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The RESOLUTE Program: today and tomorrow
Sigmund Silber, MD, PhD FESC, FACC, FAHA Professor of Medicine Heart Center at the Isar Munich, Germany
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RESOLUTE Global Clinical Program Zotarolimus eluted from BioLinx™ durable polymer
Enrollment Complete - In Follow Up RESOLUTE1 Non-RCT First-in-Human (R=139) 5 yr RESOLUTE AC2,3 1:1 RCT vs. Xience V™ EES (R=1140; X=1152) 3 yr RESOLUTE Int4 Non-RCT Observational (R=2349) 3 yr RESOLUTE US5 2.25 – 4.0 mm Non-RCT vs. Hx Control (R=1402) 2 yr RESOLUTE Japan 2.5 – 3.5 mm Non-RCT (R=100) vs. Hx Control 2 yr RESOLUTE US 38 mm sub-study Non-RCT vs. PG (R=114) 1 yr R-Japan SVS 2.25 Non-RCT vs. PG (R=65) < 1yr R-China RCT 1:1 RCT vs. Taxus™ PES (R=200; T=200) < 1yr RESOLUTE Asia Non-RCT Observational (R=312) < 1yr R-China Registry Non-RCT Observational (R=1800) < 1yr Enrolling / Planning RI-US Registry Post-approval study (R=230) enrolling 1 Meredith IT, et al. EuroIntervention. 2010;5: Serruys PW, et al. N Engl J Med. 2010;363: Silber S, et al. Lancet. 2011;377: Neumann FJ, et al. EuroIntervention. 2012;7(10): Yeung AC, et al. JACC. 2011;57: 2
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RESOLUTE All Comers Clinical Trial Design
Co-PIs: Profs. Serruys, Silber, Windecker Open label, non-inferiority trial Any patient with symptomatic coronary artery disease eligible for DES implantation (no lesion/vessel limitations) 17 European sites 2300 patients randomized 1:1 Subsets: QCA 460 pts (20%); OCT 50 pts (2%) 100% monitoring Resolute™ Stent n = 1150 Xience V™ Stent n = 1150 Clinical endpoints 30d 6mo 12mo 13mo 2yr 3yr 4yr 5yr Angio/OCT endpoints Primary Endpoint: 12-month target lesion failure (TLF), composite of cardiac death, target vessel MI & clinically driven TLR Secondary Endpoints: Clinical: Patient composite of any death, any MI, & any repeat revascularisation QCA (powered): 13-month in-stent % diameter stenosis QCA: % diameter stenosis, late loss, and binary restenosis Drug Therapy: ASA and clopidogrel/ticlopidine > 6mo (per guidelines) Serruys PW, Silber, S. et al., N Engl J Med. 2010;363(2):136-46
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RESOLUTE All Comers Patient Eligibility Inclusion Criteria
Coronary artery disease Stable angina Silent ischemia Acute coronary syndrome including UA, NSTEMI and STEMI Lesion characteristics Number of lesions : no limitation Number of vessels : no limitation Lesion length : no limitation Written informed consent Exclusion Criteria Known intolerance to Aspirin, clopidogrel, heparin, cobalt alloy, everolimus, zotarolimus, contrast material, polymer coating Planned, elective surgery within 6 months of PCI Unless dual anti-platelet therapy could be maintained Pregnancy Participation in another trial Serruys PW, Silber, S. et al., N Engl J Med. 2010;363(2):136-46
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RESOLUTE All Comers Baseline Characteristics Resolute™ ZES (N = 1140)
