The TAXUS™ Paclitaxel-Eluting Stent Program. The safety and effectiveness of the TAXUS ™ Express...

The TAXUS™ Paclitaxel-Eluting Stent Program

The safety and effectiveness of the TAXUS™ Express2™ Stent has not been established in patients with coronary artery

reference vessel diameters less than 2.5 mm or in lesions longer than 28 mm or in patients with diabetes

Table of Contents

• Drug-eluting stent overview

• Drug-eluting stent benefits

In your opinion … Part 1

– Consistently low revascularization rates


– Excellent safety with desirable healing


– Ability to treat various patients and lesions

• What does the future hold?

Drug-Eluting Stent OverviewFrom Bare Metal to Drug-Eluting Stents

Key Bare Metal Stent Characteristics Key Drug-Eluting Stent Characteristics

Healing

Restenosis Reduction

Deliverability and Conformability

• Binary restenosis • Dramatic TLR/TVR reduction• Consistent performance throughout the target

lesion• Predictable results across all patient subsets

• Various lesion access• Excellent conformability • Minimize incomplete apposition

• Deliverability

• Desirable late loss• Complete endothelialization• Wide margin of safety

• Large lumens

Drug-Eluting Stent Benefits

• Reduced angiographic restenosis

• Reduced clinical restenosis

• Comparable safety compared to bare-metal stents

• Improved patient outcomes

• Positive trends in various lesion subsets

• Positive trends in various patient populations

In your opinion ...

• Which patients should receive drug-eluting stents?

• What factors are critical to consider when trying to minimize repeat revascularizations?

• What are the most important components of a drug-eluting stent and why?

11.3

1.1

12.0

3.01.7

4.7

0

5

10

15

20

TLR TVR - non TLR TVR

Control* (n=652) TAXUS™ Stent** (n=662)

TAXUS IV Clinical TrialTLR Overall at 9 Months

RR=0.27 [0.16-0.43]

P<0.0001

P=0.48

RR=0.39 [0.26-0.59]

P<0.0001

Eve

nt

%

*= Express® Control Stent. **= TAXUS™ Express® Stent

16.7

3.1

14.7

6.8

2.74.2

0

5

10

15

20

25

TLR TVR - non TLR TVR


RR=0.29 [0.19-0.43]

P<0.0001P=0.74

RR=0.41 [0.29-0.57]

P<0.0001

Eve

nt

%TAXUS IV Clinical TrialTLR Overall at 12 Months


3.4

9.0

12.0

3.1

8.7

11.3

1.1

3.64.7

0.6

2.43.0

0

5

10

15

TLR TLR - PCI

TLR-CABG

TVR TVR - PCI

TVR-CABG


TAXUS IV Clinical Trial TLR/TVR Overall at 9 Months

P<0.0001 P<0.0001P<0.0001 P=0.0008 P=0.005P=0.0001

Eve

nt

%


4.0

13.5

16.7

3.7

11.8

14.7

1.7

5.36.8

0.8

3.54.2

0

5

10

15

20

25

TLR TLR - PCI

TLR-CABG

TVR TVR - PCI

TVR-CABG


P<0.0001 P<0.0001P<0.0001 P=0.0003 P=0.0120P<0.0001

Eve

nt

%TAXUS IV Clinical Trial TLR/TVR Overall at 12 Months


9.8

17.4

13.0

2.44.8

5.9

0

5

10

15

20

25

No diabetes Diabetes - oral meds

Diabetes - insulin requiring

TL

R (

%)


Impact of Diabetes MellitusTAXUS IV Clinical Trial TLR at 9 Months

P=0.004

P=0.32

P<0.0001

N=489 N=507 N=109 N=104 N=54 N=51


16.7

21.1

13.1

5.97.7

3.4

0

10

20

30

No Diabetes Diabetes- oral meds Diabetes - insulinrequiring

TL

R (

%)


