Randomised comparison of a novel, ultrathin
strut biodegradable polymer sirolimus-eluting
stent with a durable polymer everolimus-eluting
stent for percutaneous coronary revascularization
NCT01443104
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
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
PROGRESS WITH METALLIC DRUG-ELUTING STENTS
Antiproliferative drug
Sirolimus-analogues
Paclitaxel
SES
BES
Sirolimus
Biolimus
ZES
SES
Zotarolimus
EES
ZES
EES
SES
Everolimus
NES
SES
SES
SES
Novolimus
Polymer material
Durable polymer
Biodegradable polymer
Platform material & strut thickness
132
140
Stainless steel
120
91
87
81
91
74
60
81
100
64
Cobalt-Chromium/Platinum-Chromium
80 (μm)
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;58:1569-77
Meta-analysis of 17 RCTs with 17,101 patients and mean follow-up of 22 months
Definite stent thrombosis
Target vessel revascularization
Definite ST: RR 0.55, 95% CI 0.38-0.78
TVR: RR 0.77, 95% CI 0.64-0.92
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):1214-22
Definite stent thrombosis
Studies
BP DES DP SES
Target lesion revascularization
RR (95% CI)
Studies
BP DES DP SES
RR (95% CI)
ISAR-TEST 3
1/202
2/202
0.50 (0.05-5.47)
ISAR-TEST 3
17/202
21/202
0.81 (0.44-1.49)
ISAR-TEST 4
9/1299
9/652
0.50 (0.20-1.26)
ISAR-TEST 4
168/1299 95/652
0.89 (0.70-1.12)
LEADERS
20/857
32/850
0.62 (0.36-1.08)
LEADERS
88/857
0.79 (0.60-1.02)
Overall
0.58 (0.37-0.93)
(I2 = 0.0%, p=0.92)
0.1
0.2
0.5
1
2
5
Risk ratio
Favours biodegradable
Favours durable
polymer DES
polymer SES
Overall
111/850
0.84 (0.71-0.99)
(I2 = 0.0%, p=0.79)
0.1
0.2
0.5
1
2
5
10
Risk ratio
Favours biodegradable
Favours durable
polymer DES
polymer SES
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.
STENT PLATFORMS
ORSIRO
Platform material
Strut thickness
Passive coating
XIENCE PRIME/XPEDITION
Cobalt-Chromium, L-605
Cobalt-Chromium, L-605
60 μm
81 μm
Silicon carbide layer
Biodegradable
Durable
PLLA: poly-L-lactic acid
PBMA/PVDF-HFP
Polymer material
Antiproliferative drug
Sirolimus
(1.4
μg/mm2)
Everolimus
(1.0 μg/mm2)
TRIAL DESIGN
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
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
ELIGIBILITY FOR PATIENT ENROLLMENT
Inclusion criteria
Exclusion criteria
• Age ≥ 18 years
• Pregnancy
• Coronary artery disease
- stable CAD, silent ischemia
- acute coronary syndromes:
UA, NSTEMI, and STEMI
• Planned surgery within 6 months of
PCI
• 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
• Intolerance to aspirin, clopidogrel,
heparin, sirolimus, everolimus,
contrast material
• Inability to provide informed
consent
• Participation in another trial
SAMPLE SIZE CALCULATION
Assumptions
based on COMPARE, RESOLUTE All-comers, and LESSON registry
 Primary composite endpoint at 12 months 8%
 Non-inferiority margin
3.5%
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.
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
Lucerne
Bern
Fribourg
Lausanne
Geneva
St. Gallen
PATIENT FLOW
2,129 patients randomised
2,119 patients included
10 provided preliminary
consent but refused
definite consent
1,063 allocated to biodegradable
polymer sirolimus-eluting stent
1,056 allocated to durable
polymer everolimus-eluting stent
(1,594 lesions)
(1,545 lesions)
1,031 follow-up information for
primary endpoint available
1,036 follow-up information for
primary endpoint available
1,063 analysed for primary
clinical endpoint
1,056 analysed for primary
clinical endpoint
- 32 censored at timepoint of refusal or loss to follow-up
- 20 censored at timepoint of refusal or loss to follow-up
Baseline characteristics
BP SES (n=1,063) DP EES (n=1,056)
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%)
55.7 ± 12.1
55.9 ± 12.6
78 (7%)
74 (7%)
Non ST-segment elevation MI
288 (27%)
284 (27%)
ST-segment elevation MI
211 (20%)
196 (19%)
Stable angina
325 (31%)
332 (31%)
Silent ischemia
161 (15%)
171 (16%)
Age (years) — mean ± SD
Left ventricular ejection fraction (%) — mean ± SD
Indication — n (%)
Unstable angina
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
25.91 ± 15.40
27.45 ± 16.77
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%)
