“treatment of in-stent restenosis” · “treatment of in-stent restenosis” j. eduardo sousa,...
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““Treatment of Treatment of InIn--StentStent RestenosisRestenosis””
J. Eduardo Sousa, MD, PhD, FACC Instituto Dante Pazzanese de Cardiologia
Hospital do CoraçãoSao Paulo, Brazil
J. Eduardo Sousa, MD, PhD, FACC J. Eduardo Sousa, MD, PhD, FACC InstitutoInstituto Dante Pazzanese de Dante Pazzanese de CardiologiaCardiologia
Hospital do Hospital do CoraCoraççãoãoSao Paulo, BrazilSao Paulo, BrazilDante Dante
PazzanesePazzanese
11th Annual Meeting Angioplasty Summit 2006 11th Annual Meeting Angioplasty Summit 2006 TCT Asia PacificTCT Asia Pacific
Seoul, Korea Seoul, Korea – April 26 April 26 -- 28, 200628, 2006
J. Eduardo Sousa, MD, PhD, FACC
No relationship to disclose.
J. Eduardo Sousa, MD, PhD, FACCJ. Eduardo Sousa, MD, PhD, FACC
No relationship to disclose.No relationship to disclose.
Treatment of InTreatment of In--StentStent RestenosisRestenosis
Treatment of InTreatment of In--stentstent RestenosisRestenosis
ISR after Bare Metal ISR after Bare Metal StentStent
ISR after DrugISR after Drug--eluting eluting StentStent
The Real Question:The Real Question:
Is ISR still a problem?Is ISR still a problem?
DES for ISR: Clinical StudiesDES for ISR: Clinical StudiesSirolimusSirolimus--Eluting Eluting StentStent
-- FIM ISR (Sousa, FIM ISR (Sousa, SerruysSerruys))-- RESEARCH (RESEARCH (SaiaSaia, , SerruysSerruys))-- TROPICAL (TROPICAL (NeumanNeuman))-- ISARISAR--DESIRE (DESIRE (KastratiKastrati))-- SECURE (SECURE (TeirsteinTeirstein, Costa), Costa)-- ee--CypherCypher (Sousa)(Sousa)
PaclitaxelPaclitaxel--Eluting Eluting StentStent-- TAXUS III (TAXUS III (GrubeGrube, , SerruysSerruys))
Randomized TrialsRandomized Trials-- SISR (USA, D. Holmes)SISR (USA, D. Holmes)-- TAXUS V TAXUS V -- ISR (USA, Stone, Ellis)ISR (USA, Stone, Ellis)
DES for ISR DES for ISR -- Early ExperienceEarly Experience
Circulation 2003;107:24Circulation 2003;107:24--2727
J. Eduardo Sousa, MD, PhD, Marco A. Costa, MD, PhD, Alexandre Abizaid, MD, PhD, Amanda G.M.R. Sousa, MD, PhD, Fausto
Feres, MD, PhD, Luiz A. Mattos, MD, PhD, Marinella Centemero, MD, Galo Maldonado, MD, Andrea S. Abizaid, MD, Ibraim Pinto,
MD; Robert Falotico, PhD, Judith Jaeger, BA; Jeffrey J. Popma, MD, Patrick W. Serruys, MD, PhD
Sirolimus-Eluting Stent for the Treatment ofIn-Stent Restenosis
A Quantitative Coronary Angiography andThree-Dimensional Intravascular Ultrasound Study
Changes in % DS and MLDChanges in % DS and MLD InIn--stentstentSirolimusSirolimus Eluting Eluting StentStent: ISR (Sao Paulo): ISR (Sao Paulo)
Post(n=25)
Pre(n=25)
4mo(n=25)
66.066.0
0
10
20
30
40
50
60
70
80
2.62.67.157.15
0
0.5
1
1.5
2
2.5
3MLD(mm)MLD(mm)
%DS
InIn--stentstentLate Late LosLoss s
0.33 mm (3 years)
(%DS)(%DS)
3 y(n=24)
16.716.716.7
Dante Dante PazzanesePazzanese
J. J. PopmaPopma. . AngiographicAngiographic Core Core LabLab, Boston, Boston
1 y(n=25)
0.90.9
22.64.642.712.71
MLD2.3522.35.35 2.3822.38.38
18.118.118.1
12 Months12 Months12 Months
Death
Q-wave MI
Non-Q-wave MI
TVR (Non-TLR)
DeathDeath
QQ--wave MIwave MI
NonNon--QQ--wave MIwave MI
TVR (NonTVR (Non--TLR)TLR)
1 (4%)
0%
0%
0%
1 (4%)1 (4%)
0%0%
0%0%
0%0%
SES for the Treatment of ISR SES for the Treatment of ISR Cumulative Clinical OutcomeCumulative Clinical Outcome
24 Months24 Months24 Months 36 Months36 Months36 Months
1 (4%)
0%
0%
1 (4%)
1 (4%)1 (4%)
0%0%
0%0%
1 (4%)1 (4%)
1 (4%)
0%
0%
2 (8%)
1 (4%)1 (4%)
0%0%
0%0%
2 (8%)2 (8%)
Dante Dante PazzanesePazzanese
48 Months48 Months48 Months
1 (4%)
0%
0%
2 (8%)
1 (4%)1 (4%)
0%0%
0%0%
2 (8%)2 (8%)
60 Months60 Months60 Months
1 (4%)
0%
0%
8 (32%)
1 (4%)1 (4%)
0%0%
0%0%
8 (32%)8 (32%)
00 121200
2020
4040
6060
8080
100100
Patie
nts
wit h
out E
v ent
s ( %
)Pa
ti ent
s w
it hou
t Ev e
nts
( %)
Pati e
nts
wit h
out E
v ent
s ( %
