tct 2002 scientific sessiontaxus nirx comparative clinical - version 3.02 re 20020916 taxus ii...

TAXUSNIRx Comparative Clinical - Version 3.02RE 20020916

TCT 2002 Scientific Session

TAXUS II International StudyComparative 6 month clinical

QCA & IVUS results

TAXUS NIRx stent system

Slow and Moderate release Paclitaxel formulation Dr Adrian Banning

John Radcliffe Hospital, Oxford

On behalf of the TAXUS II Investigators



Paclitaxel (1g/mm2 total loaded) Potent microtubular inhibitor Multifunctional

Slow (SR) and Moderate (MR) release formulationsTransluteTM polymer regulates controlled biphasic release & allows variable elution profile (cf Cypher)

NIRxTM Conformer Stent System Pre-mounted

15mm Conformer stent with 20mm balloon Advance Delivery SystemDiameters 3.0 & 3.5 mm

Paclitaxel (1g/mm2 total loaded) Potent microtubular inhibitor Multifunctional

Slow (SR) and Moderate (MR) release formulationsTransluteTM polymer regulates controlled biphasic release & allows variable elution profile (cf Cypher)

NIRxTM Conformer Stent System Pre-mounted

15mm Conformer stent with 20mm balloon Advance Delivery SystemDiameters 3.0 & 3.5 mm

TAXUS NIRxTMTAXUS NIRxTM



ObjectiveObjective

TAXUS IIEvaluate safety and performance of the two consecutive cohorts for the treatment of

de novo coronary lesions:

Cohort I: Comparing TAXUS slow release randomised 1:1 against bare stent control

Cohort II: Comparing TAXUS moderate release randomised 1:1 against bare stent control

TAXUS IIEvaluate safety and performance of the two consecutive cohorts for the treatment of

de novo coronary lesions:

Cohort I: Comparing TAXUS slow release randomised 1:1 against bare stent control

Cohort II: Comparing TAXUS moderate release randomised 1:1 against bare stent control



Study OverviewStudy Overview

• Randomised (1:1)• Triple-blind• International, multi-centre • 536 patients

– TAXUSNIRx SR - 267 – TAXUSNIRx MR - 269

• 30d, 6 mo, 1- 5 year FU• Endpoints:

– Clinical– QCA– IVUS

• Randomised (1:1)• Triple-blind• International, multi-centre • 536 patients

– TAXUSNIRx SR - 267 – TAXUSNIRx MR - 269

• 30d, 6 mo, 1- 5 year FU• Endpoints:

– Clinical– QCA– IVUS

Inclusion Criteria• Standard risk de novo

lesions • Length < 12 mm• RVD > 3.0 & < 3.5mm

Anti-platelet regimen– ASA > 75mg

• Maintained indefinitely

– Clopidogrel• Loading dose 300 mg• 75 mg q.d. for 6 months

Inclusion Criteria• Standard risk de novo

lesions • Length < 12 mm• RVD > 3.0 & < 3.5mm

Anti-platelet regimen– ASA > 75mg

• Maintained indefinitely

– Clopidogrel• Loading dose 300 mg• 75 mg q.d. for 6 months



In vitro Release Kinetics Biphasic: 48h burst then slower 10 day low level phase

In vitro Release Kinetics Biphasic: 48h burst then slower 10 day low level phase

• Same total loaded dose - different release rates• Biphasic release - early burst and sustained release phases• 8 fold difference in release rate between SR and MR

• Same total loaded dose - different release rates• Biphasic release - early burst and sustained release phases• 8 fold difference in release rate between SR and MR

0%

5%

10%

15%

0 2 4 6 8 10 12

Time (days)

