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