P<0.0001 P=0.12

N=489 N=507 N=109 N=104 N=54 N=51

P=0.0063

Impact of Diabetes MellitusTAXUS IV Clinical Trial TLR at 12 Months


15.4

11.2

6.7

3.4 3.1 2.5

0

5

10

15

20

25

≤2.5 mm >2.5 - 3.0 mm >3.0 mm

TL

R (

%)


P<0.0001

P=0.057

P=0.0004

RVD (mm)RVD (mm)

N=214 N=206 N=241 N=257 N=195 N=197

Impact of Vessel Diameter (QCA)TAXUS IV Clinical Trial TLR at 9 Months


17.5

9.4

3.3 2.7

0

5

10

15

20

25

<3.0 mm ≥3.0 mm

TL

R (

%)


Impact of RVD (visual assessment)TAXUS IV Clinical Trial TLR at 9 Months

P<0.0001

P=0.0001

N=154 N=150 N=498 N=511


18.0

11.5

7.3

3.1 3.71.0

0

5

10

15

20

25

2.5 mm 3.0 mm 3.5 mm

TL

R (

%)


Impact of Stent DiameterTAXUS IV Clinical Trial TLR at 9 Months

P=0.0001

P=0.002

P=0.0002

Stent diameter (mm)Stent diameter (mm)

N=133 N=131 N=304 N=323 N=206 N=197


9.9 10.5

18.6

3.3 2.8 3.3

0

5

10

15

20

25

<10 mm 10 - 20 mm >20 mm

TL

R (

%)


P=0.01

P=0.0009

P=0.0001

Lesion length (mm)Lesion length (mm)

N=226 N=214 N=325 N=351 N=97 N=91

Impact of Lesion Length (QCA)TAXUS IV Clinical Trial TLR at 9 Months


9.211.8

17.9

3.5

0.82.6

0

5

10

15

20

25

16 mm 24 mm ≥32 mm

TL

R (

%)


Impact of Total Stent LengthTAXUS IV Clinical Trial TLR at 9 Months

P=0.002

P<0.0001

P=0.0004

Stent length (mm)

N=382 N=372 N=127 N=126 N=134 N=153


12.4 11.4

29.8

2.7 4 3.46.7

11.4 12.3

2.6 2.7 4.2

6.8 7.7 7.73.4 2.5 2.4

0

10

20

30

TL

R (

%)

TL

R (

%)

Lesion Length (mm)Lesion Length (mm)

ControlControl TAXUS™ Stent

Lesion Length Response (tertile analysis)TAXUS IV Clinical Trial TLR at 9 Months

>> 3.0 3.02.5-3.02.5-3.0

< 2.5< 2.5

RVD (mm)

RVD (mm)

TAXUS IV Clinical Trial Restenosis at 9 Months

24.426.6

7.95.5

0

10

20

30

40

In-stent Analysis segment


RR=0.23 [0.13, 0.38]

P<0.0001

RR=0.30 [0.19, 0.46]

P<0.0001

Res

ten

osi

s (

%)


38.5

27.8

15.210.2

6.7 6.8

0

10

20

30

40

50

≤2.5 mm >2.5 - 3.0 mm >3.0 mm


TAXUS IV Clinical Trial RestenosisImpact of Vessel Diameter (QCA)

P<0.0001

P=0.10

P=0.0001

RVD (mm)

N=78 N=98 N=97 N=105 N=92 N=88

In-S

egm

ent

Res

ten

osi

s (

%)


40.8

31.2

12.98.8 9.1

5.5

0

10

20

30

40

50

2.5 mm 3.0 mm 3.5 mm


N=49 N=57

TAXUS IV Clinical Trial RestenosisImpact of Stent Diameter

P=0.0002

P=0.13

P<0.0001

Stent diameter (mm)

N=125 N=143 N=93 N=91

In-S

egm

ent

Res

ten

osi

s (

%)


Reduced In-Stent Binary Restenosis No Edge Effect in TAXUS IV Clinical Trial

0%

5%

10%

15%

20%

25%

30%

35%

Analysissegment

% o

f p

atie

nts

26.6

7.9

Intent-to-treat, angiographic subset (n=732)Intent-to-treat, angiographic subset (n=732)