% P

Tx

rel

ease

d

N = 3

N = 9

Early

Burst

Phase

Sustained Low Level Release Phase

8-10 fold difference

%

Pa

cli

tax

el

Re

lea

se

d

0 2 4 6 8 10 12Days

% P

aclit

axel

rel

ease

d

0%

5%

10

15

Slow Release1g/mm2

Moderate Release1g/mm2



TAXUS II Global InvestigatorsTAXUS II Global Investigators

Banning, Adrian

Belardi, Jorge

Benit, Edouard

Bilodeau, Luc

Bonnier, Edouard

Camenzind, Edoardo

Chan, Charles

Colombo, Antonio

Dawkins, Keith

Drzewiecki, Janusz

Dudek, Dariusz

Figulla, Hans

Fort, Stephen

Grube, Eberhard

Guagliumi, Giulio

Hamburger, Jaap

Hauptmann, Karl

Kelbaek, Henning

LeBlanche, Jean-Michel

Banning, Adrian

Belardi, Jorge

Benit, Edouard

Bilodeau, Luc

Bonnier, Edouard

Camenzind, Edoardo

Chan, Charles

Colombo, Antonio

Dawkins, Keith

Drzewiecki, Janusz

Dudek, Dariusz

Figulla, Hans

Fort, Stephen

Grube, Eberhard

Guagliumi, Giulio

Hamburger, Jaap

Hauptmann, Karl

Kelbaek, Henning

LeBlanche, Jean-Michel

Meredith, Ian

Muenzel, Thomas

Neinaber, Christoph

Nordrehaug, Jan

Pfisterer, Matthias

Ormiston, John

Reeves, Francois

Roy, Louis

Rutsch, Wolfgang

Ruzyllo, Witold

Schiele, Francois

Silber, Sigmund

Siminiak, Tomasz

Strauss, Bradley

Urbaszek, Wilhelm

Webb, John

Whitbourn, Robert

Zmudka, Krzysztof

Meredith, Ian

Muenzel, Thomas

Neinaber, Christoph

Nordrehaug, Jan

Pfisterer, Matthias

Ormiston, John

Reeves, Francois

Roy, Louis

Rutsch, Wolfgang

Ruzyllo, Witold

Schiele, Francois

Silber, Sigmund

Siminiak, Tomasz

Strauss, Bradley

Urbaszek, Wilhelm

Webb, John

Whitbourn, Robert

Zmudka, Krzysztof

Real world experience (15 countries, 38 sites) Randomized, triple blinded study with 536 pts >95% Angiographic and >87% IVUS FU

Real world experience (15 countries, 38 sites) Randomized, triple blinded study with 536 pts >95% Angiographic and >87% IVUS FU



Study ManagementStudy Management

Angiographic & IVUS: Cardialysis

Core Analysis: Rotterdam, The Netherlands

CEC: 7 independent members

DMC: 4 independent members

Study Coordination: PPD Development

Paris, France

Central Lab: COVANCE Bioanalytical Services

Indianapolis, Indiana

Industry Sponsor: Boston Scientific Corporation

Angiographic & IVUS: Cardialysis

Core Analysis: Rotterdam, The Netherlands

CEC: 7 independent members

DMC: 4 independent members

Study Coordination: PPD Development

Paris, France

Central Lab: COVANCE Bioanalytical Services

Indianapolis, Indiana

Industry Sponsor: Boston Scientific Corporation



DemographicsNo Significant Differences Between Groups

DemographicsNo Significant Differences Between Groups

61.0

15.0

27.0

36.0

42.0

15.0

59.8 + 9.7

78.0

Combined Control (%)

(n=270)

63.0

11.0

21.0

35.0

35.0

11.0

61.5 + 10.5

70.0

TAXUSNIRx SR

(%)

(n=131)

60.0Hypertension17.0Diabetes24.0Smoker30.0Unstable Angina39.0Prior MI17.0Prior Intervention59.3 + 10.1Age76.0Male

TAXUSNIRx MR

(%)

(n=135)



TAXUS IIBaseline Lesion Characteristics

TAXUS IIBaseline Lesion Characteristics

Combined Control

(n=270)

TAXUSNIRx SR

(n=131)

TAXUSNIRx MR

(n=135 )

P-value

SR vs. Combined

Control

P-value MR vs.

Combined Control

P-value SR vs.

