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.