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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.