Resolute
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Resolute Document Transcript

  • 1. RESOLUTE All Comers Trial A Randomized Comparison of a Zotarolimus-Eluting Stent with an Everolimus-Eluting Stent for Percutaneous Coronary Intervention Primary Results Patrick W. Serruys MD, PhD on behalf of the Investigators Thoraxcenter, Erasmus MC, Rotterdam, the Netherlands Main arena, Tuesday 25th May 2010, 16:05 – 16:17 Potential Conflicts of Interest Speaker’s name: Patrick W. Serruys I have the following potential conflicts of interest to report: Research contracts Consulting Employment in industry Stockholder of a healthcare company Owner of a healthcare company Other(s) X I do not have any potential conflict of interest
  • 2. Background • 1st generation DES reduced rates of restenosis • Safety concerns over very late stent thrombosis have prompted a new 2nd generation of DES • These 2nd generation devices utilize new stent platforms and more biocompatible polymers • Previous DES trials were largely performed in on-label indications, restricting wider applicability of their results to routine clinical practice • Presently there are no randomized comparisons between 2nd generation DES RESOLUTE All Comers: Stents Resolute DES Xience V DES Driver BMS Multi-Link Vision BMS Stent Platform Cobalt Alloy Cobalt Alloy Modular Slotted Tube Drug Zotarolimus Everolimus Drug Density 1.6 µg/mm² 1.0 µg/mm² Complete Drug Elution 180 days 120 days BioLinx Fluoropolymer – Hydrophobic C10 Polyvinylidene fluoride Polymer System – Hydrophilic C19 – Polyvinyl pyrrolidinone
  • 3. RESOLUTE: Current Data • First In Man study in 139 patients • Angiographic outcomes: – 4-month1 in-stent late loss: 0.12 ± 0.26 mm – 9-month2 in-stent late loss: 0.22 ± 0.27 mm • Clinical outcomes at 3 years3: – MACE 11.6%, MI 5.4% and TLR 1.6% – No definite/probable ST 1Meredith IT, et al., EuroIntervention. 2007: 3: 50-53. 2Meredith IT, et al., J Am Coll Cardiol Intv. 2009: 2:977-985. 3Ian Meredith et al., Presented at TCT. 2009. RESOLUTE All Comers Trial Design Any patient with symptomatic coronary artery disease Resolute Stent 17 European sites Xience V Stent n = 1150 2300 patients randomised 1:1 n = 1150 Rapid enrolment over 6 months 1:4 1:4 Angio f/u Angio f/u n = 230 Clinical endpoints n = 230 Clinical 30d 6mo 12mo 13mo 2yr 3yr 4yr 5yr QCA 460 (20%) OCT 50 (2%) QCA & OCT endpoints Primary Endpoint: • 12-month target lesion failure (TLF), composite of cardiac death, target vessel MI 12- 12-month target and clinically driven TLR Secondary Endpoints: • Clinical: Patient composite of any death, any MI, & any repeat revascularisation revascularisation • QCA (powered): 13-month in-stent % diameter stenosis 13- 13-month in- in-stent • QCA: % diameter stenosis, late loss, and binary restenosis
  • 4. Patient Eligibility Inclusion Criteria Exclusion Criteria Coronary artery disease Known intolerance to • Stable angina Aspirin, clopidogrel, heparin, cobalt • Silent ischemia chromium, everolimus, zotarolimus, • Acute coronary syndrome including contrast material UA, NSTEMI and STEMI Lesion characteristics Planned, elective surgery within • Number of lesions : no limitation 6 months of PCI • Number of vessels : no limitation Unless dual anti-platelet therapy • Lesion length : no limitation could be maintained Lesions allowed Pregnancy ULM, CTO, bifurcation lesions, in-stent restenosis, bypass grafts Written informed consent Participation