et al 74 Yes Nonindustry PASEO 75,76 Yes Nonindustry PASSION 77,78 Yes Nonindustry Petronio et al 79 Yes NR PRISON II 80,81 Yes Industry and nonindustry PROSIT 82,83 Yes NR RAVEL 84,85 No Industry REALITY 86 Yes Industry RESET 87 NR Industry Quality of Trial* (Continued)

7 Bangalore et al DES and Outcomes 2879 Table 2. Continued Downloaded from by guest on June 28, 2018 Trial Clopidogrel Duration 6 mo Funding Source (Industry vs Nonindustry) RESOLUTE All Comers 11,12 Yes Industry SCANDSTENT 88,89 Yes Nonindustry SCORPIUS 90 Yes Industry SEA-SIDE 91 Yes Nonindustry SESAMI 92,93 Yes Nonindustry SES-SMART 94,95 No Industry and nonindustry SIRIUS 96,97 No Industry SIRTAX 98,99 Yes Nonindustry SORT OUT II 100 Yes Industry SORT OUT III 101 Yes Industry SORT OUT IV 102 Yes Nonindustry SPIRIT II 103,104 Yes Industry and nonindustry SPIRIT III 6,105 Yes Industry SPIRIT IV 7,106 Yes Industry STRATEGY 107,108 Yes Nonindustry TAXI-LATE 109,110 Yes Nonindustry TAXUS II 111,112 Yes Industry TAXUS IV 113,114 Yes Industry TAXUS V 115 Yes Industry TAXUS VI 116,117 Yes Industry TWENTE 118 Yes NR TYPHOON 119,120 Yes Industry ZEST 121 Yes Industry and nonindustry ZEST-AMI 122 Yes Nonindustry Zhang et al 123 Yes NR Quality of Trial* BASKET indicates Basel Stent Kosten Effektivitäts Trial; BASKET-PROVE, Basel Stent Kosten-Effektivitäts Trial Prospective Validation Examination; COMPARE, Comparison of the Everolimus Eluting XIENCE-V Stent With the Paclitaxel Eluting TAXUS LIBERTÉ Stent in All-Comers; NR, not reported; C-SIRIUS, Canadian Study of the Sirolimus-Eluting Stent in the Treatment of Patients With Long De Novo Lesions in Small Native Coronary Arteries; CREST MI, Carotid Revascularization Endarterectomy Versus Stenting Trial Myocardial Infarction; DEBATER, A Comparison of Drug Eluting Stents and Bare Metal Stents With or Without Abciximab in ST-Segment Elevation Myocardial Infarction, The Eindhoven Reperfusion Study; DES-Diabetes, Drug-Eluting Stent in Patients With Diabetes Mellitus; DESSERT, Diabetes Drug Eluting Sirolimus Stent Experience in Restenosis Trial; DiabeDES, The Diabetes and Drug-Eluting Stent (DiabeDES) Randomized Angiography Trial; DIABETES, DIABETes and sirolimus Eluting Stent; Endeavor, A Randomized Controlled Trial of the Medtronic Endeavor Drug ABT-578 Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions; E-SIRIUS, European multicenter, randomized, double-blind study of the SIRolImUS-coated Bx Velocity balloon expandable stent in the treatment of patients with de novo coronary artery lesions; ESSENCE-DIABETES, Everolimus-Eluting Stent Versus Sirolimus-Eluting Stent Implantation for De Novo Coronary Artery Disease in Patients With Diabetes Mellitus; EXAMINATION, a clinical Evaluation of Xience-V stent in Acute Myocardial INfArcTION; EXCELLENT, Efficacy of Xience/Promus vs Cypher to reduce Late Loss after stenting; GISSOC II-GISE, Gruppo Italiano di Studio sullo Stent nelle Occlusioni Coronariche, supported by GISE (Società Italiana di Cardiologia Invasiva); HAAMU-STENT, Helsinki Area Acute Myocardial Infarction Treatment Reevaluation; Horizons-AMI, Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction; ISAR-Diabetes, The