1. Randomised comparison of a novel, ultrathin strut biodegradable polymer sirolimus-eluting stent with a durable polymer everolimus-eluting stent for percutaneous coronary revascularization
NCT
Thomas Pilgrim, MD; Dik Heg, PhD; Marco Roffi, MD; David Tüller, MD;
Olivier Muller, MD; André Vuilliomenet, MD; Stéphane Cook, MD;
Daniel Weilenmann, MD; Christoph Kaiser, MD; Peiman Jamshidi, MD;
Bernhard Meier, MD; Peter Jüni, MD; Stephan Windecker, MD
Department of Cardiology, Swiss Cardiovascular Center, University Hospital, Bern; Institute of Social and Preventive Medicine and Clinical Trials Unit
Bern University Hospital, Switzerland

2. Speaker’s name: Thomas Pilgrim
 I have the following potential conflicts of interest to report:
 Research contracts  Consulting
 Employment in industry
 Stockholder of a healthcare company
 Owner of a healthcare company
 Other(s): travel expenses supported by Biotronik
 I do not have any potential conflict of interest

3. Progress with metallic drug-eluting stents
Antiproliferative drug
Paclitaxel
Sirolimus-analogues
SES
BES
ZES
EES
NES
Sirolimus
Biolimus
Zotarolimus
Everolimus
Novolimus
Polymer material
Durable polymer Biodegradable polymer
Platform material & strut thickness
132
140
120 91 87 81 74 60
100 64 80
(μm)
Stainless steel Cobalt-Chromium/Platinum-Chromium
Taxus
Cypher
BioMatrix
Nobori
Endeavor
Yukon PC
Xience
Promus
Resolute
Synergy
Orsiro
DESyne
Combo
Mistent
Ultimaster

4. Baber U et al. J Am Coll Cardiol 2011;58:1569-77
Durable polymer everolimus-eluting stents reduce the risk of definite ST, MI and TVR compared to non-EES
Baber U et al. J Am Coll Cardiol 2011;58:
Meta-analysis of 17 RCTs with 17,101 patients and mean follow-up of 22 months
Definite ST: RR 0.55, 95% CI
TVR: RR 0.77, 95% CI
Definite stent thrombosis
Target vessel revascularization

5. Biodegradable polymer DES reduce the risk of definite ST and TLR compared to first generation DES
Stefanini GG et al, Eur Heart J. 2012;33(10):
Definite stent thrombosis
Target lesion revascularization
Studies
BP DES
DP SES
RR (95% CI)
Studies
BP DES
DP SES
RR (95% CI)
ISAR-TEST 3
20/857
9/1299
1/202
32/850
9/652
2/202
0.62 ( )
0.50 ( )
0.50 ( )
ISAR-TEST 3
88/857
168/1299
17/202
111/850
95/652
21/202
0.79 ( )
0.89 ( )
0.81 ( )
ISAR-TEST 4
ISAR-TEST 4
LEADERS
LEADERS
Overall (I2 = 0.0%, p=0.92)
0.58 ( )
Overall (I2 = 0.0%, p=0.79)
0.84 ( )
0.1
0.2
0.5 1 2 5
0.1
0.2
0.5 1 2 5 10
Risk ratio
Risk ratio
Favours biodegradable polymer DES
Favours durable polymer SES
Favours biodegradable polymer DES
Favours durable polymer SES

6. Objective
To compare the safety and efficacy of a novel, ultrathin strut, biodegradable polymer based sirolimus-eluting stent with a thin strut, durable polymer everolimus-eluting stent for percutaneous coronary revascularization.

