LEADERS

A Prospective, Randomised, Non-Inferiority Trial Comparing Biolimus-Eluting Stent With Biodegradable Polymer Versus Sirolimus-Eluting Stent With Durable Polymer

2-Year Clinical Follow-Up Volker Klauss, MD

Patrick W. Serruys, Simon Wandel, Pawel Buszman, Axel Linke, Thomas Ischinger, Franz Eberli, Roberto Corti, William Wijns, Marie-Claude Morice, Carlo di Mario, Robert-Jan van Geuns, Pedro Eerdmans, Gerrit Anne van Es, Peter Jüni, Stephan Windecker

Disclosures

•

Volker Klauss, MD

•

Nothing to disclose

Background: LEADERS at 1-Year

• •

Comparison of BES with biodegradable polymer to SES with durable polymer resulted in:

 Non-inferior MACE rate at 9 months (primary endpoint met: 9.2% BES vs. 10.5% SES, P non-inf =0.003)*  Non-inferiority in MACE confirmed at 12 months (10.7% BES vs. 12.1% SES, P non-inf <0.001)  BES showed superior strut coverage and stent apposition at 9 months in OCT sub-analysis  Similar rates of stent thrombosis (ARC definition) at 12 months

Two year clinical outcomes have not yet been reported

* Windecker S et al. THE LANCET 2008; 372 No 9644: 1163-1173

Biolimus-A9™ Eluting Stent

• Biolimus is a semi-synthetic sirolimus analogue with 10x higher lipophilicity and similar potency as sirolimus.

• Biolimus is immersed at a concentration of 15.6  g/mm into a biodegradable polymer, polylactic acid, and applied solely to the abluminal stent surface by a fully automated process.

• Polylactic acid is co-released with biolimus and completely desolves into carbon dioxide and water after 6-9 months .

• The stainless steel stent platform has a strut thickness of 112  m with a quadrature link design.

Trial Design

Stable and ACS Patients Undergoing PCI

Assessor-blind 1:1 Randomisation N=1700 Patients BES BioMatrix Flex N=850 1:3 Randomisation SES Cypher Select N=850 Clinical F/U N=640 1 o endpoint: 2 o endpoints: Angio F/U N=210 Angiographic study: Clinical F/U N=640 Angio F/U N=210 CV death, MI, clinically-indicated TVR (9 month) Death, CV death, MI, TLR, TVR Stent thrombosis according to ARC In-stent % diameter stenosis Late loss, binary restenosis DAPT recommended for 12 month

Patient Eligibility

Inclusion Criteria Exclusion Criteria

Coronary artery disease Known allergy to

- Stable angina - aspirin, clopidogrel, heparin, - Silent ischemia stainless steel, sirolimus, biolimus, - Acute coronary syndrome contrast material including UA, NSTEMI and STEMI

At least one lesion with

- Diameter stenosis > 50% - RVD: 2.25-3.5 mm - Number of lesions: no limitation - Number of vessels: no limitation - Lesion length: no limitation

Written informed consent Planned, elective surgery within 6 months of PCI unless dual APT could be maintained Pregnancy Participation in another trial

Patient Demographics

Age in years Male gender Arterial hypertension Diabetes mellitus - insulin-dependent Hypercholesterolemia Family history Smoking Previous MI Previous PCI - with drug-eluting stent Previous CABG Chronic stable angina BES 857 Patients 65  11 75% 74%

26%

10% 65% 40% 24%

32% 36%

12% 45%

11%

SES 850 Patients 65  11 75% 73%

23%

9% 68% 44% 25%

33% 37%

14% 44%

13%

Patient Characteristics

BES 857 Patients Acute coronary syndrome - Unstable angina - Non-ST-elevation MI - ST-elevation MI Left ventricular ejection fraction Number of lesions per patient 55% 22% 17% 56  16% 11% 1.5  0.7

Lesions per patient - 1 lesion - 2 lesions - 3 lesions - > 4 lesions De novo lesions 63% 29% 7% 1% 92% Long lesions (>20 mm) Small vessels (RVD <2.75 mm) Off label use 31% 68% 81% SES 850 Patients 56% 21% 18% 55  17% 12% 1.4  0.7

69% 22% 8% 2% 91% 27% 69% 78%

Patient Flow - Clinical

Randomized (N=1,707)

BES (N=857)

Lost to F/U = 2 Patient withdrawal = 9 Other = 9

SES (N=850)

3 = Lost to F/U 6 = Patient withdrawal 12 = Other

BES (N=837)

1-year follow-up * (N=1,666; 97.6%) Lost to F/U = 0 Patient withdrawal = 2 Other = 3

SES (N=829)

0 = Lost to F/U 0 = Patient withdrawal 6 = Other 2-year follow-up * (N=1,655; 97.0%)

BES (N=832) SES (N=823)

*F/U window ± 28 days

20 BES SES 15 % 10 5

MACE

1-year HR 0.88 [0.66 to 1.17] P = 0.37* 12.1% Δ 1.4% 10.7% 2-year HR 0.84 [0.65 to 1.08] P = 0.18* 15.4% Δ 2.4% 13.0% Number at risk BES SES 0 0 857 850 3 6 9 12 Months 15 18 804 791 795 786 777 771 760 747 742 727 731 712 MACE = Cardiac Death, MI, or Clinically-Indicated TVR * P values for superiority 21 725 707 24 716 694

