The Treatment of In-Stent Restenosis

Neal Uren MD FRCP

Consultant Cardiologist Royal Infirmary

Edinburgh

MY CONFLICTS OF INTEREST ARE Travel, Accomodation & Registration §  PCR - May 2006 (BosSci) §  TCT - October 2006 (BosSci)

Travel & Accomodation §  Guidant Institute visit, Brussels - February 2006 (Abbott) §  Emerging Technologies Symposium -March 2006 (BosSci) §  Annual SpR training, Malaga – June 2006 (BosSci)

The Real Problem of Clinical Restenosis

2005 data: Ludman

0 10 20 30 40 50 60 70 80 90

100

'92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04 '05 0

2

4

6

8

10

12

14

% Stent %DES

% S

tent

Use

%

PC

I for Restenosis

Predictors of In-Stent Restenosis

§  Minimum IVUS stent area (MLA) §  Pre-intervention IVUS plaque burden §  Final MLD < 3.0 mm §  Multiple stents §  Diabetes mellitus §  Chronic total occlusions §  Previous PTCA §  Proximal LAD stent §  Ostial location §  Long stents

Cutting Balloon PCI for ISR

0 0.5

1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Acute Lumen Gain

Late Lumen Loss

Angio restenosis

TLR

Stent CBA HSRA PTCA

258 lesions 30-40% diffuse 50-60% focal

*

* *

*

Loss index CBA = 0.34±0.3, stent 0.64±0.4, rota 0.73±0.6

0 5 10 15 20 25 30 35 40 45 50

mm

Percentage

*p<0.001 vs. rest

Adamian M et al, JACC 2001;38:672

Prediction of In-Stent Re-Restenosis

§ Final MLD <2.75 mm§ Diffuse in-stent restenosis§ Aggressive restenosis <90 days§ POBA

In-stent Restenosis An Unresolved Clinical Problem

?

30%

25%

17%

TLR after VBT

Total Occlusion

Proliferative

Diffuse

Focal

83%

50%

35%

19%

TLR after PCI

Mehran et al. Circulation 1999; 100: 1872-1878 Costantino et al. Am J Cardiol 2001; 92: 1214-1217

Stairway to Evidence-Based Medicine multi-vessel

disease

bifurcations

ISR

diabetes long

lesions small

vessels work

-horse

CTO

left main disease

TRIAL:randomised, multicentre, blinded, actively controlled trial involving an independent core lab and CEC

TRIAL:feasibility studies involving only 1 to 3 centres often not using an independent core lab or CEC

TAXUS V ISR

SYNTAX

TAXUS IV

TAXUS V REALITY -TAXUS

TAXUS VI

SYNTAX

SYNTAX

SYNTAX

TAXUS VI TAXUS V

TAXUS V

TAXUS IV

TAXUS V REALITY -TAXUS

Park LL2

CORPAL-BIF

SISR

ISAR -DESIRE

FREEDOM

ISAR -DIABETES

RIBS II

RAVEL

SES-SMART

SIRIUS

ISAR -SMART

PRISON II

REALITY -CYPHER

DIABETES

CARDIA

Increasing complexity

Taxus V: Study Design

Patients with in-stent restenosis of a previously implanted bare metal stent in a native coronary artery lesion

≤46mm in length and ≥2.5 to ≤3.75mm in diameter (n=396)

Primary endpoint – 9-month target vessel revascularisation powered for sequential non-inferiority & superiority

Randomise 1:1

TAXUS (n=195)

Brachytherapy (n=201)

DES Strategy PTCA catheter Old stent New stent

5mm

Proximal edge

In-Stent

Injury Segment

Area in which balloon was inflated against the wall

Analysis Segment

Stented segment plus 5 mm on each edge

5mm

Distal edge

Vascular Brachytherapy Approach Old stent β radiation source

Injury Segment Area in which balloon was inflated against the wall

5mm

Proximal edge

5mm

Distal edge

Analysis Segment Radiation segment plus 5 mm on each edge

Radiation Segment Area exposed to brachytherapy

PTCA catheter

Cumulative TVR out to 9-Months: Superior Outcomes for DES with Early Separation

0 30 60 90 120 150 180 210 240 270 300 0%

25%

5%

10%

15%

20%

10.4%

17.4%

Log-Rank P=0.04

Days Since Index Procedure

Cum

ulat

ive

Even

t Ra

te

TAXUS (n=195)