Xience V™ EES (N = 1152) P value Age (yr) 64.4 ± 10.9 64.2 ± 10.8 0.70 Men (%) 76.7 77.2 0.80 Diabetes mellitus (%) 23.5 23.4 1.00 IDDM 8.4 7.1 0.28 ACS (%) 48.3 47.7 AMI (within 12 hr) (%) 15.4 17.8 0.13 AMI (within 72 hr) (%) 28.9 28.8 0.96 Multivessel disease (%) 58.4 59.2 0.73 Small vessel (RVD ≤2.75 mm) 67.8 67.4 0.88 Long lesion (length >18 mm) 18.2 21.2 0.11 Bifurcation/trifurcation (%) 16.9 17.7 0.62 Total occlusion (%) 16.3 17.2 0.61 In-stent restenosis (%) 8.1 8.0 0.94 Complex Patients1 (%) 67.0 65.6 0.51 1Complex patient definition: bifurcation, bypass grafts, 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). Resolute Integrity DES is not specifically approved for the following patients subsets; bypass graft, LVEF<30%, unprotected LM and renal insufficiency or failure (creatinine>140µmol/L) . Serruys PW, Silber, S. et al., N Engl J Med. 2010;363(2):136-46
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RESOLUTE All Comers Procedure Characteristics Resolute™ ZES
N = 1140 patients, 1661 lesions Xience V™ EES N = 1152 patients, 1705 lesions P value Lesions treated per patient 1.46 ± 0.73 1.48 ± 0.77 0.46 Lesion length (mm) 11.89 ± 7.50 12.15 ± 7.86 0.38 No. of stents per patient 1.9 ± 1.2 2.0 ± 1.3 0.02 Stent length per patient (mm) 34 ± 24 37 ± 26 Pre-stent balloon dilatation 69.5% 70.2% 0.75 Deployment pressure 14.85 ± 3.14 15.10 ± 3.20 0.01 Implantation of study stent only 98.0% 96.9% 0.11 Lesion success 98.9% 99.1% 0.62 Device success 97.0% 96.6% 0.52 Procedure success 94.6% 94.2% 0.78 Serruys PW, Silber, S. et al., N Engl J Med. 2010;363(2):136-46
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RESOLUTE All Comers Target Lesion Failure – Primary Endpoint 8.3% 8.2%
Resolute™ ZES (N = 1140) 20% Xience V™ EES (N = 1152) Log rank P = 0.92 15% Cumulative Incidence of Events 10% 8.3% Primary endpoint Pnon-inferiority <0.001 8.2% 5% 0% 12 24 36 Time after Initial Procedure (months)
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Cumulative Incidence of Events Time after Initial Procedure (months)
RESOLUTE All Comers Target Lesion Failure to 3 Years Resolute™ ZES (N = 1140) 20% Xience V™ EES (N = 1152) Log rank P = 0.65 HR 1.05 [0.84, 1.33] 15% 13.1% 12.4% Cumulative Incidence of Events 10% 5% 0% 12 24 36 Time after Initial Procedure (months) 8
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RESOLUTE All Comers Components of Target Lesion Failure at 3 Years
Resolute™ ZES (n = 1120) Xience V™ EES (n = 1130) P = 0.43 0.7% [-0.9%, 2.2%] P = 0.77 0.3% [-1.5%, 2.1%] P = 0.86 0.2% [-1.7%, 2.2%] Events (%) Cardiac Death TV-MI TLR
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RESOLUTE All Comers Stent Thrombosis (Definite/Probable) to 3 Years
Resolute™ ZES (N = 1140) Log rank P = 0.10 15% Xience V™ EES (N = 1152) 10% Cumulative Incidence of ARC Definite/Probable ST 5% 2.1% 1.3% 0% 1 2 3 Time After Initial Procedure (Years) RESOLUTE All Comers was not specifically designed or powered for the analysis shown above.
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RESOLUTE All Comers Very Late Stent Thrombosis (Definite/Probable) 1-3 Years 3% Resolute™ ZES (N = 1140) Xience V™ EES (N = 1152) 2% Cumulative Incidence of ARC Definite/Probable ST Log rank P = 1.00 1% 0.56% 0.55% 0% 1 2 3 Time After Initial Procedure (Years) Patients at Risk RZES 1140 1108 1081 CI% 0.00 0.27 0.55 EES 1152 1107 1083 0.56 RESOLUTE All Comers was not specifically designed or powered for the analysis shown above.