Total stent length per lesion (mm) — mean ± SD
Maximum stent diameter per lesion (mm) — mean ±
SD
PRIMARY ENDPOINT
TARGET LESION FAILURE
9
TARGET LESION FAILURE (%)
8
ABSOLUTE RISK DIFFERENCE -0.14%, UPPER LIMIT OF ONE-SIDED 95% CI 1.97%
PNON-INFERIORITY = 0.0004
6.7% - DP EES
7
6
6.7% - BP SES
5
4
3
2
1
Rate ratio = 0.99 (95% CI 0.71-1.38), p=0.95
0
0
30
60
90
120
150
180
210
240
270
300
330
365
975
964
971
960
966
958
945
941
DAYS SINCE INDEX PROCEDURE
NUMBER AT RISK
DP EES 1056
BP SES 1063
1021
1025
1004
1004
1002
1000
998
993
996
988
994
980
991
977
985
967
INDIVIDUAL COMPONENTS OF THE PRIMARY ENDPOINT
8
9
TARGET LESION FAILURE
8
7
6.7% - DP EES
CARDIAC DEATH (%)
TARGET LESION FAILURE (%)
9
6
5
6.7% - BP SES
4
3
2
CARDIAC DEATH
7
6
Rate ratio = 0.91 (95% CI 0.50-1.67), p=0.77
5
4
2.1% - DP EES
3
2
Rate ratio = 0.99 (95%CI 0.71-1.38), p=0.95
1
1.9% - BP SES
1
0
0
0
30
60
90
120 150 180 210 240 270 300 330
365
0
30
60
90
DAYS SINCE INDEX PROCEDURE
NUMBER AT RISK
998
993
996
988
994
980
991
977
985
967
975
964
971
960
966
958
945
941
TARGET VESSEL MYOCARDIAL INFARCTION
9
7
6
DP EES 1056 1043 1031 1030 1028 1027 1025 1025 1024 1018 1015 1012
BP SES 1063 1044 1028 1025 1022 1021 1017 1016 1013 1009 1006 1004
Rate ratio = 0.97 (95%CI 0.58-1.60), p=0.90
5
4
3.0% - DP EES
3
2
2.9% - DP SES
1
0
CLINCALLY INDICATED TLR (%)
TARGET VESSEL MI (%)
8
365
NUMBER AT RISK
DP EES 1056 1021 1004 1002
BP SES 1063 1025 1004 1000
9
120 150 180 210 240 270 300 330
DAYS SINCE INDEX PROCEDURE
991
987
CLINICALLY-INDICATED TLR
8
7
6
Rate ratio = 1.42 (95%CI 0.85-2.37), p=0.18
5
3.4% - BP SES
4
3
2
2.4% - DP EES
1
0
0
30
60
90
120 150 180 210 240 270 300 330
365
0
30
DAYS SINCE INDEX PROCEDURE
NUMBER AT RISK
DP EES 1056 1024 1010 1009 1006 1005 1002 1001
BP SES 1063 1027 1009 1006 1002 1000 993 992
60
90
120 150 180 210 240 270 300 330
365
DAYS SINCE INDEX PROCEDURE
NUMBER AT RISK
997
986
990
983
986
979
982
977
961
959
DP EES 1056 1038 1023 1021 1018 1016 1014 1012 1007
BP SES 1063 1038 1019 1015 1008 1003 996 992 984
997
981
993
976
988
974
969
957
STENT THROMBOSIS
DEFINITE OR PROBABLE STENT THROMBOSIS (%)
DEFINITE OR PROBABLE STENT THROMBOSIS
2.8% vs 3.4%; RR 0.83, 95% CI 0.50-1.35, p=0.45
DURABLE POLYMER EES
3.4%
2.8%
BIODEGRADABLE POLYMER SES
DEFINITE STENT THROMBOSIS
0.9% vs 0.4%; RR 2.26 (95% CI 0.70-7.33), p=0.16
Cardiac death
Myocardial infarction
3
Target lesion revascularization
DAYS SINCE INDEX PROCEDURE
DEFINITE STENT THROMBOSIS
DEFINITE STENT THROMBOSIS (%)
p=0.16
p=0.15
p=0.66
STRATIFIED ANALYSIS OF PRIMARY ENDPOINT
BP SES
DP EES
RR (95% CI)
p
Diabetes
Yes
No
0.41
27/257
42/806
21/229
49/827
1.19 (0.67-2.10)
0.88 (0.58-1.33)
0.56
0.55
Acute Coronary Syndrome
Yes
No
32/577
37/486
0.24
38/554
32/502
0.81 (0.51-1.30)
1.21 (0.75-1.95)
0.39
0.43
ST-elevation MI
Yes
No
0.014
7/211
62/852
17/196
53/860
0.38 (0.16-0.91)
1.20 (0.83-1.73)
0.024
0.33
Off-label use
Yes
No
0.35
43/629
24/427
51/646
19/407
0.50
0.51
0.87 (0.58-1.31)
1.23 (0.67-2.24)
Sex
Female
Male
0.104
12/245
57/818
20/240
50/816
0.59 (0.29-1.21)
1.15 (0.79-1.68)
0.15
0.47
Renal failure
Yes
No
pinteraction
0.44
18/151
50/857
18/130
43/865
0.88 (0.45-1.70)
1.19 (0.79-1.79)
Favours BP SES
0.70
0.40
0.25 0.5
1
2
4
Favours DP EES
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.
META-ANALYSIS OF BIOSCIENCE AND BIOFLOW II
BP SES
DP EES
Risk ratio (95% CI)
19/298
69/1,063
12/154
70/1,056
0.82 (0.41-1.64)
0.98 (0.71-1.35)
0.95 (0.71-1.27)
2/298
20/1,063
1/154
22/1,056
1.03 (0.09-11.31)
0.90 (0.50-1.64)
0.91 (0.51-1.63)
4/154
31/1,056
1.03 (0.32-3.38)
0.96 (0.59-1.58)
0.97 (0.62-1.53)
7/154
23/1,056
0.74 (0.29-1.90)
1.51 (0.90-2.54)
1.18 (0.61-2.30)
Target lesion failure
Bioflow-II
Bioscience
Overall
Cardiac death
Bioflow-II
Bioscience
Overall
Target vessel myocardial infarction
Bioflow-II
Bioscience
Overall
8/298
30/1,063
Target lesion revascularisation
Bioflow-II
Bioscience
Overall
10/298
35/1,063
0.25 0.5
1
2
4
Risk ratio (95% CI)
Favours BP SES Favours DP EES
CONCLUSIONS
• Ultrathin strut biodegradable polymer sirolimuseluting 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.
The Lancet, published online
September 1, 2014