)
2424 3636
68 %68 %
Time (Time (MonthsMonths))
66 1818 3030
ISR ISR StudyStudy: : 66--YearYear FollowFollow--UpUp
100 %100 %
EventEvent FreeFree SurvivalSurvival: MACE: MACE
EventEvent FreeFree SurvivalSurvival: TLR: TLR
Dante Dante PazzanesePazzanese
4848 6060
TROPICALClinical Outcome at 180 Days
Non-Hierarchical EventRate (%) TROPICALGAMMA I/II
0
5
10
15
20
Death MI Clinicallydriven TLR
Stentthrombosis
MACE
P=0.490 P=0.004 P<0.001 P=0.080
P<0.001
3.7
0.61.8
2.50.6
18.8
2.0
25
9.4
14
3.9
30
Franz-Joseph Neumann and Walter Desmet, PCR 2004
SES vs. Historical Gamma VBTSES vs. Historical Gamma VBT
n= 162 SES262 VBT
AHA 2004, New OrleansAHA 2004, New OrleansAHA 2004, New Orleans
ISARISAR--DESIRE TrialDESIRE Trial
Kastrati et al, ESC 2004AHA 2004, New OrleansAHA 2004, New OrleansAHA 2004, New Orleans
The eThe e––Cypher RegistryCypher Registry
Real World Use of SirolimusReal World Use of Sirolimus--Eluting Eluting Stents for the Treatment of InStents for the Treatment of In--Stent Stent
RestenosisRestenosisJ. Eduardo Sousa, Amanda Sousa, Alexandre Abizaid, J. Eduardo Sousa, Amanda Sousa, Alexandre Abizaid, Ricardo Seabra Gomes, Adriana Moreira, Manuel Cano, Ricardo Seabra Gomes, Adriana Moreira, Manuel Cano,
Philip Urban, Chaim Lotan, Anthony Gershlick, Philip Urban, Chaim Lotan, Anthony Gershlick, AshokAshok Seth, Monika DemeSeth, Monika Deme
On behalf of the eOn behalf of the e--Cypher investigatorsCypher investigators
AHA 2004, New OrleansAHA 2004, New OrleansAHA 2004, New Orleans
LATIN AMERICA 97Argentina 14Brazil 17Chile 8Colombia 9Costa Rica 2 Dominican Republic 2Guatemala 1Mexico 31Panama 3 Uruguay 3Venezuela 7
LATIN AMERICA 97Argentina 14Brazil 17Chile 8Colombia 9Costa Rica 2 Dominican Republic 2Guatemala 1Mexico 31Panama 3 Uruguay 3Venezuela 7
EUROPE 127Austria 7Belgium 4France 30Germany 1Italy 10Latvia 1Luxembourg 1Morocco 5Netherlands 1Portugal 9 Russian Federation 4UK 4Spain 36Switzerland 9 Lithuania 2Yugoslavia 1Tunisia 2
EUROPE 127Austria 7Belgium 4France 30Germany 1Italy 10Latvia 1Luxembourg 1Morocco 5Netherlands 1Portugal 9 Russian Federation 4UK 4Spain 36Switzerland 9 Lithuania 2Yugoslavia 1Tunisia 2
MIDDLE EAST 15Bahrain 1 Israel 11Lebanon 2Saudi Arabia 1
MIDDLE EAST 15Bahrain 1 Israel 11Lebanon 2Saudi Arabia 1
ASIA PACIFIC 43Australia 11India 18Malaysia 3Pakistan 2Thailand 3Vietnam 2 New Zealand 2Philippines 1Singapore
1
ASIA PACIFIC 43Australia 11India 18Malaysia 3Pakistan 2Thailand 3Vietnam 2 New Zealand 2Philippines 1Singapore
1
282 Sites282 Sites
Participating Participating CentersCenters
AHA 2004, New OrleansAHA 2004, New OrleansAHA 2004, New Orleans
Patient Enrolment Patient Enrolment
1306913970142981515715524
0
4000
8000
12000
16000
enrolled analysable* FU at 1month
FU at 6months
FU at 12months
# of patients# of patients
95 %95 %95 % 93 %93 %93 % 91 %91 %91 %98 %of enrolled
98 %98 %of enrolledof enrolled
* at least 1 SES in a CASS* at least 1 SES in a CASS--defined coronary segment at a given index datedefined coronary segment at a given index date
360 days follow-up: MACE360 days follow360 days follow--up: MACEup: MACE
1,43
0,361,08
4,09
0,79
7,17
5,53
0,3
2,111,25
0,691,5
012345678
cardiacdeath
otherdeath
MI TLR PCI* TLRCABG*
MACE
ISR
p=0.0145p=0.0145
p=0.0137p=0.0137
P<0.0001P<0.0001
*Cypher stent related Patients treated at index with ISR and de novo lesion are not included
ISRISRISR
CECCEC--adjudicated eventsadjudicated events
de novo (n=11824)de novo (n=11824) ISR (n=1395)ISR (n=1395)
(%)(%)(%)
360 days follow up: Stent Thrombosis360 days follow up: 360 days follow up: StentStent ThrombosisThrombosis
All cases with reported death, MI, TLR or stent thrombosis were reviewed and adjudicated by CEC: ST was considered “definite” if angiographic documentation was available at any time, and “likely” (up to 30 days) for cardiac death and MI without angiography.
