Slides - Clinical Trial Results
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Slides - Clinical Trial Results
Biolimus-Coated vs. Bare-Metal Coronary Stents in High Bleeding Risk Patients Philip Urban, Alexandre Abizaid, Ian T. Meredith, Stuart J. Pocock, Didier Carrié, Christoph Naber, John Gregson, Samantha Greene, Hans Peter Stoll and Marie-Claude Morice for the LEADERS FREE Investigators Disclosure Statement of Financial Interest Within the past 12 months, I, Philip Urban, have had a financial interest / arrangement or affiliation with the organization(s) listed below. Affiliation / Financial Relationship Company • Grant / Research Support • Consulting Fees / Honoraria • • • • Biosensors Europe Edwards Lifesciences Terumo Abbott Vascular High Bleeding Risk Patients (HBR) • Mostly excluded from device and APT trials Ventes • Never specifically studied • Current guideline recommendations: • BMS + one month DAPT • DES + “shortened” DAPT All-comers HBR BioFreedom™ Drug Coated Stent (DCS) BA9TM Drug 10 Times More Lipophilic than Sirolimus1 Selectively Micro-Structured Surface Holds Drug in Abluminal Surface Structures 100 % 80 60 40 20 0 Sirolimus Zotarolimus Everolimus Biolimus A9TM +/- 2.8% (valid for all drugs test) Potential Advantages: Avoid any possible polymer-related adverse effects Rapid drug transfer to vessel wall (98% within one month2) Safe to shorten DAPT? 1. Data on file at Biosensors Intl; 2. Tada et al., Circ Cardiovasc Interv 2010;3;174-183 Median In-Stent LLL at 12-month Follow-up 2nd Cohort – Primary Endpoint 0.5 p = 0.001 (non-inferiority) 0.4 0.35 0.3 0.22 0.2 0.17 0.1 0 BioFreedom N = 31 BioFreedom low-dose Taxus N = 35 N = 31 Costa R et al. JACC interv (published online October 11, 2015 – DOI 10.1016/j.jcin.2015.09.008) Hypothesis For patients with a high bleeding risk, using one month DAPT, can the BioFreedom DCS be shown to be as safe and more effective than a Gazelle BMS? LEADERS FREE Trial Design Prospective, double-blind randomized (1:1) trial 2466 High bleeding risk (HBR) PCI patients BioFreedom™ DCS vs. Gazelle™ BMS DAPT mandated for 1 month only, followed by long-term SAPT • Primary safety endpoint: Composite of cardiac death, MI, definite / probable stent thrombosis at 1 year (non-inferiority then superiority) • Primary efficacy endpoint: Clinically-driven TLR at 1 year (superiority) Inclusion Criteria (One or More) • • • • • • • • • • • • • Age ≥ 75 years OAC planned after PCI Baseline Hb < 11g / dl or transfusion during prior 4 weeks Planned major surgery (within next year) Cancer diagnosed or treated ≤ 3 years Creatinine clearance < 40 ml / min Hospital admission for bleeding during past year Thrombocytopenia (< 100.000 / mm3) Any prior intra-cerebral bleed Any stroke during the past year Severe liver disease NSAID or steroids planned after PCI Anticipated poor DAPT compliance for other medical reason Trial Organization PIs: Executive Committee: Statistics: DSMB: P. Urban, A. Abizaid and I. Meredith 3 PI’s and D. Carrié, S. Greene, M-C