MR

RVD (mm) 2.75 + 0.5 2.78 + 0.4 2.72 + 0.5 0.5996 0.4442 0.2656

MLD (mm) 1.0 + 0.4 1.0 + 0.3 0.9 + 0.3 0.2385 0.4895 0.1063

Diameter Stenosis (%) 64.7 + 11.1 63.3 + 9.6 64.9 + 10.3 0.2108 0.8434 0.2088

Lesion Length mm) 10.6 + 4.1 10.5 + 3.9 10.2 + 4.8 0.8968 0.3125 0.4498

Well matched RVD at 2.75mm and Lesion Length at 10.5mmWell matched RVD at 2.75mm and Lesion Length at 10.5mm



Stent DistributionPredominantly Single Stents Implanted

Stent DistributionPredominantly Single Stents Implanted

0.5298

0.5298

0.6480

P-value

SR vs. Control

4 (6)

94 (127)

1 (2)

15.7+3.1

50% (70)

50% (69)

96%

TAXUSNIRx MR (n=135)

1.0000

1.0000

0.3557

P-value MR vs. Control

0.628454% (72)50% (140) 3.5

0.628446% (62)50% (138) 3.0

Study Stent Distribution

0.766795%94%Clinical Procedural Success

5 (6) 4% (12) 2

93 (122)94% (254) 1

2 (3) 1% (4) None

Study Stents (per pt)

15.7+3.2Study Stent Length, mm (per pt)

TAXUSNIR SR (n=131)

P-value SR vs.

MR

Combined Control(n=270)



Early Clinical EventsNo differences in SR, MR or Controls

Early Clinical EventsNo differences in SR, MR or Controls

One peri-procedural stent thrombosis of 266 TAXUS stents placedOne peri-procedural stent thrombosis of 266 TAXUS stents placed

0.0%0.8%0.0% < 1 day

0.0%0.0%0.0% 30 days - 180 days

2.0 %(3) 2.0% (3)4.0% (12)30-day MACE

2.0% (3)Periprocedural MACE

Stent Thrombosis

TAXUSNIRx SR(n=131)

Combined Control (n=270)

TAXUSNIRx MR(n=135)

4.0% 2.0% (3)

1 day - 30 days 0.0%0.0%

MI (n)

Death (n) (1)

(11) (2) (3)

(0) (0)

0.0%



1.0000

0.7572

0.0080

0.0262

0.1567

1.0000

1.0000

0.0035

P-value

SR vs. Combined

Control

1.0 (1)

2.3 (3)

3.1 (4)

6.2 (8)

2.3 (3)

0.0

0.0

7.8 (10)

TAXUSNIRx MR

(n=135)Rate %/ (n)

1.0000

1.0000

0.0010

0.0059

0.4029

1.0000

1.0000

0.0019

P-value MR vs.

Combined Control

1.00003.1 (4)2.7 (7) TVR Remote

1.00000.8 (1)0.8 (2) CABG

0.74904.6 (6)13.3 (35) TLR

1.00008.5 (11)19.8 (52)6-Month MACE

0.8078

0.6838

P-value SR vs.

MR

7.7 (10)

1.5 (2)

0.0

0.0

TAXUSNIRx SR

(n=131)Rate % / (n)

16.0 (42) TVR - Overall

4.6 (12) Non Q-Wave MI

0.8 (2) Q-Wave MI

0.4 (1) Death

Combined Control(n=270)

Rate % / (n)

TAXUS II 6 mo. Major Adverse Cardiac Events

TAXUS II 6 mo. Major Adverse Cardiac Events

N/A

N/A

Improvements in SR and MRImprovements in SR and MR



Six month Binary Restenosis Decreased in stented segment not in edges

Six month Binary Restenosis Decreased in stented segment not in edges

3.41.6 2.3

19.0

2.3

4.73.1

1.6 2.30.0

5.0

10.0

15.0

20.0

25.0

Re

ste

no

sis

%

Combined Control TAXUS SR TAXUS MR

Stented SegmentProximal Edge Distal Edge5mm 5mm

P<0.0001P<0.0001

n=128n=263 n=128n=127n=261 n=128 n=127n=262 n=128

P<0.0001P<0.0001

P=0.500P=0.500

P=1.000P=1.000P=1.000P=1.000

P=0.509P=0.509P =0.515P =0.515

P=0.758P=0.758 P=1.000P=1.000



2.3% (3/128)1.6% (2/127) 3.1% (8/262)Distal Edge

2.3% (3/128)1.6% (2/127) 3.4 % (9/261)Proximal Edge

22.0% (58/264)