All cases with reported death, MI, TLR or stent thrombosis were All cases with reported death, MI, TLR or stent thrombosis were reviewed and adjudicated by reviewed and adjudicated by CEC: ST was considered CEC: ST was considered ““definitedefinite”” if angiographic documentation was available at any time, if angiographic documentation was available at any time, and and ““likelylikely”” (up to 30 days) for cardiac death and MI without angiography.(up to 30 days) for cardiac death and MI without angiography.
0,85
0,13
0,55
0,19
0,8
0,13
0,54
0,14
0
0,3
0,6
0,9
1,2
1,5
1,8
overall acute (<24h) subacute (2-30 days) late (31-360 days)
ISR
*Cypher stent related Patients treated at index with ISR and de novo lesion are not included**CypherCypher stentstent relatedrelated Patients Patients treatedtreated atat index index withwith ISR ISR andand de novo de novo lesionlesion are not are not includedincluded
P=NSP=NS
ISRISRISR
CECCEC--adjudicated eventsadjudicated events
de novode novo ISRISR(%)(%)(%)
e-Cypher: Conclusionsee--CypherCypher: Conclusions: ConclusionsThe ISR sub-population represents one of the important current indications for SES (1,751 patients, 12.2% of the WW registry population). The overall stent thrombosis rate was low and similar in both in the ISR (0.95%) and the non-ISR group (0.87%).With very low MACE rates at 1 year (7.1%), the subgroup of ISR patients did exceptionally well in terms of safety, contrary to expectations based on some of the previously available data from some other series.Further target lesion revascularization at 1 yearwas more often done for ISR (4.0%) than for de novo patients (2.1%).
The ISR subThe ISR sub--population represents one of the population represents one of the important current indications for SES (1,751 important current indications for SES (1,751 patients, 12.2% of the WW registry population). patients, 12.2% of the WW registry population). The overall stent thrombosis rate was low and The overall stent thrombosis rate was low and similar in both in the ISR (0.95%) and the nonsimilar in both in the ISR (0.95%) and the non--ISR ISR group (0.87%).group (0.87%).With very low MACE rates at With very low MACE rates at 11 yearyear ((7.17.1%), the %), the subgroup of ISR patients did exceptionally well in subgroup of ISR patients did exceptionally well in terms of safety,terms of safety, contrary to expectations based contrary to expectations based on some of the previously available data from on some of the previously available data from some other series.some other series.Further target lesion revascularization at Further target lesion revascularization at 1 year1 yearwas more often done for ISR (was more often done for ISR (4.04.0%) than for de %) than for de novo patients (novo patients (2.12.1%).%).
AHA 2004, New OrleansAHA 2004, New OrleansAHA 2004, New Orleans
Treatment of InTreatment of In--stentstent RestenosisRestenosis
ISR after Bare Metal ISR after Bare Metal StentStent
ISR after DrugISR after Drug--eluting eluting StentStent
The Real Question:The Real Question:
Is ISR still a problem?Is ISR still a problem?
Why do DES failure?Why do DES failure?
Causes of DES ISR:Causes of DES ISR:
StentStent underunder--expansionexpansionAsymmetric strut distribution Asymmetric strut distribution StentStent fracture fracture Polymer disruptionPolymer disruptionPeriPeri--stentstent vessel wall injuryvessel wall injuryDrug failure or resistanceDrug failure or resistancePolymer (or drug) hypersensitivityPolymer (or drug) hypersensitivity
20 pts with IVUS of both branches after 20 pts with IVUS of both branches after ““crushcrush”” DES showed frequent DES showed frequent stentstent
underexpansionunderexpansion at the side branch at the side branch ostiumostium
Main vesselMain vesselMSA <5mmMSA <5mm22 in 20%in 20%MSA <4mmMSA <4mm22 in 10%in 10%
Side branchSide branchMSA <5mmMSA <5mm22 in 90%in 90%MSA <4mmMSA <4mm22 in 55%in 55%OstiumOstium is the site of MSA in 65%is the site of MSA in 65%
Costa et al. J Am Costa et al. J Am CollColl CardiolCardiol (in press)(in press)
Bifurcation Bifurcation stenosisstenosis treated treated with 2 with 2 CypherCypher stentsstents 77--month Followmonth Follow--upup
Why do DES failure?Why do DES failure?
Causes of DES ISR:Causes of DES ISR:
StentStent underunder--expansionexpansionAsymmetric strut distribution Asymmetric strut distribution StentStent fracture fracture Polymer disruptionPolymer disruptionPeriPeri--stentstent vessel wall injuryvessel wall injuryDrug failure or resistanceDrug failure or resistancePolymer (or drug) hypersensitivityPolymer (or drug) hypersensitivity
PrePre PostPost
FU 8mFU 8m
Stent cypher 3.0x33.0mm
StentStentFractureFracture
PrePre PostPost
StentStent cyphercypher 3.0x18.0mm3.0x18.0mm
Treatment:Another Cypher
Why do DES failure?Why do DES failure?