Morice, C. Naber, S. Pocock, H-P Stoll J. Gregson, S. Copt, R. Piault B. Meier (Chair), J-P. Bassand, T. Cuisset, E. Vicaut CEC: R. Mehran (Chair), A. Baumbach, S. Cook, P. Kala, J. Machecourt, F. Mauri, G. Olivecrona, S. Petronio, F. Ribichini, L. Thuesen CRO: CERC, Massy, France (Project Leader U. Windhovel) e-CRF: Sponsor: MERGE Biosensors Europe, Morges, Switzerland Determination of Trial Size Predicted event rates in BMS control arm • Composite safety endpoint (cardiac death, MI and ST) 8% • Efficacy endpoint (clinically-driven TLR) 10% Patients per group: 1228 Endpoints • Safety: > 80% power to demonstrate non-inferiority with margin 3.2% • Efficacy: > 80% power to detect a 3.3% reduction in c-TLR Both with one-sided alpha 0.025 Enrollment and Follow-Up 2466 patients randomized 1,239 DCS 18 with no PCI performed 1,221 analyzed (modified ITT) 25 (2.0%) patients withdrew before 12-month visit or were lost to FU 1196 (98.0%) completed 12-month visit or died 1,227 BMS 16 with no PCI performed 1,211 analyzed (modified ITT) 22 (1.8%) patients withdrew before 12-month visit or Were lost to FU 1189 (98.2%) completed 12-month visit or died Inclusion Criteria Applied (1.7 criteria / patient) 64.1 64.5 Age ≥ 75 35.6 36.7 Oral anticoagulants 20.2 17.9 17.4 15.3 16 15.2 Renal failure Surgery soon Anemia or recent TF 9.9 9.7 Cancer 2.7 3.8 3.9 3.4 2.8 3.1 1.5 1.6 2 1.2 0.8 0.9 1.6 1.1 Hospital for bleeding DAPT compliance NSAID or steroids Thrombocytopenia Stroke < 1 year Severe liver disease Prior intracerebral bleed 0 BMS DCS 10 20 30 40 50 60 70 Baseline Characteristics DCS (%) BMS (%) 75.7 + 9.4 75.7+9.3 29.8 30.9 27.5 ± 4.8 27.2 ± 4.6 Diabetes 34.0 32.3 NSTEMI presentation 22.4 23.2 STEMI presentation 4.7 4.0 Prior MI 19.6 21.4 Prior PCI 22.2 21.9 Prior CABG 9.4 10.1 Multivessel CAD 62.9 61.6 Congestive heart failure 14.4 12.4 Atrial fibrillation 34.9 34.6 Peripheral vascular disease 15.7 15.8 Chronic obstructive lung disease 10.9 11.7 Mean age Female gender BMI None of the baseline characteristics differ at p < 0.05 Index Procedure DCS (%) BMS (%) Radial access 60.7 58.7 Staged procedure 4.5 5.9 Multi-lesion procedure 37.8 35.3 Multi-vessel procedure 21.8 21.4 1.6 ± 0.8 1.6 ± 0.9 LMS 3.0 3.9 SVG 1.4 1.8 Bifurcation 14.9 16.0 ISR 2.4 2.6 CTO 5.0 4.4 Number of treated lesions / patient None of the procedure characteristics differ at p < 0.05 Index Procedure (Continued) DCS BMS Mean stent diameter 3.0 ± 0.4 3.0 ± 0.4 Mean total implanted stent length / patient 34.5 ± 23.1 33.4 ± 23.4 1.9 ± 1.1 1.8 ± 1.2 Lesion success 97.7 98.0 Device success 97.7 97.6 Procedure success 94.4 93.7 UFH during procedure 90.5 89.4 LMWH during procedure 8.4 8.8 Bivalirudin during procedure 1.1 1.8 2b3a blocker during procedure 2.0 1.2 Mean number of stents implanted / patient None of the procedure characteristics differ at p < 0.05 Antithrombotic Medication at Discharge % 80 DCS 63 BMS 64.9 60 40 33.5 32 20 2.6 2.5 0.9 0.6 0 DAPT alone Triple therapy* VKA+clopidogrel None of the regimens differ at p < 0.05 * Any oral anticoagulant + DAPT Other Cumulative Percentage with Event Primary Safety Endpoint (Cardiac Death, MI, ST) % 15 12.9% 12 9 9.4% 6 3 p = 0.005 for superiority 0 0 90 180 270 390 Days Number at Risk DCS 1221 1146 1105 1081 1045 BMS 1211 1115 1066 1037 1000 390 days chosen for assessing primary EP to capture potential events driven by the 360 day FU contact Primary Safety Endpoint Primary Safety Endpoint* Cardiac Death, Myocardial Infarction, or Stent Thrombosis at 390 days DCS (n=1221) BMS (n=1211) 112 (9.4%) 154 (12.9%) Risk difference: • • • • -3.6% (95% CI -6.1% to -1.0%) HR 0.71, (95% CI = 0.56 – 0.91) p < 0.0001 for non-inferiority p = 0.005 for superiority * 3rd Universal definition of MI, Thygesen K et al Circulation 2012;126:2020 –2035 ARC definition, Cutlip D et al. Circulation 2007; 115: 2344-51 Components of Safety Endpoint % 10 9 DCS 8.9 BMS 8 7 6.1 6 5 5.3 4.2 4 3 2.0 2 2.2 1 0 Cardiac death p = 0.19 MI p = 0.01 ST (def / prob) p = 0.70 Selected Secondary Safety Endpoints % 10.0 8.0 DCS BMS 9.0 9.0 8.0 7.0 6.0 5.0 3.8 4.0 3.7 3.0 2.0 1.0 1.0 1.2 1.1 1.0 0.0 All death Non-card death ST acute / subacute None of these endpoints differ at p < 0.05 ST late Primary Efficacy Endpoint (Clinically-Driven TLR) Cumulative Percentage with Event % 12 9.8% 9 6 5.1% 3 p for superiority < 0.001 0 0 90 180 270 390 Days Number at Risk DCS 1221 1167 1130 1098 1053 BMS 1211 1131 1072 1034 984 390 days chosen for assessing primary EP to capture potential evens driven by the 360 day FU contact Primary Efficacy Endpoint Primary Efficacy Endpoint DCS (n=1221) BMS (n=1211) Clinically driven TLR at 390 days 59 (5.1%) 113 (9.8%) Difference: • -4.8% (95% CI = -6.9% to -2.6%) • HR 0.50, (95% CI = 0.37 – 0.69) • p<0.001 for superiority Secondary Efficacy Endpoints % 14 DCS BMS 12.9 12 10.9 10.5 10 9.4 8 5.8 5.7 5.8 Urgent TLR Cd-TVR Any TVR Any revasc p = 0.004 p < 0.001 p < 0.001 p < 0.005 6 4 3.3 2 0 Subgroups Composite safety endpoint (cardiac death, MI, ST) BMS: Events (%) 92 (11.6) 62 (15.5) 53 (14.4) 101 (12.3) 95 (10.9) 59 (18.5) 93 (11.5) 61 (15.9) 89 (10.4) 53 (22.2) 100 (13.0) 54 (12.8) 48 (9.1) 88 (18.6) P-value for interaction No Yes No Yes No yes No Yes No Yes No Yes No Yes DCS: Events (%) 65 (8.3) 47 (11.5) 34 (9.6) 78 (9.3) 82 (9.4) 30 (9.3) 65 (8.3) 47 (11.5) 73 (8.3) 31 (14.7) 66 (8.7) 46 (10.5) 33 (6.4) 63 (13.6) No Yes No yes No yes No yes No Yes No Yes 84 (8.5) 28 (13.6) 93 (9.4) 16 (8.4) 101 (9.3) 11 (9.6) 24 (5.4) 84 (11.4) 54 (8.0) 56 (10.9) 49 (8.3) 61 (10.2) 113 (11.4) 41 (20.3) 123 (12.7) 27 (12.9) 139 (12.9) 15 (12.9) 39 (8.6) 112 (15.4) 68 (9.6) 82 (17.4) 59 (10.1) 91 (15.3) 0.63 Category Age >80 Male ACS at admission Diabetes Renal failure at admission Planed OAC at randomization Crusade score > median (35) Anemia, transfusion or bleeding leading to hospitalization Planned major surgery in following year Cancer in last 3 years* Multi-vessel disease at admission Total stent length > 30 mm Minimal stent diameter < 3 mm 0.86 0.59 0.04 0.90 0.46 0.44 0.86 0.74 0.87 0.64 0.19 0.33 .125 .25 .5 1 Hazard