Manel Sabaté Hospital Clínic, Barcelona (On behalf of the Examination Investigators)
Disclosures Investigator Initiated Trial: NCT00828087. Unrestricted grant from Abbott to the Spanish Heart Foundation.
Background and Rationale (I) Acute coronary syndromes repeatedly appear as independent predictor of stent thrombosis in most of Clinical Registries. First generation drug-eluting stent (DES) have been evaluated in RCT in the setting of STEMI with (overall) positive results. However, most of these RCT lack of good generalizability of real world due to highly selected inclusion/exclusion criteria. Currently, no data exists regarding new generation DES in terms of safety and efficacy in this high risk group of patients with STEMI.
Background and Rationale (II) Recently, RCT with an all-comers design apply wide inclusion and few exclusion criteria that may result in a more representative sample of the target population. However, even in such design it is not expected that every consecutive patient will be enrolled. In a recent analysis from 2 all-comers RCT (Leaders and Resolute) only 48% of the total number of patients were actually included 1. We conducted a RCT with an all-comers design with the aim to evaluate the performance of 2 nd generation DES in the complex setting of STEMI and to provide data that may be generalizable to the real world population. 1 De Boer SPM. Eur Heart J 2011; May 2011, ahead of print
EXAMINATION TRIAL design Multicentre, multinational, prospective, randomized, two-arm, single-blind, controlled trial OBJECTIVE To assess the safety and performance of the XIENCE V Everolimus Eluting Coronary Stent System vs. the cobalt chromium MULTI-LINK VISION balloon expandable stent in the setting of primary percutaneous coronary intervention for treatment of patients presenting with STsegment elevation myocardial infarction.
( A Clinical Evaluation of Xience-V stent in Acute Myocardial INfArctTION) 2 1 Bergamo 3 12 centres - 3 countries
Participants (I) PI: M Sabaté; Clinic Hospital, Barcelona, SP Co-PI: PW Serruys; Erasmus MC; R dam, NL Steering Committee: M Sabaté, PW Serruys, A Cequier, A Iñiguez, M Valgimigli, R Hdez-Antolín, GA van Es. Promotor: Spanish Society of Cardiology CRO: Cardialysis, R dam, NL Monitoring: J Toro (SP), S Cellini (I), C Morelli (I), R Schneijdenber (NL) DSMB: I Ferreira (SP), B Garcia del Blanco (SP) CEC: P Vrancks (B), E McFadden (UK), B Rensing (NL), P Smits (NL) Statistics: Cardialysis, R dam, NL
Participants (II) Centres: -Spain: - H Clínic, Barcelona; Dr. M Sabaté (PI) - H Univ Bellvitge, Barcelona; Dr. A Cequier - H Sant Pau, Barcelona; Dr. A Serra - H do Meixoeiro, Vigo; Dr. A Iñiguez - H San Carlos, Madrid; Dr. R Hernández-Antolín - H Univ Alicante; Alicante; Dr. V Mainar - H Juan Canalejo; A Coruña; Dr. N Vázquez - H Son Dureta; Palma de Mallorca; Dr. A Bethencourt -Italy - Univ H Ferrara- Dr. M Valgimigli - Univ H Bolognini Seriate- Dr. M Tespili -The Netherlands - Erasmus MC, Rotterdam- Dr. PW Serruys (co-pi) - Amphia Ziekenhuis, Breda- Dr. P den Heijer
EXAMINATION TRIAL design PRIMARY ENDPOINT Patient-oriented (ARC) primary endpoint at 1 year: Composite endpoint of all-cause death, any myocardial infarction and any revascularization. SECONDARY ENDPOINTS All-cause and cardiac mortality at 1 year and yearly up to 5 years. Recurrent MI at 1 year and yearly up to 5 years. TLR and TVR at 1 year and yearly up to 5 years. Stent thrombosis (ARC) at 1 year and yearly up to 5 years. Clinical device and procedure success. Major and minor bleeding at 1 year and yearly up to 5 years.
Inclusion criteria ( all-comer ): Patients presenting with STEMI within 48 h requiring emergent PCI: STEMI < 12h ( primary PCI ) Rescue PCI After successful thrombolysis Latecomers (>12h-48h) Vessel size between 2.25-4.0 mm to allow the implantation of currently available stents. Informed consent.
Exclusion criteria: Age < 18y Pregnancy Intolerance to aspirin, clopidogrel, everolimus, cobalt chromium, heparin. Need of chronic treatment with anti vitamin K agents. STEMI secondary to stent thrombosis. Impossibility to obtain clinical follow-up.
Statistical analysis: The overall sample size for the study of 1500 patients is based on the following assumptions: A 2-sided type I error rate = 0.05 Randomization ratio is 1 (XIENCE V): 1 (Vision). A statistical power of at least 86% to detect a (approximate 30%) reduction in the rate of the primary endpoint at 1 year by the Xience V stent (14.5%) as compared to the Vision stent (20.5%) The primary combined endpoint will be analyzed for the intent-to-treat population. Staged procedures that were indicated in the CRF at the time of the initial procedure, and are performed within one month of the initial procedure will not be counted as endpoints.