in another trial Study Management Steering Committee DSMB P. W. Serruys (PI) J.P.G. Tijssen (Chair) S. Silber (Co-PI) M. E. Bertrand S. Windecker (Co-PI) U. Sigwart Clinical Event Committee Cardialysis, Rotterdam, the Netherlands W. Bocksch Angiographic core lab G. Ducrocq Clinical events committee E. McFadden Data management C. Hanet Statistical analysis J.P.R. Herrman Data Monitoring V. Legrand Premier Research Group, Switzerland P.W. Radke W. Rutsch Sponsor H.H. Tilsted Hansen Medtronic CardioVascular, Santa Rosa, CA M. Valgimigli
  • 5. Clinical Sites Investigator Hospital Patients Stephan Windecker Swiss Cardiovascular Center Bern, Switzerland 300 Patrick Serruys Erasmus University Medical Center, the Netherlands 299 Gert Richardt Segeberger Kliniken, Germany 298 Pawel Buszman American Heart of Poland, Poland 251 Henning Kelbæk The Heart Center, Denmark 233 Adrianus van Boven Leeuwarden Medical Center, the Netherlands 166 Axel Linke University Leipzig, Germany 141 Volker Klauss University of Munich, Germany 119 Sigmund Silber Kardiologische Praxis and Praxisklinik Munich, Germany 116 William Wijns O.L.V. Hospital Aalst, Belgium 76 Carlos Macaya Hospital Clinico San Carlos, Spain 58 Philippe Garot Institut Cardiovasculaire Paris-Sud, France 57 Carlo DiMario Royal Brompton Hospital, United Kingdom 55 Ganesh Manoharan Royal Victoria Hospital, United Kingdom 47 Ran Kornowski Rabin Medical Center, Israel 38 Thomas Ischinger Klinikum Bogenhausen, Germany 29 Antonio Bartorelli Centro Cardiologico Monzino, Italy 9 Clinical and Angiographic F/U 2292 patients (NL = 3366) Enrolled and randomized Zotarolimus-eluting stent Zotarolimus- Randomized Everolimus-eluting stent Everolimus- N = 1140 pts 1:1 N = 1152 pts Clinical F/U Clinical F/U 12 months 98.2% 12 months 97.7% Randomized to Angio F/U Randomized to Angio F/U N = 228 pts N = 227 pts Angiographic F/U Angiographic F/U 13 months 62.3% 13 months 57.3%
  • 6. Statistical Assumptions Primary Clinical Endpoint: Target Lesion Failure at 12 Months (Composite of cardiac death, target vessel MI and clinically driven TLR) driven Event rate at 12-months would be 8% and equal in both groups 12- Non-inferiority margin of 3.5% and one-sided type I error of 0.05 Non- one- • 2300 patients would yield >90% power to detect non-inferiority non- Secondary Angiographic Endpoint: In-stent Percent Diameter Stenosis at 13 In- Months 1.5 lesions would be treated per patient % DS at 13 months would be 16 ± 16% and equal in both groups Non-inferiority margin of 5% and one-sided type I error of 0.05 Non- one- Attrition rate 20% • 460 patients would yield >90% power to detect non-inferiority non- Baseline Patient Characteristics Zotarolimus stent Everolimus stent Variable, % N = 1140 pts N = 1152 pts Age, years (mean ± SD) 64.4 ± 10.9 64.2 ± 10.8 Men 76.7% 77.2% Diabetes mellitus 23.5% 23.4% Insulin treated 8.4% 7.1% Arterial hypertension 71.1% 71.3% Hyperlipidemia 63.9% 67.7% Current smoker 26.5% 26.5% Premature CAD in first degree relative 34.1% 36.7% Prior myocardial infarction 28.9% 30.4% Prior percutaneous coronary intervention 31.8% 32.1% Prior coronary artery bypass grafting 10.0% 9.5% Stable angina 33.5% 36.1% Unstable angina 19.4% 18.9% Acute Myocardial infarction ≤72 hours 28.9% 28.8%