Ratio (95% CI) 2 4 Subgroups (continued) Efficacy endpoint (clinically driven TLR) No Yes No Yes No yes No Yes No Yes No Yes No Yes 1602 830 738 1694 1773 659 1622 805 1754 466 1553 879 1061 962 DCS: Events (%) 31 (4.0) 28 (7.1) 17 (5.0) 42 (5.1) 47 (5.5) 12 (3.9) 40 (5.3) 19 (4.7) 42 (4.9) 16 (7.9) 39 (5.3) 20 (4.7) 21 (4.1) 33 (7.5) No Yes No yes No yes No yes No Yes No Yes 2007 425 2002 404 2193 239 906 1493 1409 999 1195 1213 41 (4.2) 18 (9.2) 49 (5.1) 8 (4.3) 55 (5.2) 4 (3.5) 12 (2.8) 46 (6.5) 21 (3.2) 38 (7.6) 26 (4.5) 33 (5.7) Category Age >80 Male ACS at admission Diabetes Renal failure at admission Planed OAC at randomization Crusade score > median (35) Anemia, transfusion or bleeding leading to hospitalization Planned major surgery in following year Cancer in last 3 years* Multi-vessel disease at admission Total stent length > 30 mm Minimal stent diameter < 3 mm N BMS: Events (%) 72 (9.4) 41 (10.6) 33 (9.3) 80 (10.0) 86 (10.1) 27 (9.0) 74 (9.4) 39 (10.7) 88 (10.6) 15 (6.7) 80 (10.7) 33 (8.2) 56 (10.7) 39 (8.7) P-value for interaction 95 (9.9) 18 (9.6) 89 (9.5) 23 (11.5) 102 (9.8) 11 (9.8) 28 (6.4) 84 (12.0) 51 (7.4) 61 (13.6) 41 (7.2) 71 (12.4) 0.03 0.17 0.92 0.55 0.57 0.02 0.61 0.02 0.43 0.59 0.64 0.48 0.26 .125 .25 .5 1 Hazard Ratio (95% CI) 2 4 DAPT During Follow-Up 94.9% % 100 SAPT 80 60 40 9.5% 20 DAPT 0 0 30 90 180 270 390 Day Since Randomization DAPT= dual antiplatelet treatment or clopidogrel alone + vitamin K antagonist during first 30 days Bleeding During 12 Months Follow-Up % 25 20 DCS 18.1 BMS 19.1 13.9 15 14.7 10 7.2 7.3 5 0 BARC 1-5 BARC 2-5 BARC 3-5 p = 0.55 p = 0.68 p = 0.96 Conclusions LEADERS FREE is the first randomized clinical trial dedicated to HBR patients Such patients are often excluded from stent and drug trials, constitute a rapidly growing proportion of PCI candidates and suffer high event rates Together with a one-month only DAPT course, the use of a BA9-DCS was both significantly safer and more effective than a control BMS in HBR patients LEADERS FREE published online October 14, 2015 Leaders Free Participating Center Principal Investigator Enrollment Pôle Santé République, FR Janusz Lipiecki 167 Segeberger Kliniken GmbH, DE Gert Richardt 165 Complejo Hospitalario Universitario de Vigo (Hospital Meixoeiro, ES) Andres Iñiguez 132 Clinique de Fontaine, FR Philippe Brunel 110 Arrixaca University Hospital, ES Mariano Valdes Chavarri 91 Hôpital Claude Galien ICPS, FR Philippe Garot 89 Royal Bournemouth Hospital, Dorset Heart Centre, UK Suneel Talwar 84 Clinique Saint Hilaire, FR Jacques Berland 81 Groupe Hospitalier Mutualiste de Grenoble (GHM), FR Mohamed Abdellaoui 77 CHU Toulouse Rangeuil, FR Didier Carrié 76 HP Jacques Cartier, FR Thomas Hovasse 65 Universität Leipzig-Herzzentrum, DE Philipp Lurz 57 GCS ES Axium – Rambot, FR Luc Maillard 52 Triemli Hospital, CH Franz Eberli 47 Charité Campus Virchow Klinikum, DE Florian Krackhardt 44 Craigavon Cardiac Centre, UK Ian B. A. Menown 43 West of Scotland Regional Heart and Lung Centre, Golden Jubilee National