Study Design = All-comer RCT Patients suffering from an AMI, presenting within 48 hours after Onset of Symptoms Requiring Emergent PCI of a Native Coronary Artery Randomization 1:1 (n=1504) 6 pts withdrew consent Everolimus-eluting Stent (751 patients) Cobalt-chromium stent (747 patients) Everolimus-eluting Stent (737 patients-98.1%) 1-YEAR FOLLOW-UP Cobalt-chromium stent (732 patients-98%)
Number of patients included per centre 70% of all STEMI! * Recruitment period < 3 mths
Baseline Characteristics Xience V n=751 Age, years 61 ± 12 (28-90) Vision n=747 62 ± 12 (27-95) Male, % 84.4 81.7 Body mass index, Kg/m 2 27 ± 4 27 ± 4 Diabetes, % 18 16 Hypertension, % 46 50 Smoker, % 72 72 Dyslipidemia, % 47 40 Family History, % 18 16 Previous Myocardial Infarction, % 4.4 6.3 Previous PCI, % 3.9 4.3 Previous CABG, % 0.4 0.9 Previous stroke, % 1.6 2.5
Clinical presentation Cardiogenic shock: 1.3 % Xience V vs. 1.1% Vision; p=ns
Anatomical Characteristics Infarct-related artery: Xience V n=751 Vision n=747 LAD, n (%) 379 (42) 343 (39) RCA, n (%) 380 (42) 396 (45) LCx, n (%) 130 (15) 132 (15) Left Main, n (%) 6 (0.7) 4 (0.5) SVG, n (%) 4 (0.4) 6 (0.7) N. diseased vessels: One, n (%) 649 (87) 659 (88) Two, n (%) 76 (10) 63 (8) Three, n (%) 24 (3.2) 25 (3.3) Ejection fraction, %; median [IQR] 52 [45-58] 51.5 [45-58]
Procedural Aspects (I) Antithrombotic Therapy Xience V n=751 Vision n=747 Unfractioned heparin, n (%) 597 (79.5) 587 (78.7) LMWH, n (%) 62 (8.3) 71 (9.5) Bivalirudin, n (%) 49 (6.5) 56 (7.5) IIb/IIIa inh.* (99% reopro), n (%) 400 (53.3) Aspirin, n (%) 692 (92.1) Clopidogrel (pre with 600 mg), n (%) 712 (94.8) 385 (51.5) 691 (92.6) 706 (94.5) * 63% vs 60% when analysed within STEMI <12h group % p=ns
Procedural Aspects (II) Variable Xience V n=739 Vision n=730 Direct stenting, n (%) 451 (61) 434 (59.5) N stents, mean (range) 1.37 (1-5) 1.36 (1-5) Max Stent diam, mm; mean (range) Total stent length, mm; median (IQR) 3.2 (2.25-4) 3.2 (2.25-4) 23 (18-35) 23 (18-33) Max Pressure, atm; mean (range) 16 (9-26) 16 (8-30) Postdilatation, n (%) 118 (15.9) 103 (14.1) Overlapping stent, n (%) 156 (21.1) 167 (22.8)
Dual Antiplatelet Regimen
1-YEAR RESULTS
100 Primary Endpoint: Composite of all-cause death, any MI or any revascularization 95 90 85 Freedom of events [%] 80 75 70 Xience-V Vision Log-Rank P-value Survival, % 88.0 85.6 0.16 65 60 55 XIENCE MULTILINK-VISION 50 0 30 60 90 120 150 180 210 240 270 300 330 360 Time af ter initial procedure [day s]
Secondary Endpoints: Cardiac Death 100 95 90 85 Freedom of events [%] 80 75 70 Xience-V Vision Log-Rank P-value Survival, % 96.8 97.2 0.68 65 60 55 XIENCE MULTILINK-VISION 50 0 30 60 90 120 150 180 210 240 270 300 330 360 Time af ter initial procedure [day s]
Secondary Endpoints: Recurrent Myocardial Infarction 100 95 90 85 Freedom of events [%] 80 75 70 65 Freedom from event, % Xience-V Vision Log-Rank P-value 98.6 97.9 0.30 60 55 XIENCE MULTILINK-VISION 50 0 30 60 90 120 150 180 210 240 270 300 330 360 Time af ter initial procedure [day s]
Secondary Endpoints: Target Lesion Revascularization 100 95 90 Freedom of events [%] 85 80 75 70 Freedom from event, % Xience-V Vision Log-Rank P-value 97.8 94.9 0.003 65 60 55 XIENCE MULTILINK-VISION 50 0 30 60 90 120 150 180 210 240 270 300 330 360 Time af ter initial procedure [day s]