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RESOLUTE Global Clinical Program Zotarolimus eluted from BioLinx™ durable polymer
Enrollment Complete - In Follow Up RESOLUTE1 Non-RCT First-in-Human (R=139) 5 yr RESOLUTE AC2,3 1:1 RCT vs. Xience V™ EES (R=1140; X=1152) 3 yr RESOLUTE Int4 Non-RCT Observational (R=2349) 3 yr RESOLUTE US5 2.25 – 4.0 mm Non-RCT vs. Hx Control (R=1402) 2 yr RESOLUTE Japan 2.5 – 3.5 mm Non-RCT (R=100) vs. Hx Control 2 yr RESOLUTE US 38 mm sub-study Non-RCT vs. PG (R=114) 1 yr R-Japan SVS 2.25 Non-RCT vs. PG (R=65) < 1yr R-China RCT 1:1 RCT vs. Taxus™ PES (R=200; T=200) < 1yr RESOLUTE Asia Non-RCT Observational (R=312) < 1yr R-China Registry Non-RCT Observational (R=1800) < 1yr Enrolling / Planning RI-US Registry Post-approval study (R=230) enrolling 1 Meredith IT, et al. EuroIntervention. 2010;5: Serruys PW, et al. N Engl J Med. 2010;363: Silber S, et al. Lancet. 2011;377: Neumann FJ, et al. EuroIntervention. 2012;7(10): Yeung AC, et al. JACC. 2011;57: 12
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5130 Resolute™ ZES population
RESOLUTE Pooled Diabetic Analysis Diabetic vs. Non-Diabetic Patient Populations RESOLUTE 139 RESOLUTE AC 1140 RESOLUTE Int 2349 RESOLUTE US 1402 RESOLUTE Japan 100 5130 Resolute™ ZES population Total diabetic patient population N = 1535 Matched cohort diabetic population N = 878 (less complex patients) “Standard risk” diabetic patient cohort pre-specified for FDA indication Matched cohort is all enrolled diabetic subjects excluding subjects with bifurcation, saphenous vein graft (SVG), ISR, AMI (≤72 hours), left ventricular ejection fraction (LVEF) <30%, an unprotected left main lesion, ≥3 vessels, renal impairment (creatinine ≥ 140µmol/L), total lesion length per vessel >27 mm, ≥2 lesions per vessel, lesion with thrombus, or lesion with total occlusion. Silber S. et al, JACC Intv, 2013, (in press) 13
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RESOLUTE Pooled Diabetic Analysis
FDA Indication for Patients with Diabetes Mellitus Prespecified diabetes analysis designed with FDA for diabetes indication Performance goal prespecified based on meta-analysis: DIABETES, RAVEL DM, SIRIUS DM, TAXUS IV, SCORPIUS, ENDEAVOR Pooled DM. Standard risk patient population from Pooled RESOLUTE matched to performance goal patient population TVF at 12 Months (powered endpoint) P = 0.001 14.5 Events (%) 7.8 Performance Goal Resolute™ DES† TVF: target vessel failure (cardiac death, TV-MI, and clinically driven TVR) †RESOLUTE matched cohort diabetes pooled analysis (N = 878). Silber S. et al, JACC Intv, 2013, (in press)
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Standard Risk Diabetics N = 878
RESOLUTE Pooled Diabetic Analysis Baseline Characteristics: All Diabetic Patients, incl. Complex % Standard Risk Diabetics N = 878 All Diabetics N = 1535 Age (yr) 65.2 ± 10.2 65.6 ± 10.2 Male 66.4 68.1 Diabetes mellitus 100.0 IDDM 28.5 29.6 Prior MI 24.9 27.6 Prior PCI 34.6 34.5 Reason for Revascularization: Stable angina 46.2 39.7 Unstable angina 28.9 26.8 Myocardial infarction 5.4 18.1 LAD 44.8 46.8 RVD (mm) 2.7 ± 0.5 Lesions per patient 1.1 ± 0.4 1.3 ± 0.6 Stent length per patient 22.5 ± 11.3 28.5 ± 18.8 Complex patients* 42.8 * Complex patient definition: bifurcation, bypass grafts, 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). Silber S. et al, JACC Intv, 2013, (in press)
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Cumulative Incidence of TLF Time After Initial Procedure (months)
RESOLUTE Pooled Diabetic Analysis All Patients – Target Lesion Failure to 2 Years 20% Non-Diabetics (N = 3595) All Diabetics (N = 1535) 15% 11.2% Cumulative Incidence of TLF 10% 7.7% 8.4% 5% 6.1% 0% 6 12 18 24 Time After Initial Procedure (months) No. at risk Non-Diabetics 3595 3540 3399 3301 3198 Diabetics 1535 1518 1447 1386 1345 The RESOLUTE Pooled analysis was not specifically designed or powered for the analysis shown above. Silber S. et al, JACC Intv, 2013, (in press)