18.6% (49/263)

19.0% (50/263)

Combined Control

(n=270)

8.6% (11/128)

0.8% ( 1/128)

4.7% (6/128)

TAXUSNIRx MR

(n=135 )

5.5% (7/128)Total Analysis Segment

1.5% (2/128)

If confounders excluded

2.3% ( 3/128)Stented Segment

TAXUSNIRx SR

(n=131)

6 mo. Restenosis Rates Improvements for TAXUS SR and MR

6 mo. Restenosis Rates Improvements for TAXUS SR and MR

Stented Segment: All stents (study and non-study) used to treat target lesion

Total Analysis Segment: Stented segment + 5 mm proximal and distal edge

Stented Segment: All stents (study and non-study) used to treat target lesion

Total Analysis Segment: Stented segment + 5 mm proximal and distal edge



QCA Analysis of Stented SegmentQCA Analysis of Stented Segment

0.80 + 0.55

0.51 + 0.32

0.78 + 0.47

1.57 + 0.37

Combined Control

(n=270)

1.29 + 0.53

0.21 + 0.41

0.30 + 0.39

1.58 + 0.41

TAXUSNIRx MR

(n=135 )

1.21 + 0.53Net Gain (mm)

0.22 + 0.30Loss Index

0.31 + 0.38Late Loss (mm)

1.52 + 0.37Acute Gain (mm)

TAXUSNIRx SR

(n=131)

Improved Acute Gain and Late Loss lead to significant improvements in Net Gain



Comparative TAXUS II Clinical SummaryComparative TAXUS II Clinical Summary

• Matched demographics in combined control, SR & MR

• Excellent control outcomes

• At 6 mo, SR & MR superior compared with combined

control

– MACE reduced by >60%

– TVR reduced by >60% due to TLR being reduced by >60%

– Beneficial edge effects on 6 mo. MLD and late loss

• Only 1/266 late TLR in regions treated by TAXUSNIRx

• SR and MR excellent with comparable late MACE rates

• Matched demographics in combined control, SR & MR

• Excellent control outcomes

• At 6 mo, SR & MR superior compared with combined

control

– MACE reduced by >60%

– TVR reduced by >60% due to TLR being reduced by >60%

– Beneficial edge effects on 6 mo. MLD and late loss

• Only 1/266 late TLR in regions treated by TAXUSNIRx

• SR and MR excellent with comparable late MACE rates



21.85

7.85 7.84

0

10

20

30

40

50

CombinedControl

TAXUS SR

TAXUS MR

n=270 n=131 n=135

+ 17.5

+9.9 + 9.7

IVUS Primary Endpoint Met Reduced 6 mo. % In-Stent Net Volume Obstruction

IVUS Primary Endpoint Met Reduced 6 mo. % In-Stent Net Volume Obstruction

P=0.997

P<0.0001

No difference in SR vs. MRNo difference in SR vs. MR

Superior SR & MR vs. ControlSuperior SR & MR vs. Control

P<0.0001



Stent Volume (mm3)Stent Volume (mm3)

130.68 128.8 132.45

0

100

200


+41.17

Stent Volume (mm3) at 6 mo. FUNo change in Stent Volume for all groupsStent Volume (mm3) at 6 mo. FUNo change in Stent Volume for all groups

+42.44 +48.81

n=244 n=118 n=118

P=0.670

P=0.718

P=0.520



Vessel Volume (mm3)Vessel Volume (mm3)

258.6 266.79 273.63

0

100

200

300

400


+76.48

Vessel Volume (mm3) at 6 mo. FUNo change in Vessel Volume for all groups Vessel Volume (mm3) at 6 mo. FU