Proximaledge

Stentedsegment

Distal edge

Control*

TAXUS™Stent**

3.4 2.7

24.4

5.51.9 0.7

P=0.81 P=0.27

P<0.001

P<0.001


9-Month % Diameter Stenosis Improved In-Stent and at Both Edges in TAXUS IV Clinical Trial

0%

10%

20%

30%

40%

50%

60%

Analysissegment

% D

iam

eter

Ste

no

sis

39.8

26.3

P<0.0001

Intent-to-treat, angiographic subset (n=732)Intent-to-treat, angiographic subset (n=732)

Proximaledge

Stentedsegment

Distal edge

Control*

TAXUS™Stent**

16.113.2

37.2

17.411.8

7.6

P=0.0167

P<0.0001

P=0.0001


0.0

1.0

2.0

3.0

0-3m

m

3-6m

m

6-9m

m

9-12

mm

12-1

5mm

Neointimal hyperplasia area

[mm2]

P=ns

P=ns

TAXUS II Clinical TrialUniform Suppression of Neointima at 6 Months

IVUS analysis of TAXUS II clinical trial patients showed uniform neointimal suppression throughout the entire stent

0-3m

m

3-6m

m

6-9m

m

9-12

mm

12-1

5mm

TAXUS™ Stent**

Control*

proximal distal proximal distal


Neointimal area (mm2)

0

1

2

3

4

proximal distal proximal distal

Control*

TAXUS™ Stent**

IVUS analysis of TAXUS IV clinical trial patients showed uniform neointimal suppression throughout the entire stent

TAXUS IV Clinical Trial Uniform Suppression of Neointima at 9 Months

P=ns

P=ns

0-3m

m

3-6m

m

6-9m

m

9-12

mm

12-1

5mm

0-3m

m

3-6m

m

6-9m

m

9-12

mm

12-1

5mm


The multifunctional effects of a drug may contribute to reducing restenosis

Polymeric coatings may provide uniform drug delivery across the stent

High degrees of lipophilicity may increase vascular absorption in the tissue surrounding the stent

Minimal overhang may potentially reduce trauma at the edges

Restenosis ReductionFormula for Fighting Restenosis

Multifunctional Effects

Uniform Drug Delivery

Rapid Drug Absorption

Balloon Overhang

Several drug-eluting stent characteristics may contribute to restenosis reduction.

Microtubule Network: Paclitaxel promotes the formation of stable microtubules, thereby inhibiting multiple cellular functions

Note: Image Courtesy of Dr. Vladimir Rodionov

Restenosis ReductionMultifunctional Activity

The TAXUSTM Stent elutes paclitaxel, a multifunctional microtubular inhibitor.

• Paclitaxel is believed to have multifunctional effects which reduce:

– Inflammation

– Proliferation and migration of smooth muscle cells

– Extra-cellular matrix secretion

Restenosis ReductionPaclitaxel and Taxol are Different

* Based on Implantation of a Single 3.5mm X 16mm TAXUS™ Express2™ Stent with Total Loaded Dose of 108 g. Dose in g/kg Calculated Using Average Body Surface Area of 1.7m2 and 70kg Body Weight. Note: Taxol is a registered trademark of Bristol Meyers Squibb.

Paclitaxel Taxol

Composition 100% Paclitaxel

Paclitaxel +

Cremophor EL +

Dehydrated alcohol

Delivery Elution from stent Intravenous

Dose 1. 5 µg/kg*3,280 µg/kg ovarian CA

- 4,250 µg/kg in breast CA

Indication Restenosis Cancer

PaclitaxelWide Safety Window

Paclitaxel’s broad safety window inhibits smooth muscle cell proliferation & migration while allowing the vessel to heal.

• Paclitaxel is a multi-functional drug which appears to:

– Inhibit proliferation

– Inhibit migration

– Inhibit inflammation

– Inhibit secretion

HealingPaclitaxel

Promotes

Endothelialization

Restenosis

Prevents

• The TAXUS™ paclitaxel-eluting stent appears not to delay endothelialization

Complete endothelialization of a paclitaxel-eluting stent in a porcine coronary artery.

