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

EuroPCR 2016

Conflicts of Interest

Christoph K Naber is shareholder of

CERC, the CRO responsible for this trial

Background

LEADERS FREE ACS

• 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)

Objectives

LEADERS FREE ACS

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

Objectives

LEADERS FREE ACS

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

Drug Coated Stent (DCS)

BioFreedom™

Potential Advantages:

• Avoid any possible polymer-related adverse effects

• Rapid drug transfer to vessel wall (98% within one month2)

• 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

Trial Design

LEADERS FREE

Prospective, double-blind randomized (1:1) trial

2466 high bleeding risk (HBR) PCI patients

vs.

DAPT mandated for 1 month only, followed by long-term SAPT

BioFreedom™

DCS

Gazelle™

BMS

• 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

Primary Endpoints

LEADERS FREE

Urban P et al. N Engl J Med 2015;373:2038-47

Efficacy (clinically driven TLR) Safety (cardiac death, MI, ST)

BMS DCS BMS DCS

Study Flow

LEADERS FREE ACS

1 did not undergo PCI 2 did not undergo PCI

331 were assigned to BMS 331 were assigned to DCS

330 are include in the analysis* 329 are include in the analysis*

662 ACS patients underwent randomized

323 (97.8%) completed

12-month visit or died

320 (97.2%) completed

12-month visit or died

*N=659 (554 NSTEMI and 105 STEMI)

Study Population

LEADERS FREE ACS

Parameter DCS

(N=330)

BMS

(N=329)

Total

(N=659)

p-value

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(%) 57 (17.2) 48 (14.5) 105 (15.9) n.s.

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

Criteria for High Risk of Bleeding*

LEADERS FREE ACS

* There were no significant differences (P<0.05) between the two groups

* n=1.8 per patient

2,1

1,2

1,6

1,8

3,6

5,8

4,6

11,2

10,9

24

24,3

30,7

69,6

2,1

1,2

1,8

1,2

4,2

5,5

7

10,6

11,5

22,1

18,8

23,9

70,6

0 10 20 30 40 50 60 70

Prior intracerebral bleed

Severe chronic liver disease

Stroke < 1 yr

Thrombocytopenia*

Glucocorticoids or NSAID ‡

Nonadherence to > 30d DAPT

In hospital for bleeding < 1 year

Cancer in previous 3 years

Major surgery in the next year

Hb < 11g/dl or TF < 4 weeks

Creat. Clearance < 40 ml/min

Oral anticoagulation after PCI

Age ≥ 75

DCS (N=330)2 BMS (N=329)

(%)

Procedural Data

LEADERS FREE ACS

Parameter DCS

(N=330)

BMS

(N=329)

Total

(N=659)

p-value

Lesion Length mm

(mean±SD)

18.3±11.3 17.6±8.9 17.9±10.1 n.s.

Lesion Length ≥30 mm N(%) 33 (6.7) 40 (7.2) 73 (7.0) n.s.

RVD mm

(mean±SD)

3.0±0.5 3.0±0.5 3.0±0.5 n.s.

RVD ≤2.75 mm

(mean±SD)

166 (33.9) 167 (30.0) 333 (31.8) n.s.

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.

Stent Length per patient (mm)

(mean±SD)

33.4±23.3 36.5±26.5 35.0±25.0 n.s.

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)

Clinically driven Target Lesion Revascularization - 12 Month FU

LEADERS FREE ACS

9,0

3,9

0

1

2

3

4

5

6

7

8

9

10

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Cu

mu

lati

ve

In

cid

en

ce

(%

)

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

Primary Efficacy Endpoint

HR 0.41: 95% Cl 0.21 to 0.82; p=0.009

Cardiac Death, MI, or Def / Prob ST- 12 Month FU

LEADERS FREE ACS

18,5

9,3

0

2

4

6

8

10

12

14

16

18

20

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Cu

mu

lati

ve

In

cid

en

ce

(%

)

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

Primary Safety Endpoint

HR 0.48: 95% Cl 0.31 to 0.75; p=0.001

12 Month Follow-up

LEADERS FREE ACS

0

2

4

6

8

10

12

14

16

Death Cardiac death Myocardial infarction ST (Def/Prob) Bleeding (BARC 3-5)

DCS BMS

n.s. n.s. p=0.048 p=0.005 0.099

12 Month Follow-up by Subgroup

LEADERS FREE ACS

Conclusions

LEADERS FREE ACS

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. Naber1, Philip Urban2, Paul J. Ong3, Mariano Valdes-Chavarri4, Alexandre A. Abizaid5, Stuart J. Pocock6, Franco Fabbiocchi7, Christophe Dubois8, Samuel Copt9, Samantha Greene9, and Marie-Claude Morice10, for the LEADERS FREE Investigators

THANK YOU FOR YOUR TIME

BACKUP SLIDES

Medication

LEADERS FREE ACS

Parameter DCS

(N=330)

BMS

(N=329)

p-value

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

Stratification of MI at 12-Month Follow-up

LEADERS FREE ACS

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.