LEADERS FREE - ACS - CK Naber, P Urban, PJ Ong, M Valdes-Chavarri, A Abizaid, SJ Pocock, F Fabbiocchi, C Dubois, S Copt, S Greene and MC Morice for the LEADERS FREE Investigators
Conflicts of Interest EuroPCR 2016 Christoph K Naber is shareholder of CERC, the CRO responsible for this trial
LEADERS FREE ACS Background • For ACS patients undergoing PCI current guidelines recommend in general 12 months DAPT • High bleeding risk patients presenting with ACS undergoing PCI have never been systematically studied. • Current guidelines recommend for these patients: I. Implantation of a DES with 3-6 months DAPT II. Implantation of a BMS with 1-month DAPT Roffi et al. Eur Heart J. 2016;37:267-315 / Levine et al. JACC 2016 (epub ahead of print)
LEADERS FREE ACS Objectives 187: RESET: Kim BK et al, JACC 2012; 60: 1340 E-ZES 3 months DAPT 188: OPTIMIZE: Feres F et al, JAMA 2013; 310: 2510 E-ZES 3 months DAPT 189: EXCELLENT: Gwon HC et al, Circ 2012; 125: 505 DES 6 months DAPT 192: ISAR-SAFE: Schulz-Schupke S et al, EHJ 2015; 36: 1252 DES 6 months DAPT
LEADERS FREE ACS Objectives The aim of this prespecified substudy was to evaluate the safety and efficacy of the BioFreedom ™ BA9 DCS followed by 1 month DAPT in high bleeding risk patients presenting with an ACS
BioFreedom ™ Drug Coated Stent (DCS) Potential Advantages: • Avoid any possible polymer-related adverse effects • Rapid drug transfer to vessel wall (98% within one month 2 ) • Safe to shorten DAPT in High Bleeding Risk patients 1. Data on file at Biosensors Intl 2. Tada et al., Circ Cardiovasc Interv 2010;3;174-183
LEADERS FREE Trial Design Prospective, double-blind randomized (1:1) trial 2466 high bleeding risk (HBR) PCI patients Gazelle™ BioFreedom™ vs. BMS DCS DAPT mandated for 1 month only, followed by long-term SAPT • Primary efficacy endpoint: Clinically-driven TLR at 1 year (superiority) • Primary safety endpoint: Composite of cardiac death, MI, definite / probable stent thrombosis at 1 year (non-inferiority then superiority) Urban P et al. Am Heart J 2013; 165: 704-9
LEADERS FREE Primary Endpoints Efficacy (clinically driven TLR) Safety (cardiac death, MI, ST) DCS BMS DCS BMS Urban P et al. N Engl J Med 2015;373:2038-47
LEADERS FREE ACS Study Flow 662 ACS patients underwent randomized 331 were assigned to DCS 331 were assigned to BMS 2 did not undergo PCI 1 did not undergo PCI 330 are include in the analysis* 329 are include in the analysis* 320 (97.2%) completed 323 (97.8%) completed 12-month visit or died 12-month visit or died *N=659 (554 NSTEMI and 105 STEMI)
LEADERS FREE ACS Study Population Parameter DCS BMS Total p-value (N=330) (N=329) (N=659) Age (mean ± SD) 76.9 ± 10.0 76.5 ± 9.0 76.7 ± 9.5 n.s. Female N(%) 122 (37.0) 110 (33.4) 232 (35.3) n.s. NSTEMI N(%) 273 (82.8) 281 (85.5) 554 (84.1) n.s. STEMI N(%) n.s. 57 (17.2) 48 (14.5) 105 (15.9) Diabetes N(%) 111 (33.8) 108 (32.8) 219 (33.3) n.s. Renal Impairment N(%) 66 (20.1) 81 (24.8) 147 (22.4) n.s. Previous Stroke N(%) 46 (14.1) 26 (7.9) 72 (11.0) 0.01* Atrial Fibrillation N(%) 84 (25.5) 109 (33.1) 193 (29.3) 0.03* Previous MI N (%) 63 (19.1) 82 (24.9) 145 (22.0) n.s. Previous CABG N(%) 24 (7.3) 23 (7) 47 (7.1) n.s. Previous PCI N(%) 55 (16.7) 67 (20.4) 122 (18.5) n.s. *=Cox proportional hazard models displayed no influence on outcomes at FU
LEADERS FREE ACS Criteria for High Risk of Bleeding* Age ≥ 75 70,6 69,6 23,9 Oral anticoagulation after PCI 30,7 18,8 Creat. Clearance < 40 ml/min 24,3 22,1 Hb < 11g/dl or TF < 4 weeks 24 11,5 Major surgery in the next year 10,9 10,6 Cancer in previous 3 years 11,2 7 In hospital for bleeding < 1 year 4,6 5,5 Nonadherence to > 30d DAPT 5,8 4,2 Glucocorticoids or NSAID ‡ 3,6 1,2 Thrombocytopenia* 1,8 1,8 Stroke < 1 yr DCS (N=330)2 BMS (N=329) 1,6 1,2 Severe chronic liver disease 1,2 2,1 Prior intracerebral bleed 2,1 (%) 0 10 20 30 40 50 60 70 * There were no significant differences (P<0.05) between the two groups * n=1.8 per patient