Intracoronary Stenting and Angiographic Results: Do Diabetic Patients Derive Similar Benefit from Paclitaxel-Eluting and Sirolimus-Eluting Stents; ISAR-Left-Main, Intracoronary Stenting and Angiographic Results: Drug-Eluting Stents for Unprotected Coronary Left Main Lesions; ISAR-SMART III, Intracoronary Drug-Eluting Stenting to Abrogate Restenosis in Small Arteries III; KOMER, Korean Multicentre Endeavor; Long-DES, Percutaneous Treatment of LONG Native Coronary Lesions With Drug-Eluting Stent; MULTISTRATEGY, Multicentre Evaluation of Single High-Dose Bolus Tirofiban vs Abciximab With Sirolimus-Eluting Stent or Bare Metal Stent in Acute Myocardial Infarction; NAPLES-Diabetes, Novel Approaches for Preventing or Limiting Events in Diabetic Patients; PASEO, Paclitaxel or Sirolimus-Eluting Stent vs Bare Metal Stent in Primary Angioplasty; PASSION, Paclitaxel-Eluting Stent vs Conventional Stent in Myocardial Infarction With ST-Segment Elevation; PRISON II, Primary Stenting of Totally Occluded Native Coronary Arteries II; PROSIT, Prospective Randomized comparison of SIrolimus- vs paclitaxel-eluting stents for the treatment of acute STEMI; RAVEL, Randomized Study With the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients With De Novo Native Coronary Artery Lesions; RESET, Randomized Evaluation of Sirolimus-eluting stent vs Everolimus-eluting stent Trial; SCANDSTENT, Stenting Coronary Arteries in Non-stress/Benestent Disease; SCORPIUS, German Multicenter Randomized Single Blind Study of the CYPHER Sirolimus-Eluting Stent in the Treatment of Diabetic Patients With De Novo Native Coronary Artery; SEA-SIDE, Sirolimus Versus Everolimus-Eluting Stent Randomized Assessment in Bifurcated Lesions and Clinical Significance of Residual Side-Branch Stenosis; SESAMI, Sirolimus-Eluting Stent Versus Bare-Metal Stent in Acute Myocardial Infarction; SES-SMART, Sirolimus-Eluting vs Uncoated Stents for Prevention of Restenosis in Small Coronary Arteries; SIRIUS, Sirolimus-Eluting Stent in De Novo Native Coronary Lesions; SIRTAX, SIRolimus-eluting stent compared with paclitaxel-eluting stent for coronary revascularization; SORT OUT, Scandinavian Organization for Randomized Trials With Clinical Outcome; STRATEGY, Single High-Dose Bolus Tirofiban and Sirolimus Eluting Stent Versus Abciximab and Bare Metal Stent in Acute Myocardial Infarction; TAXI-LATE, A Prospective Randomized Comparison Between Paclitaxel and Sirolimus Eluting Stents in the Real World of Interventional Cardiology; TWENTE, The Real-World Endeavor Resolute Versus XIENCE V Drug-Eluting Stent Study in Twente; TYPHOON, Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated With Balloon Angioplasty; ZEST, Comparison of the Efficacy and Safety of Zotarolimus-Eluting Stent With Sirolimus-Eluting and Paclitaxel-Eluting Stent for Coronary Lesions; and ZEST-AMI, Comparison of the Efficacy and Safety of Zotarolimus-Eluting Stent vs Sirolimus-Eluting Stent vs Paclitaxel-Eluting Stent for Acute Myocardial Infarction Patients. *Represents risk of bias based on sequence generation of allocation, allocation concealment, and blinding. Indicates low bias risk;, high bias risk; and, unclear bias risk.

