Prison II

Randomised Trial of Sirolimus-Eluting and Bare Metal Stents in

Patients with CTO

(Presented at TCT 2005Suttorp and Laarmen, Nieuwegein and Amsterdam)

MY CONFLICTS OF INTEREST ARE

I have accepted support for the purpose of attendingprofessional educational meetings from Boston Scientific, Cordis, Medtronic and Guidant

I am in receipt of research funding from Boston Scientific

Background

• Angiographic restenosis rates with bare metal stents in CTO :

– 22% Prison I (POBA 33%)– 32% SICCO (POBA 74%)

Methods

• Single blind RCT, two centres • Randomised after crossing a CTO > 2

weeks old• Bx velocity vs. Cypher (n=200)

• Primary end point– Binary Angiographic Restenosis at 6 months

• Secondary end points– Clinical - MACE, TVF– Angiographic - MLD, late loss, % stenosis

Results

• Baseline characteristics well matched:

– Mean age 59 years– Diabetics 13% – Single vessel disease 49%– Mean stent length 30 mm

ResultsBinary angiographic restenosis

0

5

10

15

20

25

30

35

40

45

In segment In stent

BMS

SES

73% 85%

%

711

41 36

ResultsSecondary End Points

• Angiographic– Late loss +0.64 vs. -0.07 mm (p<0.001)– % stenosis 53.3% vs. 31.9% (p<0.001)

• Clinical– MACE 20% vs. 4%– TLR 19% vs. 4% – Stent thrombosis 0% vs. 2%

Conclusions

• First RCT showing that DES reduce restenosis in CTO

• Is CTO another indication for DES?

ISAR TEST

Randomised comparison of a polymer free sirolimus coated stent vs. polymer based paclitaxel coated stent (Taxus)

Presented at TCT 2005Kastrati et al. Munich

Background

Polymers may induce chronic inflammatory

reaction causing:

delayed or incomplete re- endothelialization

stent thrombosis

restenosis

Methods

Prospective RCT comparing a polymer-free sirolimus

stent with the polymer-based paclitaxel (!) stent

(Taxus Express2)

n = 450

Primary end point: in-stent late loss at 6 months

- Powered to determine non-inferiority (not equivalence) with a

margin of difference in late loss of 0.13 mm

Secondary end points: BAR & TLR at 6 months

Stent Coating Machine and Stent with Microporous Surface

100 µm100 µm100 µm

10 µm10 µm 10 µm10 µm

A

C D

B

before after

Baseline Characteristics

• Well matched

– 43% unstable– Mean lesion length 12.8 mm– Mean vessel diameter 2.7 mm – 1.1 stents per case

mm 0.48 0.48

0

0.2

0.4

0.6

Late lumen loss

P = 0.98

(in-stent)

0.34

0.24

0.0

0.2

0.4

0.6

Late lumen loss

mm

P = 0.09

(in-segment)

Results: Late Lumen Loss

Polymer-Free Sirolimus Stent

Polymer-Based Paclitaxel Stent

Angiographic and ClinicalRestenosis

14.215.5

0

10

20

Angiog. Restenosis

Incidence, %P = 0.73

9.3 9.3

0

10

20

Clinical Restenosis

Incidence, %

(TLR)

P = 1

Polymer-Free Sirolimus Stent

Polymer-Based Paclitaxel Stent

Conclusion

The polymer-free sirolimus-eluting stent has an anti-restenotic effect that is not inferior to that of polymer-based paclitaxel-eluting stent.

Interpretation

• Early evidence of angiographic efficacy of

non polymer ‘DIY’ sirolimus eluting stent

• Clinical efficacy?

• How important is the polymer ?– Results attributable to lack of polymer or different drug?

