Pivotal Study of the Biolimus A9™

Drug-Coated Stent in High Bleeding Risk Patients:

Primary Report

Mitchell W. Krucoff on behalf of Philip Urban (EU-PI), Study Leadership and the

LEADERS FREE II Investigators

Disclosure Statementof Financial Interest

Within the past 12 months, I, Mitchell Krucoff, have had a financial interest / arrangement or affiliation with the following organizations:

Affiliate / Financial Relationship• Grant / Research Support• Consulting Fees / Honoraria

Company• Abbott Vascular• Biosensors • Boston Scientific• CSI• Medtronic• OrbusNeich• Terumo

LEADERS FREE2,466 HBR pts30 day DAPT

*Urban P et al, NEJM 2015, N Engl J Med 2015;373:2038-47

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

0

90 180 270 390

Cum

ulat

ive

Per

cent

age

with

Eve

nt

3

6

9

12

Days0

9.8%

5.1%

p for superiority < 0.001HR 0.50, (95% CI = 0.37‒0.69)

%

12.9%

BMS

0

90 180 270 390

3

6

9

12

Days0

9.4%

HR 0.71, (95% CI = 0.56‒0.91)p < 0.0001 for non-inferiorityp = 0.005 for superiority

15%

Bleeding (BARC 3-5)

%

7.3%

7.2%

DCS

Primary Endpoints and Major Bleeding at 1 Year

BioFreedom™: Polymer-free Biolimus A9™ Drug-Coated Stent (DCS)

1. Tada et al., Circ Cardiovasc Interv 2010;3; 174-183

LEADERS FREE II StudyPivotal Trial Supporting Device Registration Decision in USA

Design Objectives:ØReproducibility of LEADERS FREE findings

Ø Safety and effectiveness of DCS with 30 day DAPT in HBR patients

Ø Independent prospective HBR cohort

ØGeneralizability of LEADERS FREE findingsØ North American patients and clinical practice

ØExecuted in a single arm design:Ø No equipoise for BMS randomization

LEADERS FREE IIStatistical Analysis Plan

Propensity Analysis:• 40 baseline variable propensity profile• 5 strata (quintiles)

– Compute Primary Endpoint pertreatment within quintile

– Average treatment effect over quintiles 1 2 3 4 5

Ø Controls: Leaders Free BMS patients (n=1,189)Ø Primary Safety Endpoint: Composite of cardiac death and MI at 1 year

(non-inferiority then superiority)

Ø Primary Efficacy Endpoint: Clinically-driven TLR at 1 year (superiority)

DCS BMS

Overall Outcome per Treatment Group

Enrollment: LFII and LF Controls

12 (1.0%) patients withdrewbefore 12 month visit orwere lost to FU

DCSN=1,203

22 (1.8%) patientswithdrew before12 month visit orwere lost to FU

1,189 (98.2%)completed

12 month visitor died

BMSN=1,211

1,148 (95.4%)completed

12 month visitor died

43 (3.6%) 12 month visit pending

1.2

1.2

2.3

2.7

9.2

3.5

3.9

7.8

16.3

12.1

14.7

34.1

60.7

1.6

0.8

2.0

1.5

2.8

3.9

2.7

9.9

16

17.4

20.2

35.6

64.1

0 10 20 30 40 50 60 70

Prior intracerebral bleed

Severe liver disease

Stroke < 1 year

Thrombocytopenia

NSAID or steroids

DAPT compliance

Hospital for bleeding

Cancer

Anemia or recent TF

Surgery soon

Renal failure

Oral anticoagulants

Age ≥ 75

Inclusion Criteria Applied (1.74 criteria / patient)

BMS

DCS

% pts

Number at Risk

BMS 1,211 1,117 1,066 1,040 1,013

Primary Safety Endpoint C

ardi

ac D

eath

/ M

I*

%

0

5

10

15

90 180 3650 270

8.6%

12.3%

p < 0.0001 (non-inferiority)P = 0.0025 (superiority)

Number at Risk

BMS 1,211 1,117 1,066 1,040 1,013

DCS 1,203 1,124 1,086 1,039 469

Risk Difference:• -3.7% (95% CI -6.6% to -1.4%)

• HR 0.67 (95% CI = 0.51 – 0.88)

*3rd Universal definition of MI, Thygesen K et al Circulation 2012;126:2020 –2035.

3.4

5.95.1

8.8

0

1

2

3

4

5

6

7

8

9

10

Cardiac Death MI

DCS BMS

Components of Safety Endpoint

p = 0.0329

%

p = 0.0097

Selected Secondary Safety Endpoints

7.3

1.91.2 0.9

8.7

2.2

1.2 0.9

0

1

2

3

4

5

6

7

8

9

10

All Death ST* ST* Acute /Subacute

ST* Late

DCS BMS

%

*ARC definite / probable.

p = 0.21

p = 0.63

p = 0.75p = 0.87

Category N LF2 DCS: Events (%)

LF1 BMS: Events (%)

Hazard Ratio (95% Cl)

P-value for Interaction

Age >80 NoYes

1658756

69 (8)31 (10)

87 (11)61 (15)

0.40

Female NoYes

1663751

72 (9)28 (8)

98 (12)50 (14)

0.25

ACS at admission Noyes

13481066

47 (7)53 (10)

68 (10)80 (16)