  • 7. Baseline Patient Characteristics Zotarolimus stent Everolimus stent Variable, % N = 1140 pts N = 1152 pts Left ventricular ejection fraction <30% 2.8% 2.1% Multi-vessel disease 58.4% 59.2% Target vessel location (per patient) Left main 2.2% 2.5% Left anterior descending 52.6% 48.6% Left circumflex 33.0% 32.9% Right coronary 37.3% 41.3% Bypass graft 2.5% 2.4% Number of treated lesions per patient 1.5 ± 0.7 1.5 ± 0.8 SYNTAX score 15 ± 9 15 ± 9 ≥1 small vessel (RVD ≤2.75 mm) 67.8% 67.4% ≥1 lesion length >18 mm 18.2% 21.2% ≥1 bifurcation/trifurcation 16.9% 17.7% ≥1 total occlusion 16.3% 17.2% ≥1 In-stent restenosis 8.1% 8.0% Off-label use 67.0% 65.6% Procedural Characteristics Zotarolimus stent Everolimus stent N = 1140 pts, N = 1152 pts, 1661 lesions 1705 lesions P No. of stents per patient 1.9 ± 1.2 2.0 ± 1.3 0.02 Stent length per patient (mm) 34.4 ± 24.5 37.0 ± 26.5 0.02 Pre-stent balloon dilatation 69.5% 70.2% NS Implantation of study stent only 98.0% 96.9% NS Lesion success 98.9% 99.1% NS Device success 97.0% 96.6% NS Procedure success 94.6% 94.2% NS
  • 8. 1º Endpoint: Target Lesion Failure (Cardiac death, target vessel MI, and clinically driven TLR) at 1 year 20 ZES (N = 1140) Log-Rank P = 0.92 Cumulative incidence of events [%] EES (N = 1152) 15 ZES 8.2% vs. EES 8.3% Pnon-inferiority <0.001 non- non-inferiority 10 8.3% 8.2% 5 0 0 180 360 Time after initial procedure [days] No. at risk 0 30 60 90 120 150 180 210 240 270 300 330 360 ZES 1140 1110 Primary Non-Inferiority 1058 1051 1042 1038 10841076 Non- 1062 1060 Endpoint Met Non-Inferiority 1061 1047 1046 1038 1070 1037 1025 EES 1152 1123 10881080 1078 1074 1068 1032 1019 Error bars indicate a point-wise two-sided 95% confidence interval (±1.96*SE) Standard Error based on the Greenwood Formula 1º Endpoint Analysis: TLF (Cardiac death, target vessel MI, and clinically driven TLR) at 1 year ZES EES Non-inferiority Non- (N = 1140) (N = 1152) Difference : -0.1% P value 8.2% 8.3% Upper 1-sided 95% CI : 1.8% 1- <0.001 Zone of non-inferiority Pre-specified margin = 3.5% Non-inferior -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 % Upper one-sided 95% CI Primary Non-Inferiority Endpoint Met Non-
  • 9. 1º Endpoint Components: TLF (Cardiac death, target vessel MI, and clinically driven TLR) at 1 year Cardiac Death (%) TVMI (%) ID-TLR (%) P = 0.61 P = 0.92 P = 0.50 4.2 4.1 3.9 3.4 1.7 1.3 ZES EES ZES EES ZES EES n = 1119 n = 1126 n = 1119 n = 1126 n = 1119 n = 1126 1º Endpoint TLF to 1 Year Odds Ratio Odds Ratio P value Pre-Specified Subgroups [95% CI] [95% CI] All Patients (N = 2292) 0.98 [0.73, 1.33] 0.94 Off-Label (n = 1520) 0.91 [0.64, 1.29] 0.66 Small Vessels ≤2.75 mm (n = 1308) 1.01 [0.69, 1.48] 1.00 Acute MI <72 hr (n = 662) 1.36 [0.73, 2.57] 0.34 Multivessel Treatment (n = 570) 0.85 [0.50, 1.47] 0.58 Diabetes (n = 538) 1.45 [0.82, 2.58] 0.25 Overlapping Stents (n = 411) 1.06 [0.55, 2.05] 0.87 Bifurcations (n = 392) 0.99 [0.52, 1.87] 1.00 Long Lesions >18 mm (n = 381) 0.86 [0.44, 1.67] 0.74 In-Stent Restenosis (n = 182) 0.61 [0.24, 1.57] 0.35 Renal Insufficiency (n = 80) 0.91 [0.28, 3.02] 1.00 Bypass Graft (n = 56) 1.25 [0.30, 5.26] 1.00 Left Main (n = 54) 1.65 [0.33, 8.21] 0.69 0.1 1 10 Favors Favors ZES EES