8 2880 Circulation June 12, 2012 Downloaded from by guest on June 28, 2018 ered the most appropriate outcome for long-term analyses because they incorporate the duration of the trials, which was variable. One record per treatment group per study was used, and the outcome on the Poisson regression model was counts of events. Calculation of the probability that each treatment is best (lowest event proportion) was performed with a bayesian Markov Chain Monte Carlo method, adapted to apply to a connected network set of treatment comparisons. Minimally informative prior distributions were used for log rate ratios and for random effects standard deviations, so the findings are close to those obtained with frequentist methods. All network analyses were conducted with WinBUGS The relative efficacy and safety of the stents were compared with MTC and using the probability that a stent had the lowest event proportion (as described above). Direct Comparison An intention-to-treat meta-analysis was performed in line with recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 13,19 using standard software (Stata 9.0, Stata Corp, College Station, TX). 20 Heterogeneity was assessed with the I 2 statistic. 21 I 2 is the proportion of total variation observed between the trials attributable to differences between trials rather than sampling error (chance), with I 2 25% considered low and I 2 75% high. The pooled effect for each grouping of trials was derived from the point estimate for each separate trial weighted by the inverse of the variance (1/SE 2 ). Risk ratio was calculated with the random-effects model of DerSimonian and Laird. 22 Bias was estimated visually by funnel plots and with the Begg s test and the weighted regression test of Egger. 23 P 0.05 was used to denote statistical significance. Sensitivity Analyses To test for the robustness of the primary analyses, several sensitivity analyses were performed. Analyses were restricted to the following: (1) Trials with low-bias risk. (2) Trials with no routine angiographic follow-up, to avoid bias caused by oculostenotic reflex and a higher revascularization rates in trials with routine angiographic follow-up. For the purpose of the present analysis, routine angiographic follow-up was defined as trials in which 50% of patients received routine angiography during follow-up. (3) Trials limited to patients without acute coronary syndrome, to avoid a confounding effect of an acute coronary syndrome subgroup. An acute coronary syndrome trial was defined as a trial in which 50% of patients enrolled had acute coronary syndrome (unstable angina, non ST-segment elevation myocardial infarction, or ST-segment elevation myocardial infarction) as the reason for percutaneous coronary intervention. (4) Trials in which the duration of clopidogrel in the DES arm was at least 6 months, to avoid a confounding effect of shorter-duration clopidogrel treatment on safety outcomes. Role of the Funding Source This work was not funded, and hence, there was no role of any funding source in the conception, data synthesis, analysis, or interpretation or in drafting of the manuscript. Dr Bangalore 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 and had the final responsibility to submit this report for publication. Results Study Selection We identified 77 randomized clinical trials that satisfied our inclusion criteria (Figure 1). We included the paclitaxel slowrelease stent (SR) as opposed to the paclitaxel moderate-release stent arm of the TAXUS II trial because paclitaxel SR is the currently used paclitaxel stent type. We excluded the ZoMaxx I 24 and II 25 trials because the ZoMaxx stent is a different ZES stent platform (TriMaxx; Abbott Laboratories; stainless steel tantalum stent platform to deliver zotarolimus 10 g/mm via phosphorylcholine polymer system). Similarly, we excluded the ISAR (Intracoronary Stenting and Antithrombotic Regimen) Test 1 26 trial because it tested a non polymer-based rapamycineluting stent. The ISAR Test 2 27 data included were the SES and ZES arms only, with the polymer-free dual-des arm of the trial excluded. The network of available treatment comparisons is shown in Figure 2. Baseline Characteristics The baseline characteristics and quality analysis are described in Tables 1 and The 76 trials enrolled patients with patient-years of follow-up. Eight trials were 3-arm trials, but the remainder were 2-arm trials. Fifty-three trials were considered trials with low-bias risk and the rest were intermediate- or high-bias risk trials. Of the 76 trials, 61 used clopidogrel for at least 6 months in the DES arm (Table 2). Mean follow-up duration was 2.1 years (range, years). Short-Term Outcomes (<1 Year) Short-Term Efficacy Compared with BMS (reference odds ratio of 1), all of the DES reduced TVR by 52% to 74% (Figure 3A), but the magnitude of this reduction varied by DES type. Compared with SES, EES and ZES-R had similar efficacy but PES and ZES were less