Endothelial cells are less sensitive than smooth muscle cells to the effects of paclitaxel.

Translute Polymer is intended to control the release of the drug during the critical period of the restenotic cascade

Restenosis ReductionUniform Drug Distribution

The TransluteTM Polymer provides protection and controlled release of paclitaxel.

Translute Polymer is intended to protect the drug during crimping, packaging, distribution, preparation, sterilization, delivery to the lesion, and stent expansion

Restenosis ReductionLipophilicity

Outside the cell

Inside the cell

Paclitaxel (green)

Lipid Bi-Layer

Paclitaxel is highly lipophilic which may increase vascular absorption in tissue surrounding the stent.

In controlled clinical studies, use of the TAXUS™ Stent resulted in

consistently low revascularization rates across a broad range of patient

and lesion types

In your opinion ...

• How do you define “safety” as it relates to drug-eluting stents?

• Do you believe that late loss is an indication of efficacy, safety or both?

• How important is late loss?

• What affects vascular healing after stent implantation?

TAXUS IV Clinical Trial9-Month MACE and TVF

12.0

15.0

11.3

3.7

1.1

14.4

8.5

4.73.03.5

1.4

7.6

0

5

10

15

20

Cardiacdeath

MI TLR TVR MACE TVF


P=0.80 P=0.88 P<0.0001 P=0.0002 P=0.0001P<0.0001

Eve

nt

(%)


1.2

4.6

14.716.7

19.8 19.2

1.43.5 4.2

6.8

10.6 9.7

0

5

10

15

20

25

CardiacDeath

MI TLR TVR MACE TVF


P=1.00 P<0.0001P=0.33 P<0.0001 P<0.0001P<0.0001

Eve

nt

(%)

TAXUS IV Clinical Trial12-Month MACE and TVF


TAXUS IV Clinical TrialStent Thrombosis at 12 Months

0.3 0.3

0.3

0.2

0.3

0 0.2 0.4 0.6 0.8 1

Control*

(n=652)

TAXUS™ Stent**

(n=662)

In-hospital Discharge - 30 days

31 days - 6 months 12 months

P=0.75

Stent thrombosis, %

0.6%(n=4)

0.8%(n=5)

Note: There were no additional stent thrombosis between 6 and 9 months in

either the TAXUS Stent or Control.*= Express® Control Stent. **= TAXUS™ Express® Stent

HealingLate Loss

Late loss provides evidence of healing

• A drug-eluting stent should not completely eliminate the body’s healing response

• Neointima indicates healing after drug-eluting stent implantation

• Consistently low but positive late loss values across studies may indicate healing

Image Courtesy of Dr. Robert Schwartz

HealingLate Loss in Bare Metal Stents

• Late loss in bare metal stents is typically 1.0mm

• Late loss is thought to be largely comprised of neointima

• Late loss is nearly always a positive number, indicating the lumen decreases in size

MLD post-procedureMLD follow-up

0.50mm

0.50mm

Late Loss1.0mm

+

Illustrations by Boston Scientific. Images not to scale.

HealingLate Loss in Bare Metal Stents

• The Express2™ Stent strut thickness is 0.0052”, which converts to 0.13mm

• This is well within the amount of late loss of a bare metal stent, suggesting complete stent strut coverage

MLD follow up

0.13mm

0.50mm

0.0052”= 0.13mm


Lumen

Neointima

HealingTAXUS IV Clinical Trial Late Loss to Strut Thickness Relationship

• The Express2™ Stent strut thickness is 0.0052”, which converts to 0.13mm

• Based on the TAXUS IV trial late loss values, neointima would be sufficient to completely cover the stent struts.


MLD follow up

0.130mm 0.195mm0.0052”= 0.13mm

Lumen

Neointima

3.0

4.9

0.0

1.0

2.0

3.0

4.0

5.0

SMC EC

HealingPaclitaxel Selective Impact

• Low but positive late loss provides evidence that vessel healing has occurred.