  • 10. Composite Clinical Endpoints RESOLUTE All Comers at 1 year TLF (%) TVF (%) MACE (%) Patient Composite (%) (CD, TV MI, CI-TLR) (CD, TV MI, TVR) (D, MI, eCABG, TLR) (D, All MI, All Revasc) P = 0.94 P = 0.42 P = 0.66 P = 1.00 9.6 9.7 9.6 9.0 8.7 9.0 8.2 8.3 Resolute Xience Resolute Xience Resolute Xience Resolute Xience n = 1119 n = 1126 n = 1119 n = 1126 n = 1119 n = 1126 n = 1119 n = 1126 ARC Stent Thrombosis to 1 year Zotarolimus stent Everolimus stent % (n) n = 1119 n = 1126 P Definite ST Acute: (0 – 1 day) 0.4% (4) 0.1% (1) NS Sub-Acute: (2 – 30 days) 0.4% (5)*† 0.0% (0) 0.03 Late: (31 days – 360 days) 0.4% (5)* 0.2% (2) NS All: (0 days – 360 days) 1.2% (13) 0.3% (3) 0.01 Definite/Probable ST Acute: (0 – 1 day) 0.4% (5)† 0.2% (2) NS Sub-Acute: (2 – 30 days) 0.7% (8)*† 0.4% (4) NS Late: (31 days – 360 days) 0.6% (7)* 0.2% (2) NS All: (0 days – 360 days) 1.6% (18) 0.7% (8) NS *One patient had a definite ST at day 4 and 31 †One patient had a probable ST on day 0 and a definite ST on day 5
  • 11. Stent Thrombosis and CD/MI ARC Definite/Probable ST Cardiac Death and 10 10 Target Vessel MI Cumulative incidence of events [%] Cumulative incidence of events [%] ZES ZES EES EES Log Rank P = 0.05 Log Rank P = 0.96 5 5 0 0 0 180 360 0 180 360 Time after initial procedure [days] Time after initial procedure [days] Small, early difference in stent thrombosis did not translate into differences in cardiac death or TVMI Error bars indicate a point-wise two-sided 95% confidence interval (±1.96*SE) Standard Error based on the Greenwood Formula 2º QCA Endpoint Analysis: In-stent Percent Diameter Stenosis at 13 Months ZES EES (Lesions = 191) (Lesions = 186) Non-inferiority Non- Difference* : 2.03 P value* 21.7 ± 19.8 ± Upper 1-sided 95% CI* : 4.73 1- 0.035 14.4 14.6 Zone of non-inferiority Pre-specified margin = 5.0 Non-inferior 0.0 1.0 2.0 3.0 4.0 5.0 6.0 Upper one-sided 95% CI Powered Secondary Non-Inferiority Endpoint Met Non- *Calculated using least square means
  • 12. In stent late loss at 13 Months ZES (n = 183 lesions) EES (n = 177 lesions) 100 90 80 70 % of Lesions 60 50 40 30 0.27 ± 0.43 vs. 0.19 ± 0.40 20 (P = 0.08) 10 0 -1 0 1 2 3 In-stent Late Loss (mm) Complex Patient Subgroup Professor Stephan Windecker PCR Symposium
  • 13. RESOLUTE All Comers “Complex” or “Off-Label” Definition: • Bifurcation • SVG • ISR • AMI <72 hr • LVEF <30%, • Unprotected LM • >2 vessels stented • Renal insufficiency or failure (creatinine >140 µmol/L) • Lesion length >27 mm • >1 lesion per vessel • Lesion with thrombus or TO (preprocedure TIMI = 0) Patient Complexity All 34% 66% Resolute Resolute Xience V Xience V 33% Simple Complex 34% 67% 66% P = 0.51
  • 14. Complex Patients: Target Lesion Failure (a composite of cardiac death, target vessel MI, and clinically driven TLR) N = 698 patients 20 Resolute (ZES) P = 0.59 Cumulative incidence of events [%] Xience V (EES) 15 10 9.8% 8.9% 5 0 0 180 360 Time after initial procedure [days] Complex Patients: TLF Components RESOLUTE All Comers at 1 year Resolute (n= 764) Xience V (n=756) P = 0.80 P = 0.24 P = 0.90 % 4.4 4.3 4.4 4.0 2.2 1.3 TLR Cardiac Death MI
  • 15. Complex Patients: Composite Endpoints RESOLUTE All Comers at 1 year TLF (%) TVF (%) MACE (%) (CD, TV MI, CI-TLR) (CD, TV MI, TVR) (D, MI, eCABG, TLR) P = 0.67 P = 0.45 P = 0.15 11.1 11.5 9.7 9.8 8.9 9.2 Resolute Xience V Resolute Xience V Resolute Xience V n = 764 n = 756 n = 756 n = 764 n = 764 n = 756 Conclusion • Both the Resolute zotarolimus-eluting stent and the Xience V everolimus-eluting stent were associated with a relatively low frequency of adverse events even in this complex, all-comers patient population • The new generation Resolute zotarolimus-eluting stent was found to be as safe and effective as the Xience V everolimus-eluting stent in this predominantly off-label population