efficacious at reducing TVR (Figure 3A). Similarly, compared with PES, ZES had similar efficacy but EES was more efficacious, with a 40% decrease in the odds of TVR (Figure 3A). Compared with EES, ZES-R had similar efficacy, but ZES had higher odds of TVR (by efficacy, SES ZES-R EES PES ZES BMS). Table 3 summarizes the rate of TVR and the probability that each stent is the best (lowest event proportion). Among the stents, there was a 58% probability that SES had the lowest TVR rate compared with the other stents (Table 3), followed by ZES-R (probability 24%) and EES (probability 17%). The median TVR rate with BMS was 15.76%, and there was a 11% absolute decrease in the rate with the most efficacious DES (SES; TVR rate of 4.11%; number needed to treat, 8). The results were largely similar in the sensitivity analysis performed based on trial quality (online-only Data Supplement Table II), angiographic follow-up (online-only Data Supplement Table III), non acute coronary syndrome trials (online-only Data Supplement Table IV), in trials with 6 months of clopidogrel use (online-only Data Supplement Figure I), and in the direct comparison analysis (online-only Data Supplement Table V). In addition, the results were largely similar for the outcome of TLR (Figure 3B). Short-Term Safety Compared with BMS (reference odds ratio of 1), there was no increase in death with any of the DES (Figure 4A), with similar nondifferences for any pair of between-des comparisons (Figure 4A). The median short-term death rate was 0.3% for all stents (Table 3).

9 Bangalore et al DES and Outcomes 2881 Downloaded from by guest on June 28, 2018 Figure 3. A, Stent type and short-term risk of target-vessel revascularization. The numbers represent odds ratio (OR) and 95% credibility intervals (CrI). B, Stent type and short-term risk of target-lesion revascularization. The numbers represent OR and 95% CrI. BMS indicates bare-metal stent; Ref, reference. Compared with BMS (reference odds ratio of 1), there were significant reductions (33% 45%) in the odds of MI with all DES except PES, for which there was no significant difference. For the between-des comparisons, PES was inferior compared with SES, EES, ZES, and ZES-R, but there were no differences for other pairs of DES comparisons (SES EES ZES ZES-R BMS PES; Figure 4B). Among the stents, there was a 46% probability that ZES-R had the lowest MI rate, followed very closely by EES compared with the other stents (Table 3). The median MI rate with BMS was 4.23%, and there was a 1.92% absolute decrease with the safest DES (ZES-R, MI rate of 2.30%; number needed to treat, 52; Table 3). Compared with BMS (reference odds ratio of 1), there was no increase in the odds of any stent thrombosis with any DES, with a 56% reduction in the odds with EES (Figure 5A). For the between-des comparisons, EES decreased the odds of any stent thrombosis compared with SES, PES, and ZES, with no differences for other pairs of DES comparisons (Figure 5A). Among the stents, there was a 80% probability that EES had the lowest any stent thrombosis rate compared with other stents (Table 3). The median any stent thrombosis rate was 0.2% with all stents, 0.18% with BMS, and 0.10% with the safest DES (EES; rate of 0.08%; number needed to treat, 1000; Table 3). In a sensitivity analysis restricted to trials with clopidogrel duration 6 months, EES was better than BMS, PES, and ZES, with no difference for other combinations of stent comparisons (including ZES-R; online-only Data Supplement Figures V and VI). The results were largely similar for the outcomes of definite or probable stent thrombosis (Figure 5B) and definite stent thrombosis (Figure 5C). For all of the above analyses, sensitivity analyses, including in trials with 6 months of clopidogrel use (online-only Data Supplement Tables II through IV and Figures II through VI), and direct comparison analyses (online-only Data Supplement Table V) yielded consistent results. Long-Term Outcomes Long-Term Efficacy Compared with BMS (reference rate ratio of 1), the shortterm benefits with DES were also preserved long-term, with Table 3. Median Rate of Selected Short-Term (Up to 1 Year) Efficacy and Safety Outcomes and the Probability That Each Stent Type Is the Best (Lowest Rate) From Mixed-Treatment Comparison Analysis Stent Type TVR Rate (95% CrI) Probability Best, % Death Rate (95% CrI) Probability Best, % MI Rate (95% CrI) Probability Best, % Rate of Any ST (95% CrI) Probability Best, % Rate of Def/Prob ST (95% CrI) Probability Best, % Bare metal ( ) ( ) ( ) ( ) ( ) 0.09 Sirolimus 4.11 ( ) ( ) ( ) ( ) ( ) 2.72 Paclitaxel 7.37 ( ) ( ) ( ) ( ) ( ) 0.02 Everolimus 4.44 ( ) ( ) ( ) ( ) ( ) Zotarolimus 7.60 ( ) ( ) ( ) ( ) ( ) 0.72 Zotarolimus-R 4.90 ( ) ( ) ( ) ( ) ( ) TVR indicates target-vessel revascularization; CrI, credibility interval; MI, myocardial infarction; ST, stent thrombosis; and Def/Prob, Academic Research Consortium defined definite or probable stent thrombosis.