Causes of DES ISR:Causes of DES ISR:
StentStent underunder--expansionexpansionAsymmetric strut distribution Asymmetric strut distribution StentStent fracture fracture Polymer disruptionPolymer disruptionPeriPeri--stentstent vessel wall injuryvessel wall injuryDrug failure or resistanceDrug failure or resistancePolymer (or drug) hypersensitivityPolymer (or drug) hypersensitivity
OrmistonOrmiston
CypherCypher sideside--branch branch ostiumostium after crush and after crush and repeated 20 repeated 20 atmosatmos postpost--dilatationdilatation
Ormiston
Main branch Main branch ostiumostium after after TaxusTaxus stentstent crush and crush and Repeated high pressure kissing postRepeated high pressure kissing post--dilatationdilatation
How to Treat DES ISRHow to Treat DES ISR
Balloon PCI
Athero-ablative modalities (RA, DCA, or ELCA)
Scoring devices (cutting balloon, Fx minirail, or Angiosculpt)
Bare metal stent
Drug-eluting stent
Vascular brachytherapy
Balloon PCIBalloon PCI
AtheroAthero--ablative modalities (RA, DCA, or ablative modalities (RA, DCA, or ELCA)ELCA)
Scoring devices (cutting balloon, Scoring devices (cutting balloon, FxFx minirailminirail, or , or AngiosculptAngiosculpt))
Bare metal Bare metal stentstent
DrugDrug--eluting eluting stentstent
Vascular Vascular brachytherapybrachytherapy
Dante Dante PazzanesePazzanese
DES ISR DES ISR treatedtreated withwith anotheranother DESDES
6 months 6 months TAXUSTAXUS Post Post CypherCypherCypherCypher
3.5/18mm3.5/18mm
6 months6 months
David R. Holmes, David R. Holmes, JrJr., Mayo Clinic; Jeffrey ., Mayo Clinic; Jeffrey PopmaPopma, , Brigham & WomenBrigham & Women’’s Hospital; Richard Kuntz, Harvard s Hospital; Richard Kuntz, Harvard
Clinical Research Institute; Peter J. Fitzgerald, Stanford Clinical Research Institute; Peter J. Fitzgerald, Stanford University Medical University Medical CenterCenter; Paul S. ; Paul S. TeirsteinTeirstein, Scripps , Scripps Clinic; Lowell Clinic; Lowell SatlerSatler, Washington Hospital , Washington Hospital CenterCenter; ;
Michael Sketch, Duke University Medical Michael Sketch, Duke University Medical CenterCenter; Sidney ; Sidney A. Cohen, Cordis Corporation, Johnson & JohnsonA. Cohen, Cordis Corporation, Johnson & Johnson
The SISR Trial: 12 Month The SISR Trial: 12 Month OutocomesOutocomesof of SirolimusSirolimus--eluting eluting StentsStents for the for the Treatment of InTreatment of In--StentStent RestenosisRestenosis
Study DesignStudy Design
259 Patients259 Patients
CYPHERCYPHER®®SirolimusSirolimus--eluting eluting
stentstent
Patients with inPatients with in--stentstent restenosisrestenosis with native coronary with native coronary artery lesions artery lesions >> 15 mm and 15 mm and << 40 mm in length and 40 mm in length and >>
2.5 mm to 2.5 mm to << 3.5 mm in diameter (n=384)3.5 mm in diameter (n=384)
Randomized 2:1Randomized 2:1
Primary endpoint Primary endpoint –– Target Vessel Failure (TVF): Target Vessel Failure (TVF): Cardiac death, MI, or TVR at 9 months postCardiac death, MI, or TVR at 9 months post--procedureprocedure
Intravascular Intravascular BrachytherapyBrachytherapy Beta or Beta or
GammaGamma
125 Patients125 Patients
0
0,5
1
1,5
2
Acute Gain(mm)
Acute GainAcute Gain(mm)(mm)
1.271.27
0.680.68
BrachytherapyBrachytherapySESSES
0.500.50
p=0p=0.691.691
p=0p=0.067.067
SISR: Angiographic Outcomes @ 6 SISR: Angiographic Outcomes @ 6 mosmos
0.270.27 0.310.31
1.001.00
p<0p<0.001.001
p=0p=0.330.330
p<0p<0.001.001
Restenosis (% of Patients)
Restenosis Restenosis (% of Patients)(% of Patients)
1.021.02
0.330.33
0
10
20
30
40
50
Late Loss(mm)
Late LossLate Loss(mm)(mm)
Loss Index(mm)
Loss IndexLoss Index(mm)(mm)
Net Gain(mm)
Net GainNet Gain(mm)(mm)
19.819.8
29.529.5
0
10
20
30
40
50
DeathDeathDeath0.00.0
% o
f Pat
ient
s %
of P
atie
nts
% o
f Pat
ient
s
12.412.4
BrachytherapyBrachytherapySESSES
8.58.5
19.219.2
p=0p=0.004.004
p=0p=0.023.023
SISR: Clinical Outcomes @ 9 SISR: Clinical Outcomes @ 9 mosmos
0.00.0 0.40.4 0.00.0 2.32.3 0.00.0
10.810.8
21.621.6 21.621.6
p=0p=0.008.008
p=0p=0.183.183p=1p=1.000.000
Q-Wave MIQQ--Wave MIWave MI NQMINQMINQMI TLRTLRTLR TVRTVRTVR TVFPrimary
Endpoint
TVFTVFPrimaryPrimary
EndpointEndpoint
SISR: FREEDOM from TLR @ 12 SISR: FREEDOM from TLR @ 12 mosmosFR
EED
OM
from
TLR
FREE
DO
M fr
om T
LR
Time after Initial Procedure (days)Time after Initial Procedure (days)
89.7%89.7%89.7%
78.1%78.1%78.1%
LR p = 0.002LR p = 0.002LR p = 0.002
StentStent ThrombosisThrombosis
Stent Thrombosis:
Through 30 days
Late Thrombosis:
Day 31 through 360 days
StentStent Thrombosis:Thrombosis:
Through 30 daysThrough 30 days
Late Thrombosis:Late Thrombosis:
Day 31 through 360 daysDay 31 through 360 days
CYPHERCYPHERCYPHER BrachytherapyBrachytherapyBrachytherapy P-valuePP--valuevalue
0 / 259 (0%)
3 / 259 (1.2%)
0 / 259 (0%)0 / 259 (0%)
3 / 259 (1.2%)3 / 259 (1.2%)
0 / 125 (0%)
0 / 125 (0%)
0 / 125 (0%)0 / 125 (0%)
0 / 125 (0%)0 / 125 (0%)
-
0.554
--
0.5540.554
The TAXUSThe TAXUS--V InV In--StentStent RestenosisRestenosisTrialTrial
Stephen G. Ellis, Charles D. OStephen G. Ellis, Charles D. O’’Shaughnessy, Lowell Shaughnessy, Lowell SatlerSatler, Steven L. Martin, Thomas , Steven L. Martin, Thomas McGarryMcGarry, Dean J. , Dean J.