7. PLLA: poly-L-lactic acid
Stent platforms
Orsiro
Xience prime/xpedition
Platform material
Cobalt-Chromium, L-605
Cobalt-Chromium, L-605
Strut thickness
60 μm
81 μm
Silicon carbide layer
Passive coating
Biodegradable
Durable
Polymer material
PLLA: poly-L-lactic acid
PBMA/PVDF-HFP
Antiproliferative drug
Sirolimus
(1.4 μg/mm2)
Everolimus
(1.0 μg/mm2)

8. Trial design Primary endpoint Secondary endpoints
Patients with stable CAD or ACS undergoing PCI
1:1 Randomisation
Biodegradable polymer sirolimus-eluting stent
n = 1,030
Durable polymer everolimus-eluting stent
n = 1,030
Clinical follow-up at 30 days and 12 months
Primary endpoint
Composite of cardiac death, target vessel myocardial infarction, and clinically-indicated target lesion revascularization at 12 months
Secondary endpoints
Death, cardiac death, myocardial infarction, TLR, TVR, definite ST, definite and probable ST, target vessel failure

9. Study organisation Sponsor
Clinical Trials Unit and Department of Cardiology,
University Hospital, Bern, Switzerland
Steering committee
Thomas Pilgrim, Peter Jüni, Stephan Windecker
On-site data monitoring
Clinical Trials Unit, Bern, Switzerland (Brigitte Wanner, Lucia Kacina, Stefanie Hossmann)
Central data monitoring
Clinical Trials Unit, Bern, Switzerland (Timon Spörri)
Data coordination and analysis
Clinical Trials Unit, Bern, Switzerland (Dik Heg, Peter Jüni)
Clinical adjudication committee
Pascal Vranckx, Hasselt, Belgium (Chair); Gerrit Hellige, Solothurn, Switzerland; Daniel Mattle, Münsterlingen, Switzerland
Funding
Unrestricted grant from Biotronik, Bülach, Switzerland

10. Eligibility for patient enrollment
Masterlayout
Eligibility for patient enrollment
Age ≥ 18 years
Coronary artery disease
- stable CAD, silent ischemia
- acute coronary syndromes: UA, NSTEMI, and STEMI
At least one lesion with diameter stenosis >50% in a native coronary artery or a bypass graft
- no. of vessels: no limitation
- no. of lesions: no limitation
- lesion length: no limitation
Inclusion criteria
Exclusion criteria
Pregnancy
Planned surgery within 6 months of PCI
Intolerance to aspirin, clopidogrel, heparin, sirolimus, everolimus, contrast material
Inability to provide informed consent
Participation in another trial
© BIOTRONIK

11. Sample size calculation
Assumptions
based on COMPARE, RESOLUTE All-comers, and LESSON registry
Primary composite endpoint at 12 months 8%
Non-inferiority margin %
Sample size
2,060 randomised subjects will yield a power of >80% to detect non-inferiority at a one-sided type I error of 0.05.
Kedhi E, et al. Lancet 2010;375:201–09; Serruys PW, et al. N Engl J Med 2010;363:136–46; Räber L, et al. Circulation 2012;125:1110–21.

12. 2,119 patients were enrolled across 9 centers in Switzerland
Patient recruitment
February 2012 to May 2013
2,119 patients were enrolled across 9 centers in Switzerland
Investigator
City
Patients
Thomas Pilgrim, MD
Bern
1,216
Marco Roffi, MD
Geneva
209
David Tüller, MD
Zurich
179
André Vuilliomenet, MD
Aarau
102
Olivier Muller, MD
Lausanne
101
Stéphane Cook, MD
Fribourg
100
Daniel Weilenmann, MD
St. Gallen 99
Christoph Kaiser, MD
Basel 60
Peiman Jamshidi, MD
Lucerne 53
Basel
Aarau
Zurich
St. Gallen
Lucerne
Bern
Fribourg
Lausanne
Geneva

13. Patient flow 2,129 patients randomised 2,119 patients included
10 provided preliminary consent but refused definite consent
2,119 patients included
1,063 allocated to biodegradable polymer sirolimus-eluting stent
(1,594 lesions)
1,056 allocated to durable
polymer everolimus-eluting stent
(1,545 lesions)
1,031 follow-up information for primary endpoint available
1,036 follow-up information for primary endpoint available
1,056 analysed for primary clinical endpoint
- 20 censored at timepoint of refusal or loss to follow-up
1,063 analysed for primary clinical endpoint
- 32 censored at timepoint of refusal or loss to follow-up