10 2882 Circulation June 12, 2012 Downloaded from by guest on June 28, 2018 Figure 4. A, Stent type and short-term risk of death. The numbers represent odds ratio (OR) and 95% credibility intervals (CrI). B, Stent type and short-term risk of myocardial infarction. The numbers represent OR and 95% CrI. BMS indicates bare-metal stent; Ref, reference. a 39% to 61% reduction in the rate of TVR with any DES (Figure 6A), but the magnitude of this reduction varied with DES type (EES SES ZES-R PES ZES BMS). There was a 42% probability that EES had the lowest TVR rate (Table 4). The median TVR rate with BMS was 89 per 1000 patient-years of follow-up, and the rate with the most efficacious DES (EES) was 34 per 1000 patient-years (Table 4). The results were largely similar in the sensitivity analyses, including in trials with 6 months of clopidogrel use (onlineonly Data Supplement Tables VI through VIII and Figure VII), in direct comparison analysis (online-only Data Supplement Table IX), and for the outcome of TLR (Figure 6B). Long-Term Safety Similar to results regarding short-term death, there was no increase in death long-term with any of the DES or among any pair of DES comparisons (Figure 7A). As with short-term MI, consistent results were seen long-term, with a significant reduction (18% 37%) in the rate of MI with all DES (compared with BMS) except PES, for which there was no difference. There were differences between DES comparisons such that EES ZES ZES-R SES PES BMS (Figure 7B). Among the stents, there was a 46% probability that EES had the lowest MI rate (Table 4). Long-term any stent thrombosis rates were no different for most DES compared with BMS, except for EES, for which there was a 49% reduction in the rate ratio of stent thrombosis (Figure 8A). For the between-des comparisons, SES was better than PES and EES was better than SES, PES, and ZES, with no differences for other sets of DES comparisons (including ZES-R; Figure 8A). Among the stents, there was a 86% probability that EES had the lowest any stent thrombosis rate (Table 4). The results were largely similar for the outcomes of definite or probable stent thrombosis (Figure 8B) and definite stent thrombosis (Figure 8C). For all of the above analyses, sensitivity analyses, including in trials with 6 months of clopidogrel use (online-only Data Supplement Tables VI through XII), and direct comparison analysis (online-only Data Supplement Table IX) yielded consistent results. Discussion The results of the present study with data from patient-years of follow-up showed that DES are highly efficacious at reducing not only the short-term risk but also the long-term risk of TVR/TLR without an increase in any safety outcomes, including stent thrombosis, compared with BMS. In fact, there was a significant reduction in both shortand long-term risk of stent thrombosis with the safest DES (EES) compared with BMS. In addition, each DES, except for PES, reduced the short- and long-term risk of MI compared with BMS. Moreover, significant differences were also observed among DES types both for efficacy and safety, with evidence suggesting that EES, SES, and ZES-R had the best long-term safety and efficacy among the studied stent types. Efficacy of DES The introduction of DES has resulted in a dramatic reduction in both angiographic restenosis and the need for repeat revascularization compared with BMS. This benefit is explained by the inhibition of fibromuscular hyperplasia through targeted delivery of cytostatic/cytotoxic drugs. However, the drug eluted, the kinetics of elution, and the duration of elution vary with DES type. Moreover, in addition to the drug, various other stent characteristics determine its efficacy at reducing restenosis, including strut thickness, stent mate-