KereiakesKereiakes, Mark A. , Mark A. TurcoTurco, W. Carl Jacobs, , W. Carl Jacobs, A.R. A.R. ZakiZaki--MasudMasud, Mary E. , Mary E. RusselRussel
Stone GW et al. JAMA 2006;295:1253-63Stone GW et al. JAMA 2006;295:1253Stone GW et al. JAMA 2006;295:1253--6363
A Prospective, A Prospective, MulticenterMulticenter, Randomized Trial , Randomized Trial Evaluating the TAXUS Evaluating the TAXUS PaclitaxelPaclitaxel--Eluting Coronary Eluting Coronary
StentStent versus Vascular versus Vascular BrachytherapyBrachytherapy for the Treatment for the Treatment of Bare Metal of Bare Metal StentStent InIn--StentStent RestenosisRestenosis
Gregg W. Stone, MDGregg W. Stone, MD
9 Month Ischemic and Non-Ischemic TLR9 Month Ischemic and Non9 Month Ischemic and Non--Ischemic TLRIschemic TLR
0
10
20
30
IschemicTLR
IschemicIschemicTLRTLR
13.913.9
Even
ts (%
)Ev
ents
(%)
Even
ts (%
)
6.36.3
20.120.1
7.97.9
BrachytherapyBrachytherapy (n=194)(n=194) TAXUS (n=191)TAXUS (n=191)
Stone GW et al. JAMA 2006;295:1253-63Stone GW et al. JAMA 2006;295:1253Stone GW et al. JAMA 2006;295:1253--6363
6.76.7
1.61.6
2727N =N = 1212 1313 33 3939 1515Non-Ischemic
TLRNonNon--IschemicIschemic
TLRTLRAny TLRAny TLRAny TLR
p=0p=0.01.01 p=0p=0.01.01 p<0p<0.001.001
Cumulative MACE to 9 MonthsCumulative MACE to 9 MonthsCumulative MACE to 9 Months
Stone GW et al. JAMA 2006;295:1253-63Stone GW et al. JAMA 2006;295:1253Stone GW et al. JAMA 2006;295:1253--6363
9 Month Target Vessel Thrombosis9 Month Target Vessel Thrombosis9 Month Target Vessel Thrombosis
Stone GW et al. JAMA 2006;295:1253-63Stone GW et al. JAMA 2006;295:1253Stone GW et al. JAMA 2006;295:1253--6363*All 3 cases were stent thrombosis*All 3 cases were stent thrombosis*All 3 cases were stent thrombosis
ConclusionConclusion
CIPHERCIPHER®® and TAXUSand TAXUS®® stentsstents result in result in
superior clinical and angiographic superior clinical and angiographic
outcomes compared with vascular outcomes compared with vascular
brachytherapybrachytherapy for the treatment of for the treatment of
restenosisrestenosis within a barewithin a bare--metal metal stentstent..
Even in unfavorable subgroups
DES REIGN SUPREME
Even in unfavorable subgroupsEven in unfavorable subgroups
DES REIGN SUPREMEDES REIGN SUPREME
Trial Design and Primary EndpointTrial Design and Primary EndpointStudy OverviewStudy OverviewStudy Overview- Prospective, randomized 1:1, open-label trial- Pts with bare metal in-stent restenosis randomized to:-- Prospective, randomized 1:1, openProspective, randomized 1:1, open--label triallabel trial-- Pts with bare metal inPts with bare metal in--stentstent restenosisrestenosis randomized to:randomized to:
TAXUS Express2 slow-release paclitaxel-eluting stent
VBT with and FDA-approved beta-source
TAXUS ExpressTAXUS Express22 slowslow--release release paclitaxelpaclitaxel--eluting eluting stentstent
VBT with and FDAVBT with and FDA--approved betaapproved beta--sourcesource
- Clinical FU at 1, 4 and 9 months, and then yearly for 5 yrs- Angiographic FU at 9 months planned in all patients- IVUS FU at 9 months planned in 250 patients
-- Clinical FU at 1, 4 and 9 months, and then yearly for 5 yrsClinical FU at 1, 4 and 9 months, and then yearly for 5 yrs-- Angiographic FU at 9 months planned in all patientsAngiographic FU at 9 months planned in all patients-- IVUS FU at 9 months planned in 250 patientsIVUS FU at 9 months planned in 250 patients
Primary Endpoint: 9-month ischemic TVR Primary Endpoint: 9Primary Endpoint: 9--month ischemic TVR month ischemic TVR - Powered for sequential non-inferiority and superiority-- Powered for sequential nonPowered for sequential non--inferiority and superiorityinferiority and superiority
versusversusversus
Sample Size Power Analysis Sample Size Power Analysis
With 438 patients havin 9 month F/U (219 per group)With 438 patients With 438 patients havinhavin 9 month F/U (219 per group)9 month F/U (219 per group)
Non-Inferiority TestingNonNon--Inferiority TestingInferiority Testing
Allowing for 10% attrition, up to 488 patients could be enrolledAllowing for 10% attrition, up to 488 patients could be enrolledAllowing for 10% attrition, up to 488 patients could be enrolled
BrachytherapyBrachytherapyBrachytherapy TAXUSTAXUSTAXUSAnticipatedTVR: 20%
AnticipatedAnticipatedTVR: 20%TVR: 20%
AnticipatedTVR: 20%
AnticipatedAnticipatedTVR: 20%TVR: 20%
Delta 10%, 1-sided alpha 0.05 → 83% powerDelta 10%, 1Delta 10%, 1--sided alpha 0.05 sided alpha 0.05 →→ 83% power83% powerSuperiority TestingSuperiority TestingSuperiority Testing
BrachytherapyBrachytherapyBrachytherapy TAXUSTAXUSTAXUSAnticipatedTVR: 20%
AnticipatedAnticipatedTVR: 20%TVR: 20%
AnticipatedTVR: 10%
AnticipatedAnticipatedTVR: 10%TVR: 10%
2-sided alpha 0.05 → 80% power22--sided alpha 0.05 sided alpha 0.05 →→ 80% power80% power
9 Month Analysis Segment Results9 Month Analysis Segment Results9 Month Analysis Segment Results
0
0,5
1
1,5
2
2,5
BaselineMLD
BaselineBaselineMLDMLD
0.830.83
Med
ian,
IQR
Med
ian,
IQR
Med
ian,
IQR
1.991.99
1.551.55
BrachytherapyBrachytherapy (n=170)(n=170) TAXUS (n=172)TAXUS (n=172)
Stone GW et al. JAMA 2006;295:1253-63Stone GW et al. JAMA 2006;295:1253Stone GW et al. JAMA 2006;295:1253--6363
0.220.22
0.860.86Means Means
Post-Proc.MLD
PostPost--Proc.Proc.MLDMLD
9 monthMLD
9 month9 monthMLDMLD
p=0p=0.51.51 p<0p<0.001.001 p<0p<0.001.001
Paired Angiographic AnalysisPaired Angiographic AnalysisPaired Angiographic Analysis
0.800.800.980.98
1.621.621.841.84
2.082.08
0.130.13
p<0p<0.001.001 p=0p=0.08.08
0.610.61--1.021.020.550.55--1.041.040.710.71--1.251.25
1.381.38--1.941.941.561.56--2.132.13
1.831.83--2.482.48
--0.020.02--0.710.71--0.050.05--0.420.42
1.051.05--1.911.91
1.031.03--2.252.25
0.820.82 1.001.00 1.371.37 1.861.86 2.192.19 0.400.40 0.290.29 1.461.46 1.901.90
Acute Gain
Acute Acute GainGain
Late LossLate Late LossLoss
In-stent Restenosis Registry (ISR)InIn--stent Restenosis Registry (ISR)stent Restenosis Registry (ISR)
N = 41 patientsVessel size: 2.5–3.5mm
18mm Cypher stent (1 or 2)
N = 41 patientsN = 41 patientsVessel size: 2.5Vessel size: 2.5––3.5mm3.5mm
18mm Cypher 18mm Cypher stentstent (1 or 2)(1 or 2)2 sites: Sao Paulo (Brazil) and RotterdamSão Paulo: Patients similar to those usually treated with brachytherapyRotterdam: Including brachytherapy failures (4 pts), total occlusions (3 cases) and one heart transplant patientASA + Clopidogrel (60 days)Primary end-point: 4, 12 and 48-mo MACE
2 sites: Sao Paulo (Brazil) and Rotterdam2 sites: Sao Paulo (Brazil) and RotterdamSãoSão Paulo: Patients similar to those usually Paulo: Patients similar to those usually treated with treated with brachytherapybrachytherapyRotterdam: Including Rotterdam: Including brachytherapybrachytherapy failures failures (4 pts), total occlusions (3 cases) and one (4 pts), total occlusions (3 cases) and one heart transplant patientheart transplant patientASA + Clopidogrel (60 days)ASA + Clopidogrel (60 days)Primary endPrimary end--point: point: 4, 12 4, 12 andand 4848--mo MACE mo MACE
InIn--hospital Results (N = 25 Pts)hospital Results (N = 25 Pts)
SuccessSuccessDeathDeathMIMIEmergent CABG Emergent CABG SubSub--acute Thrombosis acute Thrombosis
100%100%0%0%0%0%0% 0% 0%0%
SirolimusSirolimus -- ElutingEluting StentStent for for thethe TreatmentTreatment of ISR (of ISR (SaoSao Paulo)Paulo)
Sousa et al. Circulation 2003;107:24Sousa et al. Circulation 2003;107:24--2727
Dante Dante PazzanesePazzanese
30 Days Follow-up MACE (n=13,138)30 Days Follow30 Days Follow--up MACE (n=13,138)up MACE (n=13,138)
00,20,40,60,8
11,21,4
MACE Death QMI NQ MI TLR TVR
(%)(%)(%)
CECCEC--adjudicated eventsadjudicated events
AHA 2004, New OrleansAHA 2004, New OrleansAHA 2004, New Orleans
1.341.34
0.990.99
0.560.560.490.49
0.260.260.060.06
0.360.36 0.310.310.40.4
0.310.310.120.12 0.120.12
1.41.41.21.2
0.80.80.60.60.40.40.20.2
NonNon--ISR (n=11,514)ISR (n=11,514) ISR (n=1,624)ISR (n=1,624)
6 Months Follow-up MACE (n= 11,920)6 Months Follow6 Months Follow--up MACE (n= 11,920)up MACE (n= 11,920)
0
1
2
3
4
MACE Death QMI Non QMI TLR TVR
(%)(%)(%)
CECCEC--adjudicated eventsadjudicated events
AHA 2004, New OrleansAHA 2004, New OrleansAHA 2004, New Orleans
33
3.83.8
1.391.39 1.421.42
0.350.350.140.14
0.580.58 0.540.54
*1.19*1.19
2.12.1
0.40.40.880.88
NonNon--ISR (n=10,442)ISR (n=10,442) ISR (n=1,478)ISR (n=1,478)
Stent Thrombosis Stent Thrombosis Stent Thrombosis
0
0,2
0,4
0,6
0,8
1
acute (<24h) sub-acute (day 2-30) late (31-180 days)
CEC - adjudicated events: all cases with death, MI, TLR or reported stent thrombosis were reviewedCEC CEC -- adjudicated events: all cases with death, MI, TLR or reported sadjudicated events: all cases with death, MI, TLR or reported stent thrombosis were reviewedtent thrombosis were reviewed
Overall ST at 6 months: non-ISR 0.87% vs. ISR 0.95% (ns)
0.130.13
(%)(%)(%)
0.140.14 0.150.15
0.580.580.740.74
0.070.07
AHA 2004, New OrleansAHA 2004, New OrleansAHA 2004, New Orleans
NonNon--ISR (n=10,442)ISR (n=10,442) ISR (n=1,478)ISR (n=1,478)
AHA 2004, New OrleansAHA 2004, New OrleansAHA 2004, New Orleans
00 3030 6060 9090 120120 150150 180180909091919292
9393949495959696979798989999100100
ISRISRTreatmentTreatmentGroupGroup
Free
dom
from
MA
CE
(%)
Free
dom
from
MA
CE
(%)
Time Time AfterAfter the the InitialInitial ProcedureProcedure (Days(Days))
6 Months MACE-Free Survival6 Months MACE6 Months MACE--Free SurvivalFree Survival
p p -- 0.00050.0005Log Log RankRank
OtherOther
Test Test p p -- 0.00450.0045p p -- 0.00050.0005
WI IsozonWI Isozon
Test Test --2 Log (LR)2 Log (LR)
Test Test
Survival Free from Major Cardiac Adverse Event (MACE)Survival Free from Major Cardiac Adverse Event (MACE)
97.0%97.0%96.2%96.2%
6 6 MonthMonth TLRTLR--free free SurvivalSurvival
AHA 2004, New OrleansAHA 2004, New OrleansAHA 2004, New Orleans
00 3030 6060 9090 120120 150150 1801809090919192929393949495959696979798989999
100100
ISRISRTreatmentTreatmentGroupGroup
Free
dom
from
(%)
Free
dom
from
(%)
Time Time AfterAfter the the InitialInitial ProcedureProcedure (Days(Days))
p p << .0001.0001Log Log RankRank
OtherOther
Test Test p p << .0001.0001p p << .0001.0001
WI IsozonWI Isozon
Test Test --2 Log (LR)2 Log (LR)
Test Test
Survival Free from Target Lesion Revascularization (TLR)Survival Free from Target Lesion Revascularization (TLR)
98.9%98.9%
97.9%97.9%
Changes in % DS and MLDChanges in % DS and MLD InIn--stentstentSirolimusSirolimus Eluting Eluting StentStent: ISR (Sao Paulo): ISR (Sao Paulo)
Post(n=25)
Pre(n=25)
4mo(n=25)
66.066.0
0
10
20
30
40
50
60
70
80
2.62.67.157.15
0
0.5
1
1.5
2
2.5
3MLD(mm)MLD(mm)
%DS
InIn--stentstentLate Late LosLoss s
0.33 mm (3 years)
(%DS)(%DS)
3 y(n=24)
16.716.716.7
Dante Dante PazzanesePazzanese
J. J. PopmaPopma. . AngiographicAngiographic Core Core LabLab, Boston, Boston
1 y(n=25)
0.90.9
22.64.642.712.71
MLD2.3522.35.35 2.3822.38.38
18.118.118.1
PrePre--InterventionIntervention Post 2 Sirolimus-Eluting Stents
DiffuseDiffuse InIn--StentStent RestenosisRestenosisDante Dante
PazzanesePazzanese
ISR: Sirolimus-Eluting StentISR: ISR: SirolimusSirolimus--ElutingEluting StentStent
