ISAR-TEST 5:ISAR-TEST 5:Randomized, Non-inferiority Randomized, Non-inferiority Trial of Rapamycin/Probucol- Trial of Rapamycin/Probucol-

and Zotarolimus-Eluting Stentsand Zotarolimus-Eluting Stents

J. Mehilli, MDJ. Mehilli, MDA. Kastrati, R.A. Byrne, S. Massberg, K. Tiroch, S. Schulz, J. Pache, A. Kastrati, R.A. Byrne, S. Massberg, K. Tiroch, S. Schulz, J. Pache,

M. Fusaro, K-L. Laugwitz, A. Schömig M. Fusaro, K-L. Laugwitz, A. Schömig

Deutsches Herzzentrum & 1. Med. Klinik rechts der IsarDeutsches Herzzentrum & 1. Med. Klinik rechts der IsarTechnische Universität Munich GermanyTechnische Universität Munich Germany

Disclosure Statement of Disclosure Statement of Financial InterestFinancial Interest

I, (Julinda Mehilli) DO NOT have a I, (Julinda Mehilli) DO NOT have a financial interest/arrangement or financial interest/arrangement or affiliation with one or more organizations affiliation with one or more organizations that could be perceived as a real or that could be perceived as a real or apparent conflict of interest in the context apparent conflict of interest in the context of the subject of this presentation.of the subject of this presentation.

BackgroundBackground

In comparison with BMS, DES are associated In comparison with BMS, DES are associated with a small excess of late events occurring with a small excess of late events occurring more than one year after interventionmore than one year after intervention

*The pathological substrateThe pathological substrateunderlying these events isunderlying these events isdelayed arterial healing anddelayed arterial healing andinflammatory response to DESinflammatory response to DESpermanent polymer coatingspermanent polymer coatings

Dual-DES:Dual-DES:Rapamycin – probucol – natural resin Rapamycin – probucol – natural resin No polymerNo polymerMicroporous stainless steel stent platformMicroporous stainless steel stent platform developed in the settings of the ISAR-Project developed in the settings of the ISAR-Project

supported by the supported by the Bayerische ForschungsstiftungBayerische Forschungsstiftung

100 µm

10 µm

Zotarolimus-eluting stent (ZES):Zotarolimus-eluting stent (ZES):(Endeavor Resolute stent)(Endeavor Resolute stent)BioLinx polymer systemBioLinx polymer system Co-Cr alloy stent platformCo-Cr alloy stent platform

Avoidance or modifications of polymer stent Avoidance or modifications of polymer stent coatings offer potential to improve arterial coatings offer potential to improve arterial healing and decrease late adverse eventshealing and decrease late adverse events

BackgroundBackground

Avoidance or modifications of polymer stent Avoidance or modifications of polymer stent coatings offer potential to improve arterial coatings offer potential to improve arterial healing and decrease late adverse eventshealing and decrease late adverse events

0.67

0.270.19

0.0

0.5

1.0

mm

Endeavor EndeavorResolute

Xience

Leon et al. JACC 2010Serruys et al., NEJM 2010

Endeavor CypherDual-DES

mm

P=0.78

P<0.001

0.58

0.23 0.24

0.0

0.5

1.0

Byrne et al. EHJ 2009

BackgroundBackground

Late Lumen LossLate Lumen Loss Late Lumen LossLate Lumen Loss

……to compare the efficacy of ato compare the efficacy of arapamycin-probucol eluting polymer-free rapamycin-probucol eluting polymer-free

stent against the permanent polymer-based stent against the permanent polymer-based zotarolimus-eluting stent (Endeavor zotarolimus-eluting stent (Endeavor

resolute) – in a trial powered for clinical resolute) – in a trial powered for clinical eventsevents

Objective of ISAR-TEST 5Objective of ISAR-TEST 5

Inclusion criteriaInclusion criteriaPatients with ischemic symptoms or evidence Patients with ischemic symptoms or evidence

of of myocardial ischemia in the presence of ≥50 % myocardial ischemia in the presence of ≥50 % de novode novo stenosis located in native coronary stenosis located in native coronary arteriesarteriesInformed, written consentInformed, written consent

Inclusion & Exclusion CriteriaInclusion & Exclusion Criteria

Exclusion criteriaAge < 18 yearsCardiogenic shock Target lesion located in the left main stemTarget lesion located in the bypass graftMalignancies with life expectancy <1 yearAllergies to study medication

Composite ofComposite of

cardiac death,cardiac death,

target vessel-related myocardial infarction target vessel-related myocardial infarction

target lesion revascularizationtarget lesion revascularization

at 1-year post index PCIat 1-year post index PCI

Primary EndpointPrimary Endpoint

Secondary EndpointsSecondary Endpoints

• All cause mortalityAll cause mortality

• Incidence of definite/probable stent thrombosisIncidence of definite/probable stent thrombosis

at 1-year post index PCIat 1-year post index PCI

• In-segment binary restenosisIn-segment binary restenosis

• In-stent late luminal lossIn-stent late luminal loss

at follow-up angiographyat follow-up angiography

Sample Size CalculationSample Size Calculation

Hypothesis:Hypothesis:Rapamycin/Probucol-eluting stent (Dual-DES) is Rapamycin/Probucol-eluting stent (Dual-DES) is

not inferior to zotarolimus-eluting stent (Endeavor not inferior to zotarolimus-eluting stent (Endeavor Resolute) in terms of device-oriented major adverse Resolute) in terms of device-oriented major adverse cardiac eventscardiac eventsAssumptions:Assumptions:

