Randomised comparison of a novel, ultrathin strut biodegradable polymer sirolimus-eluting stent with...

Randomised comparison of a novel, ultrathin strut biodegradable polymer sirolimus-eluting

stent with a durable polymer everolimus-eluting stent for percutaneous coronary revascularization

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

NCT01443104

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

Antiproliferative drugSirolimus-analoguesPaclitaxel

Durable polymer Biodegradable polymer

Stainless steel Cobalt-Chromium/Platinum-Chromium

Polymer material

Progress with metallic drug-eluting stents

Taxus

Cypher

BioMatri

x

Nobori

Endeavor

Yukon PC

Xience

Promus

Resolute

Synergy

Orsiro

DESyne

Combo

Mist

ent

Ultimaster

132 140 120 91 87 81 91 74 60 81 100 64 80 (μm)

Platform material & strut thickness

SES BES ZES SES EES ZES EES SES NES SES SES SES

Sirolimus Biolimus Zotarolimus Everolimus Novolimus

Durable polymer everolimus-eluting stents reduce the risk of definite ST, MI and TVR compared to non-

EESBaber 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 monthsMeta-analysis of 17 RCTs with 17,101 patients and mean follow-up of 22 months

Definite ST: RR 0.55, 95% CI 0.38-0.78Definite ST: RR 0.55, 95% CI 0.38-0.78 TVR: RR 0.77, 95% CI 0.64-0.92TVR: RR 0.77, 95% CI 0.64-0.92

Definite stent thrombosisDefinite stent thrombosis Target vessel revascularizationTarget vessel revascularization

Definite stent thrombosisDefinite stent thrombosis Target lesion revascularizationTarget lesion revascularization

Biodegradable polymer DES reduce the risk of definite ST and TLR compared to first generation DES

Overall (I2 = 0.0%, p=0.92)

LEADERS

ISAR-TEST 4

ISAR-TEST 3

0.58 (0.37-0.93)

20/857

9/1299

1/202

32/850

9/652

2/202

0.62 (0.36-1.08)

0.50 (0.20-1.26)

0.50 (0.05-5.47)

10.1 0.2 2 50.5

Favours biodegradable polymer DES

Favours durable polymer SES

Risk ratio

BP DES DP SES RR (95% CI)

Overall (I2 = 0.0%, p=0.79)

LEADERS

ISAR-TEST 4

ISAR-TEST 3

0.84 (0.71-0.99)

88/857

168/1299

17/202

111/850

95/652

21/202

0.79 (0.60-1.02)

0.89 (0.70-1.12)

0.81 (0.44-1.49)

10.1 0.2 2 5 100.5

RR (95% CI)BP DES DP SES

Risk ratioFavours biodegradable

polymer DESFavours durable

polymer SES

Stefanini GG et al, Eur Heart J. 2012;33(10):1214-22

Studies Studies

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.

Objective

Stent platformsOrsiro Xience prime/xpedition

Platform material

Strut thickness

Polymer material

Passive coating

Antiproliferative drug

PLLA: poly-L-lactic acid PBMA/PVDF-HFP

Trial designPatients with stable CAD or ACS undergoing PCIPatients 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

Primary endpointComposite of cardiac death, target vessel myocardial infarction, and clinically-indicated target lesion revascularization at 12 months

Secondary endpointsDeath, cardiac death, myocardial infarction, TLR, TVR, definite ST, definite and probable ST, target vessel failure

Clinical follow-up at 30 days and 12 monthsClinical follow-up at 30 days and 12 months

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

Study organisation

Eligibility for patient enrollment

• 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

Exclusion criteria• 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

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 size2,060 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.

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

2,119 patients were enrolled across 9 centers in Switzerland

Geneva

Lausanne

Fribourg

Bern

Basel

Lucerne

Aarau

Zurich St. Gallen

Patient recruitmentFebruary 2012 to May 2013

Patient flow2,129 patients randomised2,129 patients randomised

2,119 patients included2,119 patients included

10 provided preliminary consent but refused definite consent

10 provided preliminary consent but refused definite consent

1,063 allocated to biodegradable polymer sirolimus-eluting stent

(1,594 lesions)

1,063 allocated to biodegradable polymer sirolimus-eluting stent

(1,594 lesions)

1,056 allocated to durable polymer everolimus-eluting stent

(1,545 lesions)

1,056 allocated to durable polymer everolimus-eluting stent

(1,545 lesions)

1,031 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







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 325 (31%) 332 (31%)

Silent ischemia161 (15%) 171 (16%)

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%)

0

1

2

3

4

5

6

7

8

9Ta

rget

lesi

on fa

ilure

(%)

1063 1025 1004 1000 993 988 980 977 967 964 960 958 941BP SES1056 1021 1004 1002 998 996 994 991 985 975 971 966 945DP EES

Number at risk

0 30 60 90 120 150 180 210 240 270 300 330 365

Days since index procedure

Primary endpointTarget lesion failure

Absolute risk difference -0.14%, upper limit of one-sided 95% CI 1.97%Pnon-inferiority = 0.0004