11 Bangalore et al DES and Outcomes 2883 Downloaded from by guest on June 28, 2018 Figure 5. A, Stent type and short-term risk of any stent thrombosis. The numbers represent odds ratio (OR) and 95% credibility intervals (CrI). B, Stent type and short-term risk of Academic Research Consortium (ARC) defined definite or probable stent thrombosis. The numbers represents OR and 95% CrI. C, Stent type and short-term risk of ARC-defined definite stent thrombosis. The numbers represent OR and 95% CrI. BMS indicates bare-metal stent; Ref, reference. rial, type of polymer, and drug-release kinetics. 124 Newer DES (everolimus, zotarolimus) have biocompatible polymers, different drugs (everolimus, zotarolimus), and new stent platforms (cobalt chromium, nickel chromium) with thinner struts and polymers. The present analysis showed that DES reduced the risk of TVR/TLR compared with BMS, which is not surprising; however, the magnitude of this reduction varied with DES type. Our probability analysis allowed for a relative scaling of the stents such that for efficacy, EES, SES, and ZES-R were the most efficacious stents (in that order). The data for ZES-R are supported by 2 trials thus far (Resolute All Comers and TWENTE [The Real-World Endeavor Resolute Versus XIENCE V Drug-Eluting Stent Study in Twente]), both of which showed noninferiority against EES. The present results are consistent with these trials. In our sensitivity analysis, we excluded trials in which there was routine angiographic follow-up. Prior studies have shown an increased rate of repeat revascularization, even in the absence of symptoms or objective evidence of ischemia,

12 2884 Circulation June 12, 2012 Downloaded from by guest on June 28, 2018 Figure 6. A, Stent type and long-term risk of target-vessel revascularization. The numbers represent rate ratio (RR) and 95% credibility intervals (CrI). B, Stent type and long-term risk of target-lesion revascularization. The numbers represent RR and 95% CrI. BMS indicates bare-metal stent; Ref, reference. in trials with routine angiographic follow-up, perhaps because of an oculostenotic reflex. Our sensitivity analysis in the subset of trials without angiographic follow-up showed consistent results as that of the primary analyses. In addition, we showed consistent results across a wide spectrum of sensitivity/subgroup analyses. Safety of DES Despite the considerable efficacy of DES at reducing the risk of in-stent restenosis, the possibility of an increased risk of stent thrombosis, especially very late stent thrombosis, has been an important safety concern with DES Because inhibition of smooth muscle cell proliferation by currently available DES is inseparably connected with the inhibition of endothelial cell proliferation, delayed and incomplete healing has been hypothesized to result in the propensity for stent thrombosis. BMS has therefore been the benchmark for safety standards for stent evaluation. The results of the present analysis showed no increase in the risk of stent thrombosis with DES with appropriate concomitant antiplatelet therapy. In fact, there was a reduction in the risk of stent thrombosis with EES, both short- and long-term, compared with BMS. The results were consistent when trials with 6 months of clopidogrel duration in the DES arm were separately analyzed. The reduced risk of stent thrombosis with EES compared with BMS is difficult to explain but could result from extended dual-antiplatelet therapy with DES in contemporary cohorts compared with BMS. In addition, late and very late stent thrombosis with BMS is not as uncommon as once believed. 130,131 Moreover, newer-generation stents such as the EES and ZES-R have changes in stent design, including thinner struts, use of cobalt-chromium rather than stainless steel stents, and thinner and more biocompatible polymers that may elicit less inflammatory response with a consequent decrease in stent thrombosis. The present results are consistent with similar low rates of stent thrombosis with EES seen in the Bern-Rotterdam cohort study (versus other DES) 132 and in an updated analysis from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), 133 in which there was a 67% reduction in the risk of stent thrombosis compared Table 4. Median Rate (per 1000 Patient-Years of Follow-Up) of Selected Long-Term Efficacy and Safety Outcomes and the Probability That Each Stent Type Is the Best (Lowest Rate) From Mixed-Treatment Comparison Analysis Stent Type TVR Rate (95% CrI) Probability Best, % Death Rate (95% CrI) Probability Best, % MI Rate (95% CrI) Probability Best, % Any ST Rate (95% CrI) Probability Best, % Def/Prob ST Rate (95% CrI) Probability Best, % Bare metal ( ) ( ) ( ) ( ) ( ) 0.03 Sirolimus ( ) ( ) ( ) ( ) ( ) 0.11 Paclitaxel ( ) ( ) ( ) ( ) ( ) 0.00 Everolimus ( ) ( ) ( ) ( ) ( ) Zotarolimus ( ) ( ) ( ) ( ) ( ) 9.51 Zotarolimus-R ( ) ( ) ( ) ( ) ( ) TVR indicates target-vessel revascularization; CrI, credibility interval; MI, myocardial infarction; ST, stent thrombosis; and Def/Prob, Academic Research Consortium defined definite or probable stent thrombosis.