Paclitaxel allows healing to occur within the vessel, as evidenced by low but positive late loss.

Late loss =~0.30mm

0.15 mm 0.15 mm

0.30 mmP

ac

lita

xe

l IC

50

(n

M)

Note: Image courtesy of Dr. Robert Schwartz; In vitro cell culture study performed by Dr. Luszher

Endothelial cells are less sensitive than smooth muscle cells to the effects of Paclitaxel.

Late loss <0.6 mm

weak predictor of TLRP

roba

bili

t yfo

r T

LR

(%

)

Late Loss (mm)

100100

00

5050

0.000.00 1.001.00 2.502.501.501.500.500.50 2.002.00

Late loss >0.6mm increasing

probability of TLR

TAXUS IV Clinical TrialLate loss as a Predictor of TLR

Logistic regression combining all patients

TAXUS IV Clinical TrialLate loss as a Predictor of Restenosis

Pro

babi

lity

for

Res

teno

sis

(%)

Late Loss (mm)

100

0

50

0.00 1.00 2.501.500.50 2.00

Late loss >0.6 increasing

probability of restenosis

Logistic regression combining all patients

In animal and controlled human clinical studies, the TAXUS™ stent

consistently demonstrated excellent safety with desirable healing

In your opinion ...

• What role does the stent platform play in terms of drug-eluting stent safety and efficacy?

• Why is conformability important with drug-eluting stents?

• What tradeoffs are you willing to make as it relates to stent designs?

Deliverability and Conformability

Excellent deliverability and conformability will continue to be important features with drug-eluting technology…

Bare Metal Stents

(Desired Features)

Drug-Eluting Stents

(Desired Features)

Deliverability:

- access lesions Conformability

Deliverability:

- access more lesions with longer stents when necessary

Conformability:

- provide strut apposition to the vessel for uniform coverage and drug absorption

Stent apposition contributes to efficacy and safety

•The Express2 Stent platform was designed for excellent deployment with excellent stent to vessel conformability.

9 atmWorking Range*

15 atm1.1:1

18 atmRated Burst Pressure

14 atmQuarter Size

9 atmNominal

Express2™ Stent3.0 mm System

•A broad working range and high RBP combine to provide excellent sizing flexibility.

•A conformable stent provides uniform strut apposition to the vessel wall.

Importance of Stent Apposition

Contact between the vessel wall and the stent strut may be essential for drug absorption.

Uniform stent apposition allows for uniform drug absorption and uniform restenosis reduction.

Incomplete stent apposition / under-deployment may increase the risk of thrombus formation & SAT’s.

Achieving proper stent strut apposition may be a key contributor to both efficacy and safety of drug eluting stents, specifically SATs.

Efficacy (Restenosis Reduction)

Safety (Healing)

HealingIncomplete Apposition Nomenclature

– A recent study noted that “78% of SAT occurs in arteries with stent under - deployment1,” highlighting the importance of stent deployment and apposition

1Cheneau, et al. Circulation 2003;108;43-47

Incomplete Apposition

Under - deployment and incomplete apposition increase the risk of SAT

SafetySub Acute Thrombosis (SAT)

TAXUS IV Clinical TrialIncomplete Apposition at 9 Months

0.621.1%(1/94)

2.2%(2/93)

Late acquired

Paired data

3.2%(3/94)

6.4%(6/94)

4.0%(4/99)

11.6%(13/112)

TAXUS™ Stent**

0.62

1.00

0.72

0.24

P-value

1.1%(1/93)

Persistent

5.4%(5/93)

Resolved

3.0%(3/100)

9 month

6.4%(7/109)

Post-procedure

Control*


TAXUS IV Clinical TrialCorrelation of Incomplete Apposition and Safety

0%0%0% TLR

0%0%0% Non-Q-wave MI

0%0%0%Stent thrombosis

0%0%0% TVR overall

0%0%0% Q-wave MI

0%0%0% Cardiac death

0%0%0%MACE overall

Acquired IA (n=3)