Secondary Endpoints: Target Vessel Revascularization 100 95 90 Freedom of events [%] 85 80 75 70 Freedom from event, % Xience-V Vision Log-Rank P-value 96.1 93.0 0.007 65 60 55 XIENCE MULTILINK-VISION 50 0 30 60 90 120 150 180 210 240 270 300 330 360 Time af ter initial procedure [day s]
Secondary Endpoints: Definite Stent Thrombosis 100 95 90 85 Xience-V Vision Log-Rank P-value Freedom of events [%] 80 75 70 Freedom from event, % 99.5 98.1 0.01 65 60 55 XIENCE MULTILINK-VISION 50 0 30 60 90 120 150 180 210 240 270 300 330 360 Time af ter initial procedure [day s]
Secondary Endpoints: Definite/Probable Stent Thrombosis 100 95 90 Freedom of events [%] 85 80 75 70 65 60 55 Freedom from event, % Xience-V stent 11 events (9 pts): 3 Deaths 3 MI 5 Revasc XIENCE MULTILINK-VISION Xience-V Vision Log-Rank P-value 99.1 97.4 0.01 Vision stent 28 events (19 pts): 4 Deaths 11 MI 13 Revasc 50 0 30 60 90 120 150 180 210 240 270 300 330 360 Time af ter initial procedure [day s]
Definite/Probable Stent Thrombosis p = 0.01
Patient Oriented Endpoint at 360 days No. events (%) Xience V EECS System Subgroup Analysis Multilink- Vision p-value RR 95% CI Male 79/634 (12%) 82/610 (13%) 0.606 0.93 (0.69-1.24) Female 10/117 (9%) 24/137 (18%) 0.036 0.49 (0.24-0.98) < 70 years 49/565 (9%) 63/536 (12%) 0.091 0.74 (0.52-1.05) 70 years 40/186 (22%) 43/211 (20%) 0.783 1.06 (0.72-1.55) No Diabetes 63/613 (10%) 79/626 (13%) 0.196 0.81 (0.60-1.11) Diabetes 26/137 (19%) 27/121 (22%) 0.508 0.85 (0.53-1.37) No Aspiration thrombectomy 35/256 (14%) 45/266 (17%) 0.303 0.81 (0.54-1.21) Aspiration thrombectomy 54/495 (11%) 61/481 (13%) 0.390 0.86 (0.61-1.21) < 30 % EF 3/10 (30%) 2/5 (40%) 0.699 0.75 (0.18-3.14) 30 % EF 60/531 (11%) 68/510 (13%) 0.318 0.85 (0.61-1.17) Primary PCI (STEMI <12h) 77/630 (12%) 93/638 (15%) 0.219 0.84 (0.63-1.11) No Primary PCI 12/121 (10%) 13/108 (12%) 0.608 0.82 (0.39-1.73) < 120 minutes Door-to-Balloon 37/302 (12%) 40/280 (14%) 0.469 0.86 (0.57-1.30) 120 minutes Door-to-Balloon 47/356 (13%) 49/364 (13%) 0.918 0.98 (0.68-1.42) < 180 minutes Ischemia Time 29/199 (15%) 28/196 (14%) 0.935 1.02 (0.63-1.65) 180 minutes Ischemia Time 47/433 (11%) 56/413 (14%) 0.229 0.80 (0.56-1.15) Single vessel Disease 69/649 (11%) 87/659 (13%) 0.152 0.81 (0.60-1.08) Multi vessel Disease 19/100 (19%) 19/88 (22%) 0.659 0.88 (0.50-1.55) Infarct-related artery not in LAD 53/423 (13%) 62/439 (14%) 0.492 0.89 (0.63-1.25) Infarct-related artery in LAD 36/328 (11%) 44/308 (14%) 0.208 0.77 (0.51-1.16) TIMI < 3 Post 7/46 (15%) 14/44 (32%) 0.063 0.48 (0.21-1.07) TIMI 3 Post 82/703 (12%) 90/700 (13%) 0.496 0.91 (0.69-1.20) No IIa/IIIb usage 44/351 (13%) 57/362 (16%) 0.219 0.80 (0.55-1.15) IIa/IIIb usage 45/400 (11%) 49/385 (13%) 0.524 0.88 (0.60-1.29) Xience V better p-value for interaction Multilink better 0.1158 0.2185 0.8930 0.8312 0.8955 0.9674 0.6612 0.4635 0.8066 0.6227 0.1890 0.7163 Overall 89/751 (12%) 106/747 (14%) 0.179 0.84 (0.64-1.09) 0.1 1.0 10.0
Summary & Conclusions The use of Xience V stent in the setting of STEMI resulted in a non-significant reduction in the patient-oriented primary endpoint. In terms of performance, the Xience V stent significantly reduced the rates of TVR and TLR and the rates of definite and definite/probable stent thrombosis. These findings support the safety and efficacy profile of the Xience V stent in a widely representative cohort of patients presenting with STEMI.