13 Bangalore et al DES and Outcomes 2885 Downloaded from by guest on June 28, 2018 Figure 7. A, Stent type and long-term risk of death. The numbers represent rate ratio (RR) and 95% credibility intervals (CrI). B, Stent type and long-term risk of myocardial infarction. The numbers represent RR and 95% CrI. BMS indicates bare-metal stent; Ref, reference. with BMS. In our probability analyses, EES had a 80% probability of having the lowest stent thrombosis rate compared with all other stent types. In both the Resolute All Comers and the TWENTE trials, ZES-R was noninferior to EES for safety outcomes, including stent thrombosis. However, in the Resolute All Comers trial, ZES-R was associated with a higher definite stent thrombosis at 1 year than EES (1.2% versus 0.3%; P 0.01), with a trend toward higher definite or probable stent thrombosis at 2 years (1.9% versus 1.0%; P 0.08). Whether this is caused by the play of chance should be determined in future trials. There was no short- or long-term increase in death with any DES compared with BMS. In addition, there was a significant reduction in MI with DES (except PES) compared with BMS. Studies have shown that restenosis is not benign and is associated with increased risk of MI and death. 130,134 The short- and long-term reduction in the risk of MI with DES was likely caused by a reduction in the risk of restenosis. In addition, it is possible that the extended duration of dual-antiplatelet therapy with DES may have a role in reduction of MI. Data from the CHARISMA trial (Clopidogrel for High Atherothrombotic Risk and Ischemia Stabilization, Management, and Avoidance) have shown that dual-antiplatelet therapy reduced the risk of primary outcome (stroke, MI, or cardiovascular death) in the prespecified subgroup of patients with documented cardiovascular disease. 135,136 However, other trials in patients undergoing percutaneous coronary intervention have not shown similar benefit of extended dual-antiplatelet therapy, although these were likely to be underpowered to detect a difference. 137 Although the platinum chromium EES stent was not evaluated in the present analysis, in the PLATINUM trial this was noninferior to the cobalt chromium EES for efficacy and safety end points. 138 The results of the present meta-analysis are therefore likely applicable to the platinum chromium EES. Study Limitations As in other meta-analyses, given the lack of data in each trial, we did not adjust our analyses for stent dimensions, clopidogrel duration, or other medication usage or their doses. In addition, we did not adjust our analysis for any study-specific or treatment-specific covariates. Although detailed sensitivity analyses on many variables were undertaken, given heterogeneity in the study protocols, clinically relevant differences could have been missed and are best assessed in a meta-analysis of individual patient data. In addition, technical improvements over time and improvements in medical management were not accounted for in the analyses. Moreover, we used the trial definition of MI, although this was clearly not uniform across all trials. Not all of the trials reported each of the outcomes we assessed; accordingly, we are not able to exclude outcome measure reporting bias. Our analyses did not correct for multiple testing. The results of the sensitivity analyses are best described as secondary and hypothesis generating only. The differences seen within DES types are only applicable to the specific stents evaluated in the present study. Nonetheless, this study, which is the largest meta-analysis comparing DES and BMS, offers important insights into their relative safety and efficacy. Conclusions DES are highly efficacious at reducing the short- and long-term risk of TVR/TLR without any increase in any safety outcomes, including stent thrombosis, compared with BMS. In fact, each DES except for PES significantly reduced the rate of MI compared with BMS. However, within the types of DES, there were considerable differences in outcomes, such that EES, SES,