Brachytherapy (n=201)

MLD: Analysis Segment

Minimum Lumen Diameter (mm)

Perc

entil

e

0

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0% 1 2 3 4

9m Median (IQR) p<0.001

TAXUS: 1.99 (1.03, 2.25)

VBT: 1.55 (1.05, 1.91)

9-Month Median (IQR)

TAXUS: 1.90±0.63mm

VBT 1.46±0.66mm

9-Month Mean (±SD)

Brachy Post-proc

TAXUS Post-proc

Brachy Pre-proc

TAXUS Pre-proc

Brachy 9m follow-up

TAXUS 9m follow-up

p<0.001

9-Month Restenosis Superior with TAXUS DES %

Pat

ient

s

Proximal Edge

In-Stent Distal Edge

n = 8/124 11/153 12/172 6/151 4/168 53/170

Brachytherapy TAXUS

Analysis Segment

25/172

N/A

p<0.001

Injury Segment

34/169 12/171

31.2

14.5

6.5

20.1

4.0 7.2 7.0 7.0

2.4

p=0.81 p=0.53 p<0.001

TAXUS V: 9-Month Target Vessel Thrombosis

Target Vessel Thrombosis (%)

VBT

DES

1 3 1

1 2

2.6% (5/193)

1.6% (3/191)

In-Hospital D/C – 30 days 31 days – 6 mo 6 mo – 9 mo

p=0.72

DES for ISR: Study Design

SISR TAXUS V ISR

CYPHER vs VBT TAXUS vs VBT

384 patients @ 2:1 396 patients @ 1:1

6 months angio f/u 9 months clinical f/u

9 month angio f/u 9 months clinical f/u

RVD 2.5 ≤ 3.5mm Lesion 15 ≤40mm (17.2 mm mean)

RVD 2.5 ≤ 3.75mm Lesion ≤46mm (18.5 mm mean)

no additional PCI additional PCI allowed in non target vessel

TAXUS V ISR: In Perspective Clinical 9-Month Outcomes

SISR TAXUS V ISR 8.5% TLR 6.3% 10.8% TVR 10.5% 12.4% TVF 11.5% 0.4% STEMI 0.5% 2.3% Non-STEMI 3.1%

0.8% (n=2) Stent thrombosis

1.6% (n=3)

0.27+0.65 mm 0.29+0.54 mm Late loss

TROPICAL Primary Endpoint: 6-Month In-Lesion Late Loss

Cypher DES, n = 155

GAMMA I/II, n = 221

p<0.0001

0

0.5

1.0

1.5

In-Lesion Late Loss

0.68

0.08 mm

Non-randomised trial, vessel size 2.5-3.0 mm, lesion length <45 mm

Neumann F-J & Desmet W, PCR 2004

SES vs. Historical Gamma VBT

n= 162 SES 262 VBT

TROPICAL Clinical Outcome at 180 Days

Non - Hierarchical Event Rate (%) TROPICAL GAMMA I/II

0

5

10

15

20

Death MI Clinically driven TLR

Stent thrombosis

MACE

p=0.490 p=0.004 pP<0.001 p=0.080

p<0.001

3.7 0.6 1.8 2.5

0.6

18.8

2.0

25

9.4

14

3.9

30

E-Cypher Registry: 6 Months Follow-up MACE

Per

cent

age

AHA 2004, New Orleans CEC - adjudicated events: all cases with death, MI, TLR or reported stent thrombosis were reviewed

3.8

1.4

0.1 0.5

2.1

0.9 0.4

1.2 0.6

0.3

1.4

3.0

0.0

1.0

2.0

3.0

4.0

MACE Death STEMI Non STEMI TLR TVR

non-ISR (n=10,442) ISR (n=1,478)

ISAR-DESIRE Trial

Kastrati et al, JAMA 2005;293:165

Kastrati et al, JAMA 2005;293:165

ISAR-DESIRE Trial

In-Stent Restenosis: Conclusions

The use of drug-eluting stents for the treatment of in-stent restenosis has been shown to be §  safe – with low rates for target vessel thrombosis, myocardial infarction, & late stent thrombosis

§  effective –TLR rate of 6.3-8.5% and an angio restenosis rate of 14.5-19.8% at 6-9 months

when compared to vascular brachytherapy as the preexisting gold standard