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RESOLUTE Pooled Diabetic Analysis
Baseline Characteristics: ITDM = Insulin Treated Diabetes Mellitus % Non-Diabetics N = 3595 Non-ITDM N = 1080 ITDM N = 455 Age (yr) 63.1 ± 11.2 65.8 ± 10.2* 65.2 ± 10.1 Male 77.8 71.9* 59.3** Diabetes mellitus 100.0* 100.0 IDDM 100.0** Hypertension 67.8 84.6* 90.3** Hyperlipidemia 67.7 80.0* 81.8 Current smoker 26.0 19.7* 14.7** Family history 38.1 34.0* 37.6 Prior MI 25.9 26.7 29.8 Prior PCI 29.3 32.7* 38.9** Prior CABG 7.4 11.2* 11.2 Clinical status: * Stable angina 38.0 40.2 38.5 Unstable angina 25.5 26.2 28.1 Myocardial infarction 24.3 17.8 18.9 *p-value <0.05 Non-IDDM vs. Non-Diabetics ** p-value <0.05 IDDM vs Non-IDDM The RESOLUTE Pooled analysis was not specifically designed or powered for the analysis shown above. Silber S. et al, JACC Intv, 2013, (in press)
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Cumulative Incidence of TLR Time After Initial Procedure (months)
RESOLUTE Pooled Diabetic Analysis All Patients – Target Lesion Revascularization to 2 Years 20% Non-Diabetics (N = 3595) Diabetics Non-ITDM (N = 1080) Diabetics ITDM (N = 455) 15% 10% Cumulative Incidence of TLR 9.0% 6.3% 5% 4.7% 4.3% 3.0% 3.0% 0% 6 12 18 24 Time After Initial Procedure (months) No. at risk Non-Diabetics 3595 3589 3479 3385 3285 Non-IDDM 1080 1078 1046 1007 985 IDDM 455 454 428 409 389 Error bars indicate a point-wise two-sided 95% confidence interval (±1.96*SE). Standard Error based on the Greenwood Formula. Silber S. et al, JACC Intv, 2013, (in press)
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RESOLUTE Pooled Diabetic Analysis
All Patients – Cardiac Death/TVMI to 2 Years 20% Non-Diabetics (N = 3595) Diabetics Non-ITDM (N = 1080) Diabetics ITDM (N = 455) 15% Cumulative Incidence of Cardiac Death/TVMI 10% 9.6% 6.6% 5% 5.2% 4.9% 3.8% 3.5% 0% 6 12 18 24 Time After Initial Procedure (months) No. at risk Non-Diabetics 3595 3543 3442 3387 3306 Non-IDDM 1080 1075 1041 1017 1005 IDDM 455 445 423 416 400 Error bars indicate a point-wise two-sided 95% confidence interval (±1.96*SE). Standard Error based on the Greenwood Formula. Silber S. et al, JACC Intv, 2013, (in press)
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RESOLUTE Pooled Diabetic Analysis
All Patients – ARC Def/Prob Stent Thrombosis to 2 Years 10% Non-Diabetics (N = 3595) Diabetics Non-ITDM (N = 1080) Diabetics ITDM (N = 455) 8% 6% Cumulative Incidence of ARC Def/Prob ST 4% 1.6 % 0.8 % 2% 0.7 % 1.8 % 0.9 % 0.8 % 0% 6 12 18 24 Time After Initial Procedure (months) No. at risk Non-Diabetics 3595 3590 3522 3471 3396 Non-IDDM 1080 1078 1054 1032 1020 IDDM 455 454 437 431 417 Error bars indicate a point-wise two-sided 95% confidence interval (±1.96*SE). Standard Error based on the Greenwood Formula. Silber S. et al, JACC Intv, 2013, (in press)
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RESOLUTE Global Clinical Program Zotarolimus eluted from BioLinx™ durable polymer
Take Home Messages: In an all-comer patient population, the Resolute ZES and Xience V EES remained clinically equivalent through 3 years (TLF 13.1% vs. 12.4, P = 0.65). The incidence of very late stent thrombosis rate is low and similar between Resolute ZES and Xience V EES (definite ST 0.3% vs. 0.5%, P = 0.48). In patients with diabetes, the Resolute ZES is safe and effective. Patients with diabetes not taking insulin had similar clinical outcomes as patients without diabetes. But for patients with diabetes who are taking insulin, continued attention is needed and bypass surgery should be considered as an alternative.
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