0.59

Diabetes NoYes

1609805

48 (6)52 (13)

88 (11)60 (16)

0.15

Renal failure at admission NoYes

1992422

78 (8)22 (14)

97 (10)51 (21)

0.35

Planed OAC at randomization NoYes

1573841

70 (9)30 (7)

98 (13)50 (12)

0.66

Crusade score > median (35) NoYes

13961018

46 (7)54 (11)

63 (9)85 (18)

0.20

Anemia, transfusion / bleedingleading to hospitalization

NoYes

1977437

74 (8)26 (12)

108 (11)40 (20)

0.50

Planned major surgeryin following year

Noyes

2005387

87 (9)12 (7)

124 (13)24 (11)

0.70

Cancer in last 3 years Noyes

2181231

90 (9)10 (9)

133 (12)15 (13)

0.86

Multi-vessel diseaseat admission

Noyes

7701644

10 (3)90 (10)

40 (9)108 (15)

0.17

Total stent length > 30 mm NoYes

13841030

42 (7)58 (11)

66 (9)82 (17)

0.72

Minimal stent diameter < 3 mm NoYes

11831226

47 (9)53 (9)

58 (10)90 (15)

0.14

1.00.0 0.5 1.5 2.0LF2 Better BMA Better

Subgroups: Composite Safety Endpoint (Cardiac Death, MI)

2.5The p-value is calculated from a Cox proportional hazards model

Number at Risk

BMS 1,211 1,131 1,071 1,030 997

Number at Risk

BMS 1,211 1,131 1,071 1,030 997

DCS 1,203 1,147 1,094 1,035 465

TLR

(%)

%

(Days)

0

5

10

15

90 180 3650

p = 0.0111 (superiority)

6.1%

9.3%

270

Primary Efficacy Endpoint

Difference:• -3.2% (95% CI = -5.5% to -0.7%)• HR 0.63 (95% CI = 0.45 – 0.87)

Secondary Efficacy Endpoints

3.7

6.8

8.7

5.6

10.0

11.6

0

2

4

6

8

10

12

14

Urgent TLR TVR Any Revasc

DCS BMS%

p = 0.022

p = 0.006

p = 0.014

Category N LF2 DCS: Events (%)

LF1 BMS: Events (%)

Hazard Ratio(95% Cl)

P-value for Interaction

Age >80 NoYes

1658756

51 (6)16 (5)

67 (9)40 (10) 0.22

Female NoYes

1163751

46 (6)21 (7)

75 (9)32 (9) 0.94

ACS at admission Noyes

13481066

33 (5)34 (7)

66 (10)41 (8) 0.18

Diabetes NoYes

1609805

33 (5)34 (9)

70 (9)37 (10) 0.07

Renal failure at admission NoYes

1992422

54 (6)13 (9)

93 (10)14 (6) 0.05

Planed OAC at randomization NoYes

1573841

49 (7)18 (5)

75 (10)32 (8) 0.77

Crusade score > median (35) NoYes

13961018

35 (5)32 (7)

69 (10)38 (8) 0.32

Anemia, transfusion / bleedingleading to hospitalization

NoYes

1977437

55 (6)12 (6)

91 (9)16 (8)

0.86

Planned major surgeryin following year

Noyes

2005387

59 (6)7 (4)

86 (9)21 (10) 0.26

Cancer in last 3 years Noyes

2181231

63 (6)4 (4)

96 (9)11 (10) 0.42

Multi-vessel diseaseat admission

Noyes

7701644

7 (2)60 (7)

28 (6)79 (11) 0.36

Total stent length > 30 mm NoYes

13841030

23 (4)44 (9)

48 (7)59 (13) 0.49

Minimal stent diameter < 3 mm NoYes

11831226

23 (4)44 (8)

41 (7)66 (11) 0.82

Subgroups ContinuedEfficacy Endpoint (Clinically-driven TLR)

1.00.0 0.5 1.5 2.0LF2 Better BMS Better

2.5

Number at Risk

BMS 1,211 1,118 1,067 1,041 1,013

DCS 1,203 1,124 1,086 1,039 469

Number at Risk

BMS 1,211 1,118 1,067 1,041 1,013

Unadjusted Primary Safety EndpointLeaders Free and Leaders Free II

(Cardiac Death / MI)

Cum

ulat

ive

Perc

enta

ge w

ith E

vent

0

5

10

15

20%

Days90 180 3650 270

Number at Risk

BMS 1,211 1,118 1,067 1,041 1,013

DCS (LFII) 1,203 1,124 1,086 1,039 469

DCS (LF) 1,221 1,146 1,106 1,082 1,054

12.4%

9.0%

8.6%

Bleeding During 12 Month Follow-Up

19.7

14.3

7.0

19.0

14.5

7.3

0

5

10

15

20

25

BARC 1-5 BARC 2-5 BARC 3-5

DCS BMS%

p = 0.56

p = 0.89

p = 0.88

Conclusionsü Designed to support pivotal U.S.A. registration decision

for polymer-free, Biolimus A9™ coated stent with 30 day DAPT in HBR patients

ü Demonstrates reproducibility of Leaders Free findings showing superior safety (1 year death, MI) and superior efficacy (1 year TLR) of DCS vs. BMS

ü Supports generalizability to patients and practice in North America

ü Implications:

ü Approval decisions for U.S.A.

ü Access & knowledge for best practice in HBR pts