6.7% - BP SES

6.7% - DP EES

Rate ratio = 0.99 (95% CI 0.71-1.38), p=0.95

0

1

2

3

4

5

6

7

8

9

Clin

cally

indi

cate

d TL

R (%

)

0 30 60 90 120 150 180 210 240 270 300 330 365

Clinically-indicated TLR

Number at riskDays since index procedure

0

1

2

3

4

5

6

7

8

9

Targ

et v

esse

l MI (

%)

0 30 60 90 120 150 180 210 240 270 300 330 365

Target vessel myocardial infarction


0

1

2

3

4

5

6

7

8

9

Card

iac

deat

h (%

)

0 30 60 90 120 150 180 210 240 270 300 330 365

Cardiac death


Rate ratio = 0.91 (95% CI 0.50-1.67), p=0.77

1063 1044 1028 1025 1022 1021 1017 1016 1013 1009 1006 1004 987BP SES1056 1043 1031 1030 1028 1027 1025 1025 1024 1018 1015 1012 991DP EES

Rate ratio = 0.97 (95%CI 0.58-1.60), p=0.90

1063 1027 1009 1006 1002 1000 993 992 986 983 979 977 959BP SES1056 1024 1010 1009 1006 1005 1002 1001 997 990 986 982 961DP EES

Rate ratio = 1.42 (95%CI 0.85-2.37), p=0.18

1063 1038 1019 1015 1008 1003 996 992 984 981 976 974 957BP SES1056 1038 1023 1021 1018 1016 1014 1012 1007 997 993 988 969DP EES

Individual components of the primary endpoint

Rate ratio = 0.99 (95%CI 0.71-1.38), p=0.95

0

1

2

3

4

5

6

7

8

9Ta

rget

lesi

on fa

ilure

(%)

1063 1025 1004 1000 993 988 980 977 967 964 960 958 941BP SES1056 1021 1004 1002 998 996 994 991 985 975 971 966 945DP EES

Number at risk

0 30 60 90 120 150 180 210 240 270 300 330 365Days since index procedure

Target lesion failure

1.9% - BP SES

2.1% - DP EES

2.9% - DP SES

3.0% - DP EES 3.4% - BP SES

2.4% - DP EES

6.7% - BP SES

6.7% - DP EES

Stent thrombosis

Biodegradable polymer SES

Durable polymer EES

3

Days since index procedure

Defi

nite

or p

roba

ble

sten

t thr

ombo

sis

(%)

2.8%

3.4%

2.8% vs 3.4%; RR 0.83, 95% CI 0.50-1.35, p=0.45Definite or probable stent thrombosis

Cardiac death

Myocardial infarction

Target lesion revascularization

Definite stent thrombosis0.9% vs 0.4%; RR 2.26 (95% CI 0.70-7.33), p=0.16

Definite stent thrombosis

p=0.66

p=0.15

p=0.16

BP SES DP EES RR (95% CI) p pinteraction

Diabetes

Acute Coronary Syndrome

ST-elevation MI

Off-label use

Sex

Renal failure

YesNo

YesNo

YesNo

YesNo

FemaleMale

YesNo

Favours BP SES Favours DP EES

27/25742/806

21/22949/827

1.19 (0.67-2.10)0.88 (0.58-1.33)

0.560.55

0.41

32/57737/486

38/55432/502

0.81 (0.51-1.30)1.21 (0.75-1.95)

0.390.43

0.24

7/21162/852

17/19653/860

0.38 (0.16-0.91)1.20 (0.83-1.73)

0.0240.33

0.014

43/62924/427

51/64619/407

0.87 (0.58-1.31)1.23 (0.67-2.24)

0.500.51

0.35

12/24557/818

20/24050/816

0.59 (0.29-1.21)1.15 (0.79-1.68)

0.150.47

0.104

18/15150/857

18/13043/865

0.88 (0.45-1.70)1.19 (0.79-1.79)

0.700.40

0.44

0.25 0.5 1 2 4

Stratified analysis of primary endpoint

• 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.

Limitations

Meta-analysis of BIOSCIENCE and BIOFLOW II

Risk ratio (95% CI)

Favours BP SES Favours DP EES

Target lesion failure Bioflow-II Bioscience Overall

Cardiac death Bioflow-II Bioscience Overall

Target vessel myocardial infarction Bioflow-II Bioscience Overall

Target lesion revascularisation Bioflow-II Bioscience Overall

BP SES DP EES

0.82 (0.41-1.64)0.98 (0.71-1.35)0.95 (0.71-1.27)

19/29869/1,063

12/15470/1,056

1.03 (0.09-11.31)0.90 (0.50-1.64)0.91 (0.51-1.63)

2/29820/1,063

1/15422/1,056

1.03 (0.32-3.38)0.96 (0.59-1.58)0.97 (0.62-1.53)

8/29830/1,063

4/15431/1,056

0.74 (0.29-1.90)1.51 (0.90-2.54)1.18 (0.61-2.30)

10/29835/1,063

7/15423/1,056

0.25 0.5 1 2 4

Risk ratio (95% CI)

• 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.

Conclusions

The Lancet, published onlineSeptember 1, 2014

Randomised comparison of a novel, ultrathin strut biodegradable polymer sirolimus-eluting stent with...

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