No change in Vessel Volume for all groups

+89.66 +97.55

n=214 n=110 n=104

P=0.414

P=0.142

P=0.558



29.1

10.25 11.2

0.0

10.0

20.0

30.0

40.0

50.0


+28.23

+13.26

Neointimal Hyperplasia (mm3) at 6 monthsReduced for TAXUS SR & MR vs control

Neointimal Hyperplasia (mm3) at 6 monthsReduced for TAXUS SR & MR vs control

+17.29

n=244 n=118 n=118

P<0.0001

P=0.742

P<0.0001



Summary of key IVUS findingsSummary of key IVUS findings

Blinded, randomized study of 536 patients provides largest IVUS data set in

DES field with paired FU

Comprehensive IVUS (pre, post & 6 mo. FU) data set for TAXUS & large

control group shows:

1) Stent volumes stable for TAXUS (SR & MR) & Controls

2) Vessel volumes stable for TAXUS (SR & MR) & Controls

3) Improved TAXUS SR & MR volumetric indices

neointimal hyperplasia reduced

% net volume obstruction reduced

No differences between SR & MR

4) IVUS improvements concordant with QCA gains

Blinded, randomized study of 536 patients provides largest IVUS data set in

DES field with paired FU

Comprehensive IVUS (pre, post & 6 mo. FU) data set for TAXUS & large

control group shows:

1) Stent volumes stable for TAXUS (SR & MR) & Controls

2) Vessel volumes stable for TAXUS (SR & MR) & Controls

3) Improved TAXUS SR & MR volumetric indices

neointimal hyperplasia reduced

% net volume obstruction reduced

No differences between SR & MR

4) IVUS improvements concordant with QCA gains



Cumulative Frequency Distribution of Percent Diameter Stenosis by QCA

Cumulative Frequency Distribution of Percent Diameter Stenosis by QCA

Per

cen

tile

0

20

40

60

80

100

% Diameter Stenosis

-10 0 10 20 30 40 50 60 70 80 90 100

Pre procedureNo differences

PostprocedureNo differences Control

Improved % DS SR & MR at 6-mo

SR MR

TAXUS SR

TAXUS MR

Control

TAXUS SR

TAXUS MR

Control



0

10

20

30

40

-1.0

-0.8

-0.6

-0.4

-0.2 0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

2.4

2.6P

erc

en

tag

e o

f P

ati

en

ts

Taxus SR Taxus MR Control

6 mo. Late Loss within Stented SegmentImproved in TAXUS SR and MR vs. Combined Control

6 mo. Late Loss within Stented SegmentImproved in TAXUS SR and MR vs. Combined Control

TAXUS SR & MR– Left shift towards reduced late loss for TAXUS SR & MR

– Tighter frequency distribution for TAXUS vs. Control

TAXUS SR & MR– Left shift towards reduced late loss for TAXUS SR & MR

– Tighter frequency distribution for TAXUS vs. Control

TAXUS lower frequency of high late loss

NegativeLate lossSimilar toControl

TAXUS SR0.30 + 0.36

TAXUS MR0.26 + 0.34

Control0.78 + 0.47



Stent segmentStent segment

Incompete AppositionIncompete Apposition



Fates of Incomplete Apposition

Baseline

Incomplete Apposition

Baseline


Preserved


Preserved


Healed/Resolved


Healed/Resolved




Follow-up IA (+ remodeling)

BaselineBaseline

Follow-up IA(remodeling)Follow-up IA(remodeling)

Follow-up IA(no remodeling)Follow-up IA

(no remodeling)



Incomplete Apposition in TAXUS IISummary

Incomplete Apposition in TAXUS IISummary

Late acquired mal-apposition • Incidence of 5.3% in control (bare stent)• Incidence in TAXUS (SR 8.5% & MR 9.6%)

not significantly different from control • No correlation with MACE incidence

Late acquired mal-apposition • Incidence of 5.3% in control (bare stent)• Incidence in TAXUS (SR 8.5% & MR 9.6%)

not significantly different from control • No correlation with MACE incidence



TAXUS Angiographic Aneurysm Incidence Summary

TAXUS Angiographic Aneurysm Incidence Summary

SR Cohortn=4

SR Cohortn=4

MR Cohortn=4

MR Cohortn=4

TAXUSTAXUS ControlControl3

1283

1281

1341

134

TAXUSTAXUS ControlControl1

1281

1283

1303

130

Incidence (%)Incidence (%) 2.32.3 0.70.7 0.80.8 2.32.3

Diabetics (%) Diabetics (%) 0.00.0 0.00.0 0.00.0 0.00.0



Comparative IVUS & QCA TAXUS II For TAXUS SR & MR vs. Combined ControlComparative IVUS & QCA TAXUS II For TAXUS SR & MR vs. Combined Control