4 Months4 4 MonthsMonths 1 Year1 1 YearYear 3 Years3 Y3 Yearearss
Dante Dante PazzanesePazzanese
00 121200
2020
4040
6060
8080
100100
Patie
nts
wit h
out E
v ent
s ( %
)Pa
ti ent
s w
it hou
t Ev e
nts
( %)
Pati e
nts
wit h
out E
v ent
s ( %
)
2424 3636
88 %88 %
Time (Time (MonthsMonths))
66 1818 3030
ISR ISR StudyStudy: 4: 4--YearYear FollowFollow--UpUp
100 %100 %
EventEvent FreeFree SurvivalSurvival: MACE: MACE
EventEvent FreeFree SurvivalSurvival: TLR: TLR
Dante Dante PazzanesePazzanese
4848
Back of ostium. Ormiston
Ormiston
CypherCypher and and TaxusTaxus Trials: TLR Trials: TLR SIRIUS, C-SIRIUS, E-SIRIUS, RAVEL, DIRECT,
SVELT, TAXUS II, IV, and VISIRIUS, CSIRIUS, C--SIRIUS, ESIRIUS, E--SIRIUS, RAVEL, DIRECT, SIRIUS, RAVEL, DIRECT,
SVELT, TAXUS II, IV, and VISVELT, TAXUS II, IV, and VI
P<0.0001P<0.0001P<0.0001P<0.0001
80%80%80% 70%70%70%
3.5%3.5%
17.1%17.1%
4.9%4.9%
15.6%15.6%
DES Control
CYPHER TAXUSN=1204 n=870 N=1141 n=1148
(6 months) (12 months)
Recommended Strategy to Treat DES ISRRecommended Strategy to Treat DES ISR
POBA, scoring balloons,Another DES POBA, scoring balloons,POBA, scoring balloons,Another DES Another DES
IVUS is recommended to identify IVUS is recommended to identify mechanical problemsmechanical problems
FocalFocalFocal
Focal at edgesFocal at edgesFocal at edges
DES ISRDES ISRDES ISR
DiffuseDiffuseDiffuse
Another DESAnother DESAnother DES
Another DES Another DES Another DES
ISR after Bare Metal StentsISR after Bare Metal Stents
InIn--Stent Restenosis = Intimal HyperplasiaStent Restenosis = Intimal Hyperplasia
SirolimusSirolimus--Eluting Eluting StentStent for the Treatment for the Treatment of ISR of ISR Patterns of InPatterns of In--stent Restenosisstent Restenosis
Diffuse ProliferativeDiffuse Diffuse ProliferativeProliferative
Diffuse IntrastentDiffuse Diffuse IntrastentIntrastent
FocalFocalFocal
10 (40%)10 (40%)10 (40%)
8 (32%)8 (32%)8 (32%)
7 (28%)7 (28%)7 (28%)
Sousa et al. Circulation 2003;107:24Sousa et al. Circulation 2003;107:24--2727
DES ISR ConclusionsDES ISR Conclusions
Several mechanisms may explain DES ISR (stentunder-expansion, fracture, polymer disruption, geographic miss, drug resistance and hypersensitivity)
The frequency of ISR after DES is low (< 5%).
The pattern of ISR after DES, in contra-distinction to bare metal stents, is predominantly focal (~80%).
ISR after DES is usually easily treated and 2ry
success rates appear excellent.
Another DES seems to be the most reasonable approach to treat DES in-stent restenosis
Several mechanisms may explain DES ISR (Several mechanisms may explain DES ISR (stentstentunderunder--expansion, fracture, polymer disruption, expansion, fracture, polymer disruption, geographic miss, drug resistance and geographic miss, drug resistance and hypersensitivity) hypersensitivity)
The frequency of ISR after DES is low (< 5%).The frequency of ISR after DES is low (< 5%).
The pattern of ISR after DES, in contraThe pattern of ISR after DES, in contra--distinction to distinction to bare metal bare metal stentsstents, is predominantly focal (~80%)., is predominantly focal (~80%).
ISR after DES is usually easily treated and 2ISR after DES is usually easily treated and 2ryry
success rates appear excellent.success rates appear excellent.
Another DES seems to be the most reasonable Another DES seems to be the most reasonable approach to treat DES inapproach to treat DES in--stentstent restenosisrestenosis
Conclusions and Clinical ImplicationsConclusions and Clinical ImplicationsCompared to PCI with VBT, treatment of BMS ISR with Compared to PCI with VBT, treatment of BMS ISR with the the paclitaxelpaclitaxel--eluting TAXUS eluting TAXUS stentstent::
-- Is safeIs safe
. Comparable rates of target vessel thrombosis, MI, . Comparable rates of target vessel thrombosis, MI, and deathand death
-- Provides superior efficacyProvides superior efficacy
. Significant reduction in clinical and angiographic . Significant reduction in clinical and angiographic restenosisrestenosis
For pts in whom BMS are implanted, should For pts in whom BMS are implanted, should restenosisrestenosis occur, the availability of the TAXUS occur, the availability of the TAXUS stentstentrepresents a simple, safe therapy resulting in a high represents a simple, safe therapy resulting in a high rate of 9 month eventrate of 9 month event--free survival, a reassuring free survival, a reassuring option for an otherwise difficult to treat cohort of pts.option for an otherwise difficult to treat cohort of pts.