Hospital, UK Keith G. Oldroyd 42 Tan Tock Seng Hospital, SG Paul Ong 41 Kings College Hospital, UK Jonathan Byrne 41 St. Thomas' Hospital, UK Simon Redwood 41 Leaders Free Participating Center Principal Investigator Enrollment Aarhus University Hospital – Skejby, DK Evald H. Christiansen 39 Universitäts-Herz-Zentrum Freiburg-Bad Krozingen, DE Franz-Josef Neumann 35 Queen Mary Hospital, HK Stephen Lee 35 Schwarzwald-Baar Klinikum, Villingen-Schwenningen GmbH, DE Werner Jung 32 San Camillo Forlanini – Circonvallazione, IT Roberto Violini 32 University of Catania – Ferrarotto Hospital, IT Corrado Tamburino 31 National Hear Institute, MY Robaayah Zambahari 31 University Hospital La Paz, ES Raul Moreno 30 Siriraj Hospital, TH Damras Tresukosol 30 University of Milan, Department of Cardiovascular Sciences, IT Antonio Bartorelli 29 Newcastle Upon Tyne Hospitals NHS Trust, IT Latvian Center of Cardiology, Pauls Stradins Clinical University Hospital, LV European Hospital Georges Pompidou, FR Azfar Zaman 27 Andrejs Erglis 26 Christian Spaulding 24 Ospedale Bolognini, IT Maurizio Tespili 24 Hospital 12 de Octubre, ES Agustin Albarran 24 Trondheim University Hospital, NO Rune Wiseth 23 University Hospital Zurich, CH Oliver Gamperli 23 Centre Hospitalier Universitaire Vaudois (CHUV), CH Eric Eeckhout 23 ZNA Middleheim, BE Stefan Verheye 22 Isala Klinieken Zwolle, NL Marcel Gosselink 22 Leaders Free Participating Center Principal Investigator Enrollment Ospedale Niguarda Ca Granda, IT Silvio Klugmann 21 Royal Victoria Hospital, CA Sonny Dandona 20 Brighton and Sussex University Hospitals NHS Trust, UK David Hildick-Smith 20 The James Cook University Hospital, UK Mark De Belder 20 National Heart Centre Singapore, SG LIM Soo Teik 19 Cardiocentro Ticino, CH Tiziano Moccetti 19 MonashHeart, AU Ian Meredith 17 Northern General Hospital, UK Ever Grech 16 CHU Rennes, Hôpital Pontchaillou, FR Marc Bedossa 15 Queen Alexandra Hospital, UK Philip Strike 15 The Prince Charles Hospital, AU Darren Walters 14 San Raffaele Hospital – Invasive Cardiology Unit, IT Antonio Colombo 14 Clinique Pasteur, FR Jean Fajadet 13 Elisabeth-Krankenhaus Essen, DE Christoph Naber 13 Beaumont Hospital, IE David Foley 12 Rabin Medical Center – Belinson and Hasharon Hospitals, IL Ran Kornowski 12 Belfast Health and Social Care Trust, Belfast City Hospital, UK Simon James Walsh 11 Harefield Hospital, UK Piers Clifford 11 Clinique les Franciscaines, FR Eric Maupas 10 La Tour Hospital, CH Philip Urban 10 Leaders Free Participating Center Principal Investigator Enrollment Hadassah Hebrew University Medical Center, IL Haim Danenberg 9 UZ Leuven, BE Christophe Dubois 8 Copenhagen University Hospital, DK Thomas Engström 8 Clinique Saint-Pierre, FR Marc Eric Moulichon 7 Hôpital Cardiologique – CHRU de Lille, FR Eric Van Belle 7 National University Health System, SG Chan Koo Hui 7 Medical University of Vienna, AT Irene Lang 6 Tel Aviv Medical Center – Intervential Cardiology, IL Shmuel Banai 5
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