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