14. Baseline characteristics
BP SES (n=1,063)
DP EES (n=1,056)
Age (years) — mean ± SD
66.1 ± 11.6
65.9 ± 11.4
Male gender — n (%)
818 (77%)
816 (77%)
Diabetes mellitus — n (%)
257 (24%)
229 (22%)
Hypertension — n (%)
728 (69%)
706 (67%)
Hypercholesterolemia — n (%)
712 (67%)
716 (68%)
Previous PCI — n (%)
325 (31%)
292 (28%)
Previous CABG — n (%)
113 (11%)
98 (9%)
Renal Failure (GFR<60 ml/min) — n (%)
151 (15%)
130 (13%)
Left ventricular ejection fraction (%) — mean ± SD
55.7 ± 12.1
55.9 ± 12.6
Indication — n (%)
Unstable angina
78 (7%)
74 (7%)
Non ST-segment elevation MI
288 (27%)
284 (27%)
ST-segment elevation MI
211 (20%)
196 (19%)
Stable angina
332 (31%)
Silent ischemia
161 (15%)
171 (16%)

15. Angiographic characteristics
BP SES (n=1,594)
DP EES (n=1,545)
Target-vessel location per lesion — n (%)
Left main artery
29 (2%)
27 (2%)
Left anterior descending artery
649 (41%)
679 (44%)
Left circumflex artery
370 (23%)
341 (22%)
Right coronary artery
505 (32%)
452 (29%)
Saphenous vein graft
38 (2%)
40 (3%)
Arterial graft
3 (0.2%)
6 (0.4%)
Number of treated lesions per patient — mean ± SD
1.50 ± 0.79
1.46 ± 0.73
Number of stents per lesion — mean ± SD
1.31 ± 0.61
1.34 ± 0.64
Total stent length per lesion (mm) — mean ± SD
25.91 ± 15.40
27.45 ± 16.77
Maximum stent diameter per lesion (mm) — mean ± SD
3.05 ± 0.49
3.03 ± 0.49
Off-label stent use per lesion — n (%)
690 (46%)
735 (50%)
Long lesion per lesion (>20 mm) — n (%)
826 (54%)
839 (57%)
Small-vessel per lesion (<2.75 mm) — n (%)
439 (29%)
468 (32%)

16. Primary endpoint Target lesion failure9
Absolute risk difference -0.14%, upper limit of one-sided 95% CI 1.97%
Pnon-inferiority = 8 7
6.7% - DP EES 6
6.7% - BP SES
Target lesion failure (%) 5 4 3 2 1
Rate ratio = 0.99 (95% CI ), p=0.95 30 60 90
120
150
180
210
240
270
300
330
365
Days since index procedure
Number at risk
1056
1021
1004
1002
998
996
994
991
985
975
971
966
945
DP EES
1063
1025
1004
1000
993
988
980
977
967
964
960
958
941
BP SES

17. Individual components of the primary endpoint
Rate ratio = 0.99 (95%CI ), p=0.95 1 2 3 4 5 6 7 8 9
Target lesion failure (%)
1063
1025
1004
1000
993
988
980
977
967
964
960
958
941
BP SES
1056
1021
1002
998
996
994
991
985
975
971
966
945
DP EES
Number at risk 30 60 90
120
150
180
210
240
270
300
330
365
Days since index procedure
Target lesion failure 1 2 3 4 5 6 7 8 9
Cardiac death (%) 30 60 90
120
150
180
210
240
270
300
330
365
Cardiac death
Number at risk
Days since index procedure
6.7% - DP EES
Rate ratio = 0.91 (95% CI ), p=0.77
6.7% - BP SES
2.1% - DP EES
1.9% - BP SES
1056
1043
1031
1030
1028
1027
1025
1024
1018
1015
1012
991
DP EES
1063
1044
1028
1025
1022
1021
1017
1016
1013
1009
1006
1004
987
BP SES 1 2 3 4 5 6 7 8 9
Target vessel MI (%) 30 60 90
120
150
180
210
240
270
300
330
365
Target vessel myocardial infarction
Number at risk
Days since index procedure 1 2 3 4 5 6 7 8 9
Clincally indicated TLR (%) 30 60 90
120
150
180
210
240
270
300
330
365
Clinically-indicated TLR
Number at risk
Days since index procedure
Rate ratio = 0.97 (95%CI ), p=0.90
Rate ratio = 1.42 (95%CI ), p=0.18
3.0% - DP EES
3.4% - BP SES
2.9% - DP SES
2.4% - DP EES
1056
1024
1010
1009
1006
1005
1002
1001
997
990
986
982
961
DP EES
1056
1038
1023
1021
1018
1016
1014
1012
1007
997
993
988
969
DP EES
1063
1027
1009
1006
1002
1000
993
992
986
983
979
977
959
BP SES
1063
1038
1019
1015
1008
1003
996
992
984
981
976
974
957
BP SES