ENDEAVOR III

Prospective randomized comparison of Endeavor zotarolimus-eluting stent with

Cypher sirolimus-eluting stent

(Presented at TCT 2005PIs David E. Kandzari PIs David E. Kandzari and Martin B. Leon)

ENDEAVOR IIIENDEAVOR III

Hypothesis:

Treatment with the Endeavor zotarolimus-eluting stent will be non-inferior compared with the Cypher sirolimus-eluting stent with respect to in-segment late lumen loss

Head to Head Non Inferiority TrialHead to Head Non Inferiority Trial

ENDEAVOR III - DesignENDEAVOR III - Design

436 patients30 U.S. sites

Io Endpoint: In-segment late loss at 8 months(powered for a margin of difference of 0.2 mm)

2o Endpoints: Angiographic binary restenosis at 8 months;Clinical TLR, TVR, TVF at 9 months

Io Endpoint: In-segment late loss at 8 months(powered for a margin of difference of 0.2 mm)

2o Endpoints: Angiographic binary restenosis at 8 months;Clinical TLR, TVR, TVF at 9 months

Endeavor Stentn=327

Endeavor Stentn=327

Cypher Stentn=109

Cypher Stentn=109

Single de novo native coronary lesion

Vessel diameter: 2.5-3.5 mmLesion length: 14-27 mmStent lengths: 18-33 mm

Single de novo native coronary lesion

Vessel diameter: 2.5-3.5 mmLesion length: 14-27 mmStent lengths: 18-33 mm

3:1 Randomization

Baseline Characteristics

• Imbalanced for gender

– 65% male Endeavor, 85% male Cypher (p<0.01)

• Otherwise well balanced

– Diabetes 29%, unstable 53%,

• Procedure success

– 99% Endeavor, 95% Cypher (p<0.002)

Results: Primary End PointIn-segment Late LossIn-segment Late Loss

Non-Inferiority Margin of Difference:Non-Inferiority Margin of Difference: 0.20 mm0.20 mm

Observed Difference:Observed Difference: 0.21 mm0.21 mm

p = NS for non-inferiority, <0.001 for Cypher superiorityp = NS for non-inferiority, <0.001 for Cypher superiority

Non-Inferiority Margin of Difference:Non-Inferiority Margin of Difference: 0.20 mm0.20 mm

Observed Difference:Observed Difference: 0.21 mm0.21 mm

p = NS for non-inferiority, <0.001 for Cypher superiorityp = NS for non-inferiority, <0.001 for Cypher superiority

(mm)

0

0.1

0.2

0.3

0.4

Endeavor

Cypher

0.21 mm0.34

0.13

Distribution of Late Loss

0

5

10

15

20

25

30

-0.6 -0.2 0.2 0.6 1.0 1.4 1.8 2.2 2.6

Insegment LLL (mm)

% o

f Pat

ient

s

Endeavor Cypher0.13±0.32 0.34±0.44

Angiographic End Points

0

0.1

0.2

0.3

0.4

0.5

0.6

In stent Insegment

Endeavor

Cypher

0

2

4

6

8

10

12

In stent Insegment

Endeavor

Cypher

mm

Late Loss Binary Restenosis

%

Clinical End PointsClinical End PointsTVF Free Survival to 270-daysTVF Free Survival to 270-days

P=0.923, log rank

88.5%

88. 0%

Cypher ENDEAVOR

Free

dom

from

TV

F

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Time after Initial Procedure (days)0 30 60 90 120 150 180 210 240 270

No difference in MACE, TVF, TLR, death…

The non-inferiority primary endpoint of in-The non-inferiority primary endpoint of in-segment late loss was not met segment late loss was not met

i.e. Endeavor was not not (= was) inferior to i.e. Endeavor was not not (= was) inferior to CypherCypher

No significant differences in 9 month clinical No significant differences in 9 month clinical outcomes (TLR, MACE, TVR and TVF)outcomes (TLR, MACE, TVR and TVF)

Conclusions

“Endeavor angiographically inferior but clinically equivalent”?

Which is the better discriminator of restenosis propensity: angiographic late loss or clinical events ?

InterpretationInterpretation

“Late loss is more reliable than restenosis rates for discriminating restenosis propensity between new drug eluting stent platforms…”

Circ 2005,112 2833

Circ 2005; 111: 3435

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En

BM

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