Incidence of primary endpoint in both groups 10%Incidence of primary endpoint in both groups 10%Margin of non-inferiority 3%Margin of non-inferiority 3%Power of 80%Power of 80%One-sided One-sided -level of 0.05-level of 0.05Random sequence 2:1 Random sequence 2:1 Needed total # of patients: Needed total # of patients: 3000 3000

(accounting for possible losses at follow-up)(accounting for possible losses at follow-up)

Rapamycin/Probucol-Eluting DES Rapamycin/Probucol-Eluting DES (Dual-DES)(Dual-DES)

n=2002n=2002

Zotarolimus-Eluting DESZotarolimus-Eluting DES(ZES)(ZES)

n=1000n=1000

3002 patients with 3002 patients with de novode novo lesions lesions

IIntracoronary ntracoronary SStenting and tenting and AAngiographic ngiographic RResults:esults:TTest est EEfficacy of Rapamycis/Probucol- and Zotarolimus-Eluting fficacy of Rapamycis/Probucol- and Zotarolimus-Eluting STSTents - 5ents - 5

ISAR-TEST-5ISAR-TEST-5

6 to 8-month repeat angiogram6 to 8-month repeat angiogram

12-month clinical follow-up12-month clinical follow-up

Dual-DES:Dual-DES:Rapamycin – probucol – natural resinRapamycin – probucol – natural resinNo polymerNo polymerMicroporous stainless steel stent platformMicroporous stainless steel stent platform developed in the settings of the ISAR-Project developed in the settings of the ISAR-Project

supported by the supported by the Bayerische ForschungsstiftungBayerische Forschungsstiftung

100 µm

10 µm

Study DES TypesStudy DES Types

Zotarolimus-eluting stent (ZES):Zotarolimus-eluting stent (ZES):(Endeavor Resolute stent)(Endeavor Resolute stent)BioLinx polymer system BioLinx polymer system Co-Cr alloy stent platformCo-Cr alloy stent platform

serial CKserial CK+ CKMB+ CKMB

measurementsmeasurements

600 mg Clopidogrel600 mg Clopidogrel

PCIPCIASS 500 mgASS 500 mg

00

repeat repeat angiographyangiography

(76%)(76%)

clinicalclinicalfollow-upfollow-up

(98%)(98%)

6-8 mo.6-8 mo. 12 mo.12 mo.

Follow-Up ProtocolFollow-Up Protocol

30 d30 d

clinicalclinicalfollow-upfollow-up

(100%)(100%)

ClopidogrelClopidogrel 2x75 mg/day until discharge 2x75 mg/day until discharge 75 mg at least 6 months after index PCI75 mg at least 6 months after index PCI

AspirinAspirin 200 mg/d indefinitely 200 mg/d indefinitely

Dual-DESDual-DES

n=2002n=2002

ZESZES

n=1000n=1000

Age, yearsAge, years 67.767.7±±11.211.2 68.168.1±±10.810.8

Female, %Female, % 2424 2424

Art. hypertension, %Art. hypertension, % 6767 6767

Diabetes, %Diabetes, % 2929 3030

Current smoker, %Current smoker, % 1818 1717

Prior bypass surgery, %Prior bypass surgery, % 99 1010

Prior MI, %Prior MI, % 2929 3030

Hyperlipidemia, %Hyperlipidemia, % 6363 6565

Baseline clinical characteristicsBaseline clinical characteristics

Dual-DESDual-DES

n=2002n=2002

ZESZES

n=1000n=1000

Clinical presentation, %Clinical presentation, %

acute MIacute MI 1111 1010

unstable anginaunstable angina 3030 3333

stable anginastable angina 5959 5757

Multivessel disease, %Multivessel disease, % 8282 8686

Multilesion PCI, %Multilesion PCI, % 3636 3838

LV ejection fraction, %LV ejection fraction, % 52.652.6±±11.911.9 52.452.4±±11.411.4