Persistent IA (n=4)

Resolved IA (n=11)

The TAXUS™ Stent showed no safety events at 9 months in patients with resolved, persistent or late

acquired IA

Excellent deliverability and conformability of the Express® stent

platform makes it easy to treat various patient and lesion types

Drug-Eluting Stent BenefitsSummary of Ideal Characteristics

DES

Polymer

Stent Drug

Deliverability and Conformability Healing

TLR and Restenosis Reduction

Access to various lesions

Strut apposition

Sustained TLR and restenosis reduction, within the stent and at the edges

Consistent results across patients and lesions

Low rates of major adverse events

Consistently low and desirable late loss

TAXUSTM Express2TM Paclitaxel-Eluting Coronary Stent System

INDICATIONS

The TAXUS™ Express2™ Paclitaxel-Eluting Coronary Stent System is indicated for improving luminal diameter for the treatment of de novo lesions <28 mm in length in native coronary arteries >2.5 to <3.75 mm in diameter.

CONTRAINDICATIONS

Use of the TAXUS Express2 Paclitaxel-Eluting Coronary Stent System is contraindicated in patients with:

• Known hypersensitivity to paclitaxel or structurally related compounds.• Known hypersensitivity to the polymer or its individual components.

Coronary Artery Stenting is contraindicated for use in:

• Patients in whom antiplatelet and/or anticoagulant therapy is contraindicated.• Patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the stent or delivery device.


WARNINGS

• To maintain sterility, the inner package should not be opened or damaged prior to use.• The use of this product carries the risks associated with coronary artery stenting, including subacute thrombosis, vascular complications, and/or bleeding events.• Patients with known hypersensitivity to 316L stainless steel may suffer an allergic reaction to this implant.

Potential adverse events (in alphabetical order) which may be associated with the use of a coronary stent in native coronary arteries include but are not limited to:

Aneurysm, Arrhythmias, Bleeding complications, Death, Distal Emboli, Emergent CABG, Myocardial Infarction, Myocardial Ischemia, Occlusion, Stent Delivery Failures, Target Lesion Revascularization, Thrombosis, Vascular complications, Vessel Dissection.

Potential adverse events not captured above that may be unique to the paclitaxel drug coating:

Alopecia, Allergic reaction to the drug or the polymer, Anemia, Blood product transfusion, Gastrointestinal symptoms, Hematologic dyscrasia, Hepatic enzyme changes, Histologic changes in vessel wall, including inflammation, cellular damage or necrosis, Myalgia/Arthralgia, Peripheral neuropathy.


The safety and effectiveness of the TAXUS Express2 Paclitaxel-Eluting Coronary Stent System have not been established in the following patient populations:

• Women who are pregnant or lactating.• Men intending to father children. • Pediatric patients.• Patients with unresolved vessel thrombus at the lesion site.• Patients with coronary artery reference vessel diameters <2.5 mm or >3.75 mm.• Patients with lesions located in the saphenous vein grafts, in the unprotected left main coronary artery, ostial lesions, or lesions located at a bifurcation. • Patients with diffuse disease or poor flow distal to the identified lesions.• Patients with tortuous vessels (>60 degrees) in the region of the obstruction or proximal to the lesion.• Patients with a recent acute myocardial infarction where there is evidence of thrombus or poor flow.• Patients with multiple overlapping stents. • Patients with longer than 12 month follow-up.


Prior to use, please see the complete “Directions for Use” at www.taxus-stent.com for more information on Indications, Contraindications, Warnings, Precautions, Adverse Events and Operator’s Instructions.

CAUTION

Federal law restricts this product to sale by or on the order of a physician.

TRADEMARKS

TAXUS and Express2 are trademarks and Express is a registered trademark of Boston Scientific Corporation or its affiliates.

The TAXUS™ Paclitaxel-Eluting Stent Program. The safety and effectiveness of the TAXUS ™ Express...

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