10 8 6

Cardiac Death or MI

1-year HR 1.01 [0.70 to 1.45] P = 0.95* BES 2-year HR 0.92 [0.66 to 1.27] P = 0.59* SES 6.9% 6.9% Δ0% 9.1% Δ0.8% 8.3%

4 2

Number at risk BES SES

0 0

857 850

3

804 801

6

797 798

9

788 793

12

Months 780 779

15

772 770 *P values for superiority

18

764 758 760 755

21

752 742

24

10 8

Clinically-Indicated TVR

BES SES 1-year HR 0.82 [0.56 to 1.19] P = 0.29* 2-year HR 0.86 [0.62 to 1.20] P = 0.37* 8.8% Δ1.1% 7.2% Δ1.2% 7.7%

6

6.0%

4 2

Number at risk BES SES

0 0

857 850

3

832 8814

6

823 809

9

805 791

12

Months 788 770

15

767 747 *P values for superiority

18

755 735

21

750 729

24

741 717

%

2-Year Safety Endpoints

P=0.71* P=0.42* P=0.57* P=0.35* P=0.24* P=0.59*

*P values for superiority

2-Year Efficacy Endpoints

P=0.25* P=0.58* P=0.54* P=0.37* P=0.17*

% 1 1 1 Clinically Indicated *P values for superiority

Stratified Analysis of MACE @ 2 Years

Overall Diabetes mellitus Yes No Acute coronary Yes No ST-elevation MI Yes No Left anterior Yes No Multivessel disease Yes No Off-label use Yes No De-novo lesions Yes No Small-vessel disease Yes No Long lesions Yes No BES 109/857 44/223 66/634 56/470 54/387 11/135 99/722 46/407 64/449 31/209 79/648 97/696 13/160 96/788 14/68 80/585 30/271 43/262 67/594 SES

Risk Ratio (95% CI)

129/850 0.83 (0.64 to 1.07) 36/191 93/659 70/473 59/377 27/140 102/710 62/417 67/431 41/176 88/674 113/665 16/183 113/774 16/74 85/568 44/280 45/225 84/623 1.06 (0.68 to 1.65) 0.73 (0.53 to 1.00) 0.80 (0.56 to 1.13) 0.89 (0.61 to 1.29) 0.40 (0.20 to 0.80) 0.96 (0.73 to 1.27) 0.75 (0.51 to 1.10) 0.92 (0.65 to 1.29) 0.63 (0.39 to 1.00) 0.93 (0.68 to 1.26) 0.81 (0.62 to 1.07) 0.93 (0.45 to 1.94) 0.83 (0.63 to 1.09) 0.96 (0.47 to 1.96) 0.91 (0.67 to 1.24) 0.69 (0.43 to 1.10) 0.80 (0.53 to 1.23) 0.83 (0.60 to 1.15)

P Value

0.79

0.05

0.2

0.53

< 0.01

0.76

0.14

0.62

0.05

0.63

0.13

0.85

0.18

0.9

0.57

0.11

0.31

0.26

P Int

ns ns ns 0.02

ns ns ns ns ns ns

.25

.5

1 2 4

3.0

2.5

2.0

Definite ST through 2 years

Zoom at 1% scale 2.5% +0.5% BES SES 2.2% 2.0% +0.2% 2.0%

1.5

1.0

0.5

0.0

0 3 6 9 12 15 18 21 24

Primary and Secondary Definite ST

early (30d) late (30d-1 year) very late (>1year) BES N=857 1,6 0,4 0,2 SES* N=850 1,7 0,5 0,5 0 1 2 3 Definite Stent Thrombosis % According to ARC Definition

*Includes one secondary, definite ST occurring at 60 days in a patient who had early ST at 3 days

Antiplatelet Agent Utilization

BES SES

P value

Aspirin

- At 9 months - At 12 months

96.6% (n=818) 97.0% (n=810)

- At 24 months

94.9% (n=789)

Clopidrogel/Thienopyridine

- At 9 months

95.6% (n=818)

- At 12 months

68.1% (n=810)

- At 24 months

23.4% (n=789) 97.4% (n=798) 96.1% (n=801) 94.2% (n=778) 95.2% (n=798) 66.5% (n=801) 24.3% (n=778)

0.39

0.34

0.58

0.81

0.52

0.72

Effect of DAPT Discontinuation

Overall Population

P = 0.73*

Patient who d/c DAPT

*P values for superiority N=0/154 N=2/163 N=0/484 N=3/479

Conclusions

•

Overall population

Non-inferiority of BES vs SES in an all-comers population was sustained up to 2 years

•

In the overall LEADERS population there were similar outcomes for BES and SES with respect to:

• • • MACE - BES:13% vs SES: 15.4% (

P Sup =

0.18) Cardiac Death/MI - BES: 8.3% vs SES: 9.1% (

P Sup =

0.59) Clinically indicated TVR – BES: 7.7% vs SES: 8.8% (

P Sup =

0.37)

Conclusions

•

Subgroup analysis STEMI patients

• improved rate of MACE with BES compared to SES •

(8.1% vs 19.3%

P sup < 0.01

) Very Late Stent Thrombosis

•

Although this was an all-comers study, very late stent thrombosis events were rare (BES 0.2% vs SES 0.5%

P Sup =

0.73)

•

There were no VLST events in BES patients following discontinuation of DAPT