LEADERS FREE ACS Procedural Data Parameter DCS BMS Total p-value (N=330) (N=329) (N=659) 18.3 ± 11.3 17.6 ± 8.9 17.9 ± 10.1 Lesion Length mm n.s. (mean ± SD) Lesion Length ≥30 mm N(%) 33 (6.7) 40 (7.2) 73 (7.0) n.s. 3.0 ± 0.5 3.0 ± 0.5 3.0 ± 0.5 RVD mm n.s. (mean ± SD) RVD ≤2.75 mm 166 (33.9) 167 (30.0) 333 (31.8) n.s. (mean ± SD) ACC-Class B2&C* N (%) 244 (30.6) 266 (29.5) 500 (30.0) n.s. LAD N/(%) 192 (58.2) 174 (52.9) 366 (55.5) n.s. 33.4 ± 23.3 36.5 ± 26.5 35.0 ± 25.0 Stent Length per patient (mm) n.s. (mean ± SD) Overlapping Stent N(%) 49 (14.8) 62 (18.9) 111 (16.9) n.s. Procedural Success N(%)** 326 (95.0) 341 (94.7) 667 (94.9) n.s. * Lesion Level; LL=Lesion Length; RVD=Reference Vessel Diameter; LAD=Left Anterior Descending; SD = Standard Deviation; **: includes all procedures (index and staged)
LEADERS FREE ACS Clinically driven Target Lesion Revascularization - 12 Month FU 10 9,0 Primary Efficacy Endpoint Cumulative Incidence (%) 9 HR 0.41: 95% Cl 0.21 to 0.82; p=0.009 8 7 6 5 3,9 4 3 2 1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Months 329 321 316 302 292 284 282 279 277 275 272 266 260 255 330 324 318 317 313 310 307 302 299 297 294 291 287 283
LEADERS FREE ACS Cardiac Death, MI, or Def / Prob ST- 12 Month FU 18,5 20 Primary Safety Endpoint Cumulative Incidence (%) 18 HR 0.48: 95% Cl 0.31 to 0.75; p=0.001 16 14 12 9,3 10 8 6 4 2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Months 329 312 307 295 283 274 272 269 265 260 258 254 247 245 330 319 310 308 303 299 294 288 285 284 284 281 279 275
LEADERS FREE ACS 12 Month Follow-up DCS BMS n.s. p=0.048 p=0.005 0.099 n.s. 16 14 12 10 8 6 4 2 0 Death Cardiac death Myocardial infarction ST (Def/Prob) Bleeding (BARC 3-5)
LEADERS FREE ACS 12 Month Follow-up by Subgroup
LEADERS FREE ACS Conclusions In ACS patients with high bleeding risk a polymer-free BA9- DCS combined with 1-month DAPT displays significantly better efficacy and safety than a BMS, the latter driven by significantly lower cardiac mortality and MI. Current guidelines should be reconsidered for high bleeding risk patients presenting with ACS: → BMS can no longer be recommended → Data on DES with shortened DAPT are scarce → BioFreedom ™ BA9 -DCS has strongest evidence in these patients.
LEADERS FREE ACS Christoph K. Naber 1 , Philip Urban 2 , Paul J. Ong 3 , Mariano Valdes-Chavarri 4 , Alexandre A. Abizaid 5 , Stuart J. Pocock 6 , Franco Fabbiocchi 7 , Christophe Dubois 8 , Samuel Copt 9 , Samantha Greene 9 , and Marie-Claude Morice 10 , for the LEADERS FREE Investigators
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BACKUP SLIDES
LEADERS FREE ACS Medication Parameter DCS BMS p-value (N=330) (N=329) UFH 282 (82.2) 280 (77.6) 0.12 LMWH 28 (8.2) 34 (9.4) 0.56 Bivalirudin 7 (2) 16 (4.4) 0.07 GPIIbIIIa antagonist 7 (2) 5 (1.4) 0.50 DAPT at day 23 317 (97.8) 311 (95.7) 0.18 DAPT at day 37 28 (8.7) 49 (15.2) 0.01* In LEADERS FREE 659/2466 patients had an ACS (554 NSTEMI and 105 STEMI) *=Cox proportional hazard models displayed no influence on outcomes at FU
LEADERS FREE ACS Stratification of MI at 12-Month Follow-up Given that many patients di not undergo control angiography when readmitted during follow-up, a definite distinction between Types I, 4b and 4c was sometimes difficult to establish.
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