IVUS• >60% improvement IVUS volumetric indices • Stable vessel & stent volumes comparable to control

QCA Binary Restenosis Rates reduced• Improvements of at least 60% for all RVDs• Optimal placement may reduce confounding restenosis (gap & bare

stents)

QCA parameters by 40%-60% for MLD & Late Loss• Beneficial edge effect by MLD & LL• Beneficial improvements for Diabetics

No significant differences in excellent outcomes between TAXUS SR & TAXUS MR

IVUS• >60% improvement IVUS volumetric indices • Stable vessel & stent volumes comparable to control

QCA Binary Restenosis Rates reduced• Improvements of at least 60% for all RVDs• Optimal placement may reduce confounding restenosis (gap & bare

stents)

QCA parameters by 40%-60% for MLD & Late Loss• Beneficial edge effect by MLD & LL• Beneficial improvements for Diabetics

No significant differences in excellent outcomes between TAXUS SR & TAXUS MR



Key practice messagesKey practice messages

• Drug eluting stents will reduce (but not abolish) restenosis within the stent but…

• Must optimise stent deployment• Must cover all the atheroma (mind the edges)• Do not leave gaps between stents (overlap not a problem) • Don’t mix your stents

(Drugs & bare metal might not mix)

• Drug eluting stents will reduce (but not abolish) restenosis within the stent but…

• Must optimise stent deployment• Must cover all the atheroma (mind the edges)• Do not leave gaps between stents (overlap not a problem) • Don’t mix your stents

(Drugs & bare metal might not mix)



Key practice messagesKey practice messages

More IVUS / pressure wire assessment

More IIb/IIIa Inhibitor use

Longer stented segments

particularly in small vessels and diabetics

-Taxus 6

More IVUS / pressure wire assessment

More IIb/IIIa Inhibitor use

Longer stented segments

particularly in small vessels and diabetics

-Taxus 6



Taxus 6Taxus 6

• Lesions - >18 mm and <40mm length– Randomised 1:1 with bare stents– >2.5m and <3.75 diameter– De Novo Lesions– Express stent– Moderate release polymer

– 9 month QCA and IVUS follow up

• Lesions - >18 mm and <40mm length– Randomised 1:1 with bare stents– >2.5m and <3.75 diameter– De Novo Lesions– Express stent– Moderate release polymer

– 9 month QCA and IVUS follow up



Taxus 6Taxus 6

• 47 centres in Europe• Co-PI, Prof Grubbe and Dr K Dawkins• 448 pts enrolled Dec 28th 2002

– Banning/Channon 28 pts– Dawkins 19 pts– Thomas 7 pts– Adam DeBelder 5 pts

– United Kingdom 13% total study

• 47 centres in Europe• Co-PI, Prof Grubbe and Dr K Dawkins• 448 pts enrolled Dec 28th 2002

– Banning/Channon 28 pts– Dawkins 19 pts– Thomas 7 pts– Adam DeBelder 5 pts

– United Kingdom 13% total study



AcknowledgementsAcknowledgements

• Co investigator - Prof Keith Channon

• Medical study team– C McKenna, G Niccoli, P Heck, F Khan, – D Nicholson

• Cath lab, cardiology ward and DCU– Nurses, techs, radiographers (N Searle)– K Lucas

• Colleagues referred pts – (OO, DS, JB, MH, DL, MP, RC-W)

• Co investigator - Prof Keith Channon

• Medical study team– C McKenna, G Niccoli, P Heck, F Khan, – D Nicholson

• Cath lab, cardiology ward and DCU– Nurses, techs, radiographers (N Searle)– K Lucas

• Colleagues referred pts – (OO, DS, JB, MH, DL, MP, RC-W)

tct 2002 scientific sessiontaxus nirx comparative clinical - version 3.02 re 20020916 taxus ii...

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