14 2886 Circulation June 12, 2012 Downloaded from by guest on June 28, 2018 Figure 8. A, Stent type and long-term risk of any stent thrombosis. The numbers represent rate ratio (RR) and 95% credibility intervals (CrI). B, Stent type and long-term risk of Academic Research Consortium (ARC) defined definite or probable stent thrombosis. The numbers represent RR and 95% CrI. C, Stent type and long-term risk of ARC-defined definite stent thrombosis. The numbers represent RR and 95% CrI. BMS indicates bare-metal stent; Ref, reference. and ZES-R were the most effective in terms of TVR/TLR and EES was the safest in terms of stent thrombosis for long-term outcomes. Disclosures Dr Bhatt has served on an advisory board for Medscape Cardiology; on the board of directors for Boston VA Research Institute and the Society of Chest Pain Centers; and as the chair of the American Heart Association Get With The Guidelines Science Subcommittee; he also received honoraria from the American College of Cardiology (Editor, Clinical Trials, CardioSource), Duke Clinical Research Institute (clinical trial steering committees), Slack Publications (Chief Medical Editor, Cardiology Today Intervention), WebMD (CME steering committees) and research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-aventis, and The Medicines Company. He has conducted unfunded research for PLx Pharma and Takeda. Dr Feit is a shareholder of Boston Scientific, Johnson and Johnson, and Medtronic. The other authors report no conflicts. None of the authors received any compensation for their work on this manuscript. References 1. McFadden EP, Stabile E, Regar E, Cheneau E, Ong AT, Kinnaird T, Suddath WO, Weissman NJ, Torguson R, Kent KM, Pichard AD, Satler

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A prospective, randomized evaluation of a novel everolimus-eluting coronary stent: the PLATINUM (A Prospective, Randomized, Multicenter Trial to Assess an Everolimus-Eluting Coronary Stent System [PROMUS Element] for the Treatment of up to Two De Novo Coronary Artery Lesions) trial. J Am Coll Cardiol. 2011;57: CLINICAL PERSPECTIVE With the Food and Drug Administration s approval of more drug-eluting stents (DES), the relative short- and long-term efficacy and safety of DES compared with bare-metal stents and among the DES types are less well defined. Although each of the DES has had claims of superior efficacy or safety, direct comparisons have been limited. Our analyses from 76 randomized clinical trials with patient-years of follow-up showed that DES are highly efficacious at reducing the risk of target-vessel revascularization without causing an increase in any safety outcomes, including stent thrombosis. However, among the DES types, there were considerable differences, such that the everolimus-eluting stent, sirolimus-eluting stent, and zotarolimus-eluting Resolute stent were the most efficacious and the everolimus-eluting stent was the safest stent.

20 Short- and Long-Term Outcomes With Drug-Eluting and Bare-Metal Coronary Stents: A Mixed-Treatment Comparison Analysis of Patient-Years of Follow-Up From Randomized Trials Sripal Bangalore, Sunil Kumar, Mario Fusaro, Nicholas Amoroso, Michael J. Attubato, Frederick Feit, Deepak L. Bhatt and James Slater Downloaded from by guest on June 28, 2018 Circulation. 2012;125: ; originally published online May 14, 2012; doi: /CIRCULATIONAHA Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright 2012 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: The online version of this article, along with updated information and services, is located on the World Wide Web at: Data Supplement (unedited) at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Circulation is online at: