two$year)outcomes)of) high)bleeding)risk)patients)after...
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Two-Year Outcomes of High Bleeding Risk Patients after Polymer-Free Drug-Coated Stents
Philip Urban, Philippe Garot, Damras Tresukosol, Stuart J. Pocock, Ian Meredith, Alex Abizaid, Didier Carrié,
Christoph Naber, Andrés Iñiguez, Suneel Talwar, Ian B.A. Menown, Evald H. Christensen, Samuel Copt, John Gregson, Hans-Peter Stoll,Samantha Greene,
and Marie-Claude Morice for the LEADERS FREE Investigators
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
All-comers HBR
≈20%
BioFreedom™ Drug Coated Stent (DCS)
Advantages:• Avoid any possible polymer-related adverse effects• Rapid drug transfer to vessel wall (98% within one month2)• Good fit with short DAPT
Selectively Micro-Structured Surface Holds Drug in Abluminal Surface Structures
BA9TMDrug 10 Times More Lipophilic than Sirolimus1
Sirolimus Zotarolimus Everolimus Biolimus A9TM0
20
40
60
80
100 %
+/- 2.8% (valid for all drugs test)
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) trial2466 High bleeding risk (HBR) PCI patients
vs.
DAPT mandated for 1 month only, followed by long-term SAPT
BioFreedom™ DCS
Gazelle™BMS
• Primary safety endpoint:Composite of cardiac death, MI, definite / probable stent thrombosisat 1 year (non-inferiority then superiority)
• Primary efficacy endpoint:Clinically-driven TLR at 1 year (superiority)
Efficacy (cd-TLR) Safety (cardiac death, MI, ST)
BMSDCS BMSDCS
Primary Endpoints at 1 Year
0
90 180 270 390
Cumulative Percentage with Event
3
6
9
12
Days0
12.9%
9.4%
HR 0.71, (95% CI = 0.56‒0.91)p < 0.0001 for non-inferiorityp = 0.005 for superiority
15%
0
90 180 270 390
Cumulative Percentage with Event
3
6
9
12
Days0
9.8%
5.1%
p for superiority < 0.001HR 0.50, (95% CI = 0.37‒0.69)
%
Urban P et al. N Engl J Med 2015;;373:2038-47
Two Year Follow-up
Enrollment and Follow-Up2466 patients randomized
16 with no PCIperformed
18 with no PCIperformed
20 (1.7%) patientswithdrew before24-month visit orwere lost to FU
28 (2.3%) patientswithdrew before24-month visit or were lost to FU
1191 (98.3%) completed24-month visit or died
1193 (97.7%) completed24-month visit or died
1,227 BMS 1,239 DCS
1,211 analyzed (modified ITT)1,221 analyzed (modified ITT)
96.6
3.1 0.4
36.3
96.9
2.8 0.2
34.6
DAPT SAPT no APT OAC0
20
40
60
80
100DCS BMS
Antithrombotic Medication at Discharge
None of the regimens differ at p < 0.05
%
9.2
88.1
2.8
35.9
9.7
87.2
2.9
34.9
DAPT SAPT no APT OAC0
20
40
60
80
100
DCS BMS
Antithrombotic Medication after 1 month visit*
%
None of the regimens differ at p < 0.05
* at day 37
5.3
78.8
15.8
37.7
7.6
76.8
15.6
38.0
DAPT SAPT no APT* OAC0
20
40
60
80
100DCS BMS
Antithrombotic Medication at 2 years
%
*82% on OACp=0.03
Primary Safety Endpoint (Cardiac Death, MI, ST) at 2 year
0180 365 545 730
Patients with Event (%)
5
10
15
Days0
15.3%
12.6%
HR 0.80 (95%CI 0.64-0.99) p = 0.039
20
Number at Risk
DCS 1221 1104 1052 1006 620
BMS 1211 1067 1010 973 587
12.7%
9.2%
2 year FU was obtained at 730 days +60 days
6.67.4
2.1
6.9
10.1
2.3
0
2
4
6
8
10
12
Cardiac death MI ST (def / prob)
DCS BMS
Components of Safety Endpoint(2 years)%
p = 0.04 p = 0.76p = 0.69
13.1
6.5
1.0 1.10.1
13.8
6.9
1.2 1.00.1
All death Non-card death ST acute / subacute
ST late ST very late0
2
4
6
8
10
12
14
16DCS BMS
Selected Secondary Safety Endpoints(2 years)
%
None of these endpoints differ at p < 0.05
Primary Efficacy Endpoint (Clinically-Driven TLR) at 2 Years
0
Patients with Event (%)
5
10
15
12.0%
6.8%
20
Number at Risk
DCS 1221 1129 1061 1013 626
BMS 1211 1074 999 945 561
180 365 545 730 Days0
9.3%
4.9% HR 0.54 (95%CI = 0.41-0.72)P<0.0001
2 year FU was obtained at 730 days +60 days
Age >80NoYes
MaleNoYes
ACS at admissionNoYes
DiabetesNoYes
Renal failure at admissionNoYes
Planned OAC at randomizationNoYes
Crusade score > median (35)NoYes
Anemia, transfusion or bleeding leading to hospitalizationNoYes
Planned major surgery in following yearNoYes
Cancer in last 3 years*NoYes
Multi-vessel disease at admissionNoYes
Total stent length > 30 mmNoYes
Minimal stent diameter < 3 mmNoYes
Category
1602830
7381694
1773659
1622805
1754466
1553879
1061962
2007425
2000406
2193239
9061493
1409999
11951213
N
41 (5.5)36 (9.4)
21 (6.3)56 (7.0)
62 (7.5)15 (5.0)
52 (7.1)25 (6.4)
56 (6.8)19 (9.5)
47 (6.4)30 (7.5)
31 (6.4)40 (9.2)
58 (6.2)19 (9.8)
66 (7.1)9 (4.8)
73 (7.1)4 (3.5)
15 (3.5)61 (8.9)
27 (4.2)50 (10.3)
31 (5.5)46 (8.2)
Events (%)DCS:
90 (11.9)46 (12.1)
42 (12.1)94 (12.0)
105 (12.6)31 (10.4)
92 (11.9)44 (12.2)
100 (12.1)22 (10.4)
92 (12.4)44 (11.2)
65 (12.6)45 (10.2)
114 (12.0)22 (12.3)
110 (11.9)25 (12.5)
123 (12.0)13 (11.9)
37 (8.6)97 (14.1)
64 (9.4)71 (16.1)
48 (8.5)87 (15.5)
Events (%)BMS:
0.07
0.67
0.49
0.79
0.14
0.43
0.04
0.18
0.45
0.30
0.27
0.27
0.39
interactionP-value for
0.07
0.67
0.49
0.79
0.14
0.43
0.04
0.18
0.45
0.30
0.27
0.27
0.39
interactionP-value for
1.125 .25 .5 1 2 4Hazard ratio (95% CI)
Efficacy endpoint(clinically driven TLR)
Age >80NoYes
MaleNoYes
ACS at admissionNoYes
DiabetesNoYes
Renal failure at admissionNoYes
Planned OAC at randomizationNoYes
Crusade score > median (35)NoYes
Anemia, transfusion or bleeding leading to hospitalizationNoYes
Planned major surgery in following yearNoYes
Cancer in last 3 years*NoYes
Multi-vessel disease at admissionNoYes
Total stent length > 30 mmNoYes
Minimal stent diameter < 3 mmNoYes
Category
1602830
7381694
1773659
1622805
1754466
1553879
1061962
2007425
2000406
2193239
9061493
1409999
11951213
N
80 (10.3)67 (16.9)
43 (12.4)104 (12.6)
106 (12.4)41 (13.0)
87 (11.4)60 (14.9)
97 (11.3)39 (18.8)
85 (11.5)62 (14.4)
47 (9.4)81 (17.9)
112 (11.6)35 (17.4)
124 (12.7)20 (10.9)
135 (12.7)12 (10.6)
32 (7.5)111 (15.4)
72 (11.0)73 (14.4)
64 (11.2)81 (13.8)
Events (%)DCS:
106 (13.5)74 (18.7)
62 (17.0)118 (14.5)
113 (13.0)67 (21.5)
106 (13.2)74 (19.7)
106 (12.6)60 (25.5)
117 (15.4)63 (15.0)
58 (11.0)99 (21.2)
129 (13.1)51 (26.3)
147 (15.3)29 (13.9)
163 (15.3)17 (15.4)
46 (10.3)131 (18.2)
87 (12.4)89 (19.1)
71 (12.3)105 (17.8)
Events (%)BMS:
0.52
0.42
0.05
0.73
0.34
0.26
1.00
0.22
0.80
0.81
0.63
0.35
0.37
interactionP-value for
0.52
0.42
0.05
0.73
0.34
0.26
1.00
0.22
0.80
0.81
0.63
0.35
0.37
interactionP-value for
1.125 .25 .5 1 2 4Hazard ratio (95% CI)
Composite safety endpoint(cardiac death, MI, ST)
Subgroups at 2 years follow-up
The Balance ofThrombosis and Bleeding
Age > 75 1.56 (1.23–1.97) p<0.001 1.52 (1.13–2.06) p=0.006
Haemoglobin (per 1 mmol/l lower)* 1.32 (1.19–1.46) p<0.001 1.73 (1.52–1.96) p<0.001
* Below 9 mmol/l (145 g/l)
Multivariate Predictors of Primary Safety Endpoint and Major Bleeding (BARC 3-5)
Cardiac death/MI/ST Major Bleeding
Congestive heart failure 1.61 (1.23-2.11) p=0.001
Multivessel disease 1.66 (1.27–2.18) p<0.001 -
Number of stents / patient (per stent) 1.20 (1.09–1.32) p<0.001 -
BMS (vs. DCS) 1.28 (1.03–1.59) p=0.027 -
Serum creatinine > 150 umol/l - 1.58 (1.10–2.27) p=0.012
Planned oral anticoagulants - 2.01 (1.51–2.68) p<0.001
12.9
8.2 8.9
15.3
10.69.2
0
5
10
15
20
cardiac death, MI, ST MI and/or ST BARC 3-5
DCS BMS
Cardiac, Coronary and Major Bleeding events (2 Years Follow-Up)
%
p=0.045p=0.039 p=0.95All % derived from Kaplan-Meier estimates
Mortality During the Year Following a Coronary Thrombotic Event (MI and/or ST) or a Major Bleeding event (BARC 3-5)
Major Bleed Thrombotic Event
0
90 180 270 365
Patients Dead (%)
10
20
25
30
Days Since Event
0
15
5
1-year mortality = 6% for patients with neither thrombotic nor major bleeding events
26%
27%
ConclusionsüAt two years, the use of a BA9-DCS remained both significantly safer and more effective than a control BMS in HBR patients treated with a one-month only DAPT course
üNo subgroup was identified for which use of a BMS was superior to a DCS
üHBR patients suffer from a persistently high incidence of bleeding and thrombotic events, both of which are associated with a high and similar mortality over a one year period
ü Identification of predictors of both the composite primary safety event and major bleeding may help design future trials of DAPT duration for HBR patients