Biolimus-Coated vs. Bare-Metal Coronary Stents in High Bleeding Risk Patients

Transcription

1 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

2 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 Grant / Research Support Consulting Fees / Honoraria Company Biosensors Europe Edwards Lifesciences Terumo Abbott Vascular

3 High Bleeding Risk Patients (HBR) Mostly excluded from device and APT trials Never specifically studied Current guideline recommendations: BMS + one month DAPT DES + shortened DAPT Ventes All-comers HBR

4 BioFreedom Drug Coated Stent (DCS) Selectively Micro-Structured Surface Holds Drug in Abluminal Surface Structures BA9 TM Drug 10 Times More Lipophilic than Sirolimus 1 Potential Advantages: 100 % Sirolimus Zotarolimus Everolimus Biolimus A9 TM Avoid any possible polymer-related adverse effects Rapid drug transfer to vessel wall (98% within one month 2 ) Safe to shorten DAPT? /- 2.8% (valid for all drugs test) 1. Data on file at Biosensors Intl; 2. Tada et al., Circ Cardiovasc Interv 2010;3;

5 Median In-Stent LLL at 12-month Follow-up 2 nd Cohort Primary Endpoint 0.5 p = (non-inferiority) BioFreedom BioFreedom low-dose Taxus N = 31 N = 35 N = 31 Costa R et al. JACC interv (published online October 11, 2015 DOI /j.jcin )

6 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?

7 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)

8 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 (< / 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

9 Trial Organization PIs: Executive Committee: Statistics: DSMB: CEC: CRO: e-crf: Sponsor: 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 R. Mehran (Chair), A. Baumbach, S. Cook, P. Kala, J. Machecourt, F. Mauri, G. Olivecrona, S. Petronio, F. Ribichini, L. Thuesen CERC, Massy, France (Project Leader U. Windhovel) MERGE Biosensors Europe, Morges, Switzerland

10 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% Endpoints Patients per group: 1228 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

11 Enrollment and Follow-Up 2466 patients randomized 1,239 DCS 1,227 BMS 18 with no PCI performed 16 with no PCI performed 1,221 analyzed (modified ITT) 1,211 analyzed (modified ITT) 25 (2.0%) patients withdrew before 12-month visit or were lost to FU 22 (1.8%) patients withdrew before 12-month visit or Were lost to FU 1196 (98.0%) completed 12-month visit or died 1189 (98.2%) completed 12-month visit or died

12 Inclusion Criteria Applied (1.7 criteria / patient) Age 75 Oral anticoagulants Renal failure Surgery soon Anemia or recent TF Cancer Hospital for bleeding DAPT compliance NSAID or steroids Thrombocytopenia Stroke < 1 year Severe liver disease Prior intracerebral bleed BMS DCS

13 Baseline Characteristics DCS (%) BMS (%) Mean age Female gender BMI 27.5 ± ± 4.6 Diabetes NSTEMI presentation STEMI presentation Prior MI Prior PCI Prior CABG Multivessel CAD Congestive heart failure Atrial fibrillation Peripheral vascular disease Chronic obstructive lung disease ne of the baseline characteristics differ at p < 0.05

14 Index Procedure DCS (%) BMS (%) Radial access Staged procedure Multi-lesion procedure Multi-vessel procedure Number of treated lesions / patient 1.6 ± ± 0.9 LMS SVG Bifurcation ISR CTO ne of the procedure characteristics differ at p < 0.05

15 Index Procedure (Continued) DCS BMS Mean stent diameter 3.0± ±0.4 Mean total implanted stent length / patient 34.5 ± ± 23.4 Mean number of stents implanted / patient 1.9 ± ± 1.2 Lesion success Device success Procedure success UFH during procedure LMWH during procedure Bivalirudin during procedure b3a blocker during procedure ne of the procedure characteristics differ at p < 0.05

16 Antithrombotic Medication at Discharge % 80 DCS BMS DAPT alone Triple therapy* VKA+clopidogrel Other ne of the regimens differ at p < 0.05 * Any oral anticoagulant + DAPT

17 Primary Safety Endpoint (Cardiac Death, MI, ST) % Cumulative Percentage with Event p = for superiority 12.9% 9.4% Days Number at Risk DCS BMS days chosen for assessing primary EP to capture potential events driven by the 360 day FU contact

18 Primary Safety Endpoint Primary Safety Endpoint * DCS (n=1221) BMS (n=1211) Cardiac Death, Myocardial Infarction, or Stent Thrombosis at 390 days 112 (9.4%) 154 (12.9%) Risk difference: -3.6% (95% CI -6.1% to -1.0%) HR 0.71, (95% CI = ) p < for non-inferiority p = for superiority * 3rd Universal definition of MI, Thygesen K et al Circulation 2012;126: ARC definition, Cutlip D et al. Circulation 2007; 115:

19 Components of Safety Endpoint % 10 9 DCS BMS Cardiac death MI ST (def / prob) p = 0.19 p = 0.01 p = 0.70

20 % Selected Secondary Safety Endpoints DCS BMS All death n-card death ST acute / subacute ne of these endpoints differ at p < 0.05 ST late

21 Primary Efficacy Endpoint (Clinically-Driven TLR) % 12 Cumulative Percentage with Event p for superiority < % 5.1% Number at Risk Days DCS BMS days chosen for assessing primary EP to capture potential evens driven by the 360 day FU contact

22 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 = ) p<0.001 for superiority

23 % 14 Secondary Efficacy Endpoints DCS BMS Urgent TLR Cd-TVR Any TVR Any revasc p = p < p < p < 0.005

24 Subgroups Composite safety endpoint (cardiac death, MI, ST) 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 yes yes yes 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) 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) 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) 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) P-value for interaction Hazard Ratio (95% CI)

25 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 Subgroups (continued) Efficacy endpoint (clinically driven TLR) yes yes yes yes N 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) 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) 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) 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) P-value for interaction Hazard Ratio (95% CI)

26 DAPT During Follow-Up % % SAPT % DAPT Day Since Randomization DAPT= dual antiplatelet treatment or clopidogrel alone + vitamin K antagonist during first 30 days

27 Bleeding During 12 Months Follow-Up % 25 DCS BMS BARC 1-5 BARC 2-5 BARC 3-5 p = 0.55 p = 0.68 p = 0.96

28 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

29 LEADERS FREE published online October 14, 2015

30 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

31 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 Azfar Zaman 27 Latvian Center of Cardiology, Pauls Stradins Clinical University Hospital, LV Andrejs Erglis 26 European Hospital Georges Pompidou, FR 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

32 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 rthern 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

33 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