18. Stent thrombosis Definite or probable stent thrombosis
2.8% vs 3.4%; RR 0.83, 95% CI , p=0.45
Durable polymer EES
3.4%
2.8%
Definite or probable stent thrombosis (%)
Biodegradable polymer SES
Cardiac death
Myocardial infarction
Target lesion revascularization
Definite stent thrombosis
0.9% vs 0.4%; RR 2.26 (95% CI ), p=0.16 3
Days since index procedure

19. Definite stent thrombosis Definite stent thrombosis (%)
p=0.16
Definite stent thrombosis (%)
p=0.15
p=0.66

20. Stratified analysis of primary endpoint
BP SES
DP EES
RR (95% CI) p
pinteraction
Diabetes
Acute Coronary Syndrome
ST-elevation MI
Off-label use
Sex
Renal failure
Yes No
Female
Male
27/257
42/806
21/229
49/827
1.19 ( )
0.88 ( )
0.56
0.55
0.41
32/577
37/486
38/554
32/502
0.81 ( )
1.21 ( )
0.39
0.43
0.24
7/211
62/852
17/196
53/860
0.38 ( )
1.20 ( )
0.024
0.33
0.014
43/629
24/427
51/646
19/407
0.87 ( )
1.23 ( )
0.50
0.51
0.35
12/245
57/818
20/240
50/816
0.59 ( )
1.15 ( )
0.15
0.47
0.104
18/151
50/857
18/130
43/865
0.88 ( )
1.19 ( )
0.70
0.40
0.44
Favours BP SES
Favours DP EES

21. Masterlayout
Limitations
Missing information on patients assessed for eligibility, but not included into the trial.
The trial was powered for the primary composite outcome but not individual components.
The primary endpoint results were determined at 12 months precluding conclusions regarding the long-term safety and efficacy.
One third of patients had undergone previous PCI and some adverse events may have been related to previously implanted devices.
© BIOTRONIK

22. Meta-analysis of BIOSCIENCE and BIOFLOW II
BP SES
DP EES
Risk ratio (95% CI)
Target lesion failure
Bioflow-II
Bioscience
Overall
0.82 ( )
0.98 ( )
0.95 ( )
19/298
69/1,063
12/154
70/1,056
Cardiac death
Bioflow-II
Bioscience
Overall
1.03 ( )
0.90 ( )
0.91 ( )
2/298
20/1,063
1/154
22/1,056
Target vessel myocardial infarction
Bioflow-II
Bioscience
Overall
1.03 ( )
0.96 ( )
0.97 ( )
8/298
30/1,063
4/154
31/1,056
Target lesion revascularisation
Bioflow-II
Bioscience
Overall
0.74 ( )
1.51 ( )
1.18 ( )
10/298
35/1,063
7/154
23/1,056
Risk ratio (95% CI)
Favours BP SES
Favours DP EES

23. Masterlayout
Conclusions
Ultrathin strut biodegradable polymer sirolimus- eluting stents were non-inferior to durable polymer everolimus-eluting stents for the primary endpoint target lesion failure at 1 year in a population with minimal exclusion criteria.
The observed benefit in the subgroup of patients with ST-segment elevation myocardial infarction warrants confirmation in appropriately designed studies.
© BIOTRONIK

24. The Lancet, published online
September 1, 2014