ISAR-TEST-2 Trial Two-year Clinical and Angiographic

Outcomes from a Randomized Trial of Polymer-Free Dual Drug-Eluting Stents

versus Polymer-Based Cypher and Endeavor Drug-Eluting Stents

Robert A. Byrne, MB MRCPIAdnan Kastrati, MD; Klaus Tiroch, MD; Stefanie Schulz, MD; Jürgen Pache, MD;

Susanne Pinieck; Steffen Massberg, MD; Melchior Seyfarth, MD; Karl-Ludwig Laugwitz, MD; Katrin A. Birkmeier, MD; Albert Schömig, MD; Julinda Mehilli, MD

ACC/i2 2010 – LBCT III

Deutsches Herzzentrum & 1. Med. Klinikum rechts der IsarTechnische Universität Munich Germany

Lecture fees from Medtronic

Presenter Disclosure Information

First generation DES systems deliver high antirestenotic efficacy in comparison with BMS but do so at the cost of a delay in structural and functional healing of stented segment

Background

*

Byrne, Joner, Kastrati Minerva Cardioangiol 2009

Incomplete Incomplete EndothelialisationEndothelialisation

Late Fibrin Late Fibrin DepositionDeposition

ChronicChronicInflammationInflammation

Platelet ActivationPlatelet Activation

Delayed Arterial Healing

*Incomplete Incomplete

EndothelialisationEndothelialisation

Late Fibrin Late Fibrin DepositionDeposition

ChronicChronicInflammationInflammation

Platelet ActivationPlatelet Activation

Delayed Arterial Healing

Inflammatory Response to Polymer

Residue May Play a Central Role

Byrne, Joner, Kastrati Minerva Cardioangiol 2009

Avoidance of polymer imposes efficacy limitations related to suboptimal drug release kinetics

The incorporation of a second active agent targeted at a different element of the restenotic response cascade is a potential option to enhance anti-restenotic performance

Probucol is a potent antioxidant which is also highly lipophilic and enhances the release kinetics of sirolimus

Background

to compare the anti-restenotic efficacy of:

polymer-free sirolimus+probucol-eluting stent (Dual-DES)

with

permanent polymer sirolimus-eluting stent (Cypher)

and

permanent polymer zotarolimus-eluting stent (Endeavor)

in patients with coronary artery disease

Aim of ISAR-TEST-2 Study

Inclusion Criteria “De novo” lesions in native coronary arteries Written informed consent

Exclusion Criteria Left main lesion Cardiogenic shock Comorbidities with a life expectancy < 12 months Contraindication to aspirin, limus agents, probucol,

stainless steel, thienopyridines

Patient Selection

Two-year Safety Endpoints:

Composite of death and myocardial infarction

Stent thrombosis according to ARC criteria

Two-year Efficacy Endpoints:

Target lesion revascularization (TLR) due to restenosis in the presence of symptoms or signs of ischemia

Composite binary restenosis at 2 years based on latest available angiogram (whether at 6-8 months or 2 years)

ISAR-TEST-2 Study Endpoints

1007 pts randomized

Dual-DES

333 pts

Endeavor

339 pts

Cypher

335 pts

942 pts (93.6%)with 2-year clinical FU*

828 pts (82.2%) with 6-8-mo. angiogram

*Among n=65 patients without 2-yr FU, median FU was 21 [20-22] months

493 pts (67.3% eligible)with 2-yr. angiogram

ISAR-TEST-2 Study Flow

Baseline Clinical Characteristics

Dual-DESn=333

Endeavorn=339

Data are percentage or mean ± standard deviation; Percentages may not total 100 due to rounding

Cyphern=335

Hypercholesterolemia 63 6669

Current smoker 20 1817

Diabetes 29 2627

Arterial hypertension 65 6864

Women 23 2523

67±11 67±11Age, years 67±11

History of MI 25 2630

LV ejection fraction (%)

Stable angina

Unstable angina

Acute MI

Dual-DESn=333

53±12

58

30

12

Endeavorn=339

55±10

56

30

15

Cyphern=335

52±12

61

25

13

Data are percentage or mean ± standard deviation; Percentages may not total 100 due to rounding

Baseline Clinical Characteristics

Target vesselLADLCxRCA

Complex lesions

Multivessel disease

Total occlusions

Data are percentage; percentages may not total 100 due to rounding

Dual-DESn=427

70

81

312544

12

Cyphern=419

73

86

2625

49

12

Endeavorn=420

75

83

2931

41

12

Angiographic Characteristics

QCA Measurements

Dual-DESn=427

Cyphern=419

Endeavorn=420

Vessel size, mm 2.75±.46 2.71±.492.69±.52

Lesion length, mm 14.8±8.3 14.7±8.014.0±8.2

MLD after PCI, mm 2.55±.43 2.51±.472.49±.48

DS after PCI, % 10.8±5.7 10.7±7.011.6±5.0

Data are mean ± standard deviation

ISAR-TEST-2

Primary Results

ISAR-TEST-2 Eur Heart J 2009

ISAR-TEST-2

12.011.0

19.3

0

5

10

15

20

EndeavorCypher Dual-DES

p=0.003

6-8 months

%

Binary Angiographic Restenosis

12.011.0

19.3

0

5

10

15

20

EndeavorCypher Dual-DES

%

p=0.68 p=0.002

Binary Angiographic Restenosis6-8 months

ISAR-TEST-2

Two-year Results

0

10

20

30

40

50

0 2 4 6 8 10 12 14 16 18 20 22 24

%

mos

p=0.61

Death or myocardial infarction

Dual-DES 7.8%Endeavor ZES 9.2%

Cypher SES 10.2%

0.3

1.2 1.2

0.6 0.6 0.60.9

0.0

0.9

0

2

4

6

Incidence

Definite Probable Possible

p=0.67p=0.37p=0.87

EndeavorCypher Dual-DES

%

Stent Thrombosis at 2 years

13.6

6.87.2

14.3

7.7

10.7

0

5

10

15

20

25

1 yr 2 yrs

EndeavorCypher Dual-DES

p=0.009

1 yr 2 yrs 1 yr 2 yrs

%

Target Lesion Revascularization

13.6

6.87.2

14.3

7.7

10.7

0

5

10

15

20

25

1 yr 2 yrs

Δ = 3.5% Δ = 0.7%Δ = 0.9%

EndeavorCypher Dual-DES

p=0.009 p=0.72

1 yr 2 yrs 1 yr 2 yrs

%

Target Lesion Revascularization

19.3

11.012.0

20.9

13.9

18.8

0

5

10

15

20

25

30

6-8 m 2 yrs*

%

6-8 m 2 yrs* 6-8 m 2 yrs*

Binary restenosis

EndeavorCypher Dual-DES

p=0.045

19.3

11.012.0

20.9

13.9

18.8

0

5

10

15

20

25

30

6-8 m 2 yrs*

%Δ = 6.8% Δ = 1.6%Δ = 2.9%

p=0.016 p=0.28

6-8 m 2 yrs* 6-8 m 2 yrs*

Binary restenosis

EndeavorCypher Dual-DES

The occurrence of safety events beyond 1 year was rare; there was no signal of a differential safety profile between the Dual-DES, Cypher and Endeavor out to 2 years

The antirestenotic efficacy of both Dual-DES and Endeavor remained durable between 1 and 2 years with Dual-DES maintaining an edge

There was evidence of a slight decrement in efficacy with Cypher from 1 to 2 years

Conclusions

ISAR-TEST-2 TrialDeutsches Herzzentrum, Munich. Germany

Thank You