“treatment of in-stent restenosis” · “treatment of in-stent restenosis” j. eduardo sousa,...

““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%)



1 (4%)

0%

0%

2 (8%)

1 (4%)1 (4%)

0%0%

0%0%

2 (8%)2 (8%)


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


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


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


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


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%).%).


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

PrePre PostPost

FU 8mFU 8m

Stent cypher 3.0x33.0mm

StentStentFractureFracture

PrePre PostPost

StentStent cyphercypher 3.0x18.0mm3.0x18.0mm

Treatment:Another Cypher

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


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)


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


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%


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%


AnticipatedTVR: 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)


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


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

(%)(%)(%)



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

(%)(%)(%)



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


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




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


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


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


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


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.

“treatment of in-stent restenosis” · “treatment of in-stent restenosis” j. eduardo sousa,...

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