Baseline clinical characteristicsBaseline clinical characteristics

Angiographic characteristicsAngiographic characteristics

Dual-DESDual-DES

n=2912n=2912

ZESZES

n=1479n=1479

Target vessel, %Target vessel, %

left anterior descendingleft anterior descending 4545 4545

left circumflexleft circumflex 2424 2626

right coronary arteryright coronary artery 3131 2929

Bifurcation, %Bifurcation, % 2727 2929

Complex morphology, %Complex morphology, % 7474 7474

Lesion length, mmLesion length, mm 16.416.4±±9.69.6 16.916.9±±10.010.0

Vessel size, mmVessel size, mm 2.782.78±±0.500.50 2.802.80±±0.500.50

30-Day Clinical Outcomes30-Day Clinical Outcomes

0.6

2.3

0.6

2.8

0.7

2.6

0.8

3.4

0

5

10

15

20

%

ZESZES

Dual-DESDual-DES

P=.61 P=.55 P=.52 P=.41

Cardiac death TV-relatedmyocardial infarction

Target-lesionrevascularization

Device-orientedcombined endpoint*

* device-oriented combined endpoint of cardiac death,* device-oriented combined endpoint of cardiac death, target vessel myocardial infarction or target lesion revascularizationtarget vessel myocardial infarction or target lesion revascularization

Months After RandomizationMonths After Randomization00 11 22 33 44 55 66 77 88 99 1010 1111 1212

00

1010

2020

3030

5050

%%

4040

ZES 4.4%ZES 4.4%

Dual-DES 3.6%Dual-DES 3.6%

P=0.31P=0.31RR 0.82 [0.56-1.20]RR 0.82 [0.56-1.20]

All-Cause Death at 1 YearAll-Cause Death at 1 Year

Months After RandomizationMonths After Randomization

00 11 22 33 44 55 66 77 88 99 1010 1111 1212

Stent Thrombosis at 1 YearStent Thrombosis at 1 Year

11

22

33

55

%%

44

00

ZES 1.2%ZES 1.2%

Dual-DES 1.1%Dual-DES 1.1%

P=0.91P=0.91RR 0.94 [0.45-1.84]RR 0.94 [0.45-1.84]

Definite/ProbableDefinite/Probable

Months After RandomizationMonths After Randomization

00

1010

2020

3030

5050

00 11 22 33 44 55 66 77 88 99 1010 1111 1212

Cardiac Death or MI at 1 YearCardiac Death or MI at 1 Year

%%

4040

ZES 4.4%ZES 4.4%

Dual-DES 4.1%Dual-DES 4.1%

P=0.73P=0.73RR 0.94 [0.65-1.36]RR 0.94 [0.65-1.36]

Months After RandomizationMonths After Randomization

00 11 22 33 44 55 66 77 88 99 1010 1111 1212

Target Lesion RevascularizationTarget Lesion Revascularization

00

1010

2020

3030

5050

%%

4040

ZES 10.0%ZES 10.0%

Dual-DES 10.3%Dual-DES 10.3%

P=0.94P=0.94RR 0.99 [0.80-1.23]RR 0.99 [0.80-1.23]

Angiographic RestenosisAngiographic Restenosis

0.31 0.30

0.0

0.5

1.0

mm

ZESDual-DES

P=.62

In-stent late lumen loss

13.2 13.5

0

10

20

%

In-segment binary restenosis

P=.81

Months After RandomizationMonths After Randomization

00 11 22 33 44 55 66 77 88 99 1010 1111 1212

Cardiac Death/TV-related MI/TLRCardiac Death/TV-related MI/TLR

00

1010

2020

3030

5050

%%

4040

ZES 13.1%ZES 13.1%

Dual-DES 13.1%Dual-DES 13.1%

P=0.83P=0.83RR 1.03 [0.80-1.31]RR 1.03 [0.80-1.31]

0.50.5 11 1.51.5 22 2.52.5

>67.8 yrs>67.8 yrs

WomenWomen

≤≤67.8 yrs67.8 yrs

<2.79 mm<2.79 mm

≥≥2.79 mm2.79 mm

MenMen

AgeAge

SexSex

Vessel sizeVessel size

YesYes

NoNo

DiabetesDiabetes

0.91 (0.69, 1.20)0.91 (0.69, 1.20)

1.40 (0.87, 2.26)1.40 (0.87, 2.26)

1.12 (0.81, 1.55)1.12 (0.81, 1.55)

0.95 (0.71, 1.27)0.95 (0.71, 1.27)

1.07 (0.78, 1.47)1.07 (0.78, 1.47)

0.90 (0.71, 1.14)0.90 (0.71, 1.14)

PPinteractioninteraction

0.510.51

0.100.10

0.380.38

1.03 (0.80, 1.31)1.03 (0.80, 1.31)All

0.97 (0.69, 1.36)0.97 (0.69, 1.36)

1.02 (0.77, 1.34)1.02 (0.77, 1.34)

0.820.82

Relative RiskRelative Risk(95% CI)(95% CI)

Dual-DESDual-DESbetterbetter

ZESZESbetterbetter

Primary Endpoint in Different Primary Endpoint in Different SubgroupsSubgroups

Summary

Out to 12 months polymer-free rapamycin/probucol-eluting stent is non-inferior to the permanent polymer-based zotarolimus-eluting stent in a large-scale study powered for clinical endpoints.

Their performance was comparable with regard to hard clinical endpoints – stent thrombosis, death or MI – as well as clinical and angiographic parameters of restenosis.