ADVANCE ANGIOPLASTY 2004LONDON, Jan 15-16 2004

LATEST CLINICAL EVIDENCEWITH DEXAMET

GERMANO DI SCIASCIO, MD, FACC, FESC

Professor and Chairman of Cardiology,Campus Bio-Medico University of Rome

DexametTM is the BiodivYsio PC coated stents preloaded with Dexamethasone

• BiodivYsio Interdependent cell design• Non-inflammatory PC coating • Non-thrombogenic PC coating• Long term implant history

1 m

StentStrut

} Targeted drug delivery direct to arterial wall

0.5 µg/mm2 DexamethasonePC coating

Arterial Side

Lumen Side

Stent strutcross-section

• is a potent anti-inflammatory agent that treats the first step of the neointima formation/restenosis process

• has also anti-proliferative action by affecting the inflammation process

• is non-cytotoxic and does not destroy healthy cells and does not reduce or slow down the re-endothelisation

DexamethasoneO

HO

F

HOO

OH

1 S.H.Park and A.M.Lincoff, Semin. Interv. Cardiol., 1998, 3, 191-195

• is delivered (when it’s most needed) early to target the inflammatory cells

• has strong clinical experience in humans

demonstrated clinical benefits preferably in unstable in STRIDE and SAFE

Dexamethasone (II)O

HO

F

HOO

OH

1 S.H.Park and A.M.Lincoff, Semin. Interv. Cardiol., 1998, 3, 191-195

- A pilot Phase II trial, multi-centre, prospective, non-randomised study. Dexamethasone dose 0.5 ug/mm2

- 71 patients in 8 centres in Belgium

- PI: Ivan De Scheerder

- Endpoints:

- 30-day and 6-month MACE

- In-stent restenosis 6 months

- Clinical and QCA :Late loss, loss index, MLD

Dexamet’s first clinical trial :STRIDEStudy of anti-restenosis with BiodivYsio Dexamethasone-Eluting stent

STRIDESTudy of Anti-Restenosis with BIodivYsio Dexamethasone-Eluting Stent

71 patients with 6-month angiographic follow-up

Stent: BiodivYsio stent (dexamethasone 45 μg) %

in-s

tent

sten

osis

Unstable angina Stable angina

p=0.017

MACE at 30 days = 1% (TLR =1%)MACE at 6 months = 3% (TLR=3%)MACE at 12 months: 3% (TLR=3%)

0

10

20

30

40

BiodivYsio TrialsLate Loss Comparisons

0

0.2

0.4

0.6

0.8

1

STRIDE(Unstable)

STRIDE (Stable)

SOPHOS DISTINCT

% L

ate

Lo

ss

PC coated stents without Dexamethasone

- A multi-centre registry with DexametTM & Dexamet SV

- PI: Dr Pieter Stella, Utrecht, Netherlands

- 1000 “Real-world” patients with no specific inclusion/exclusion criteria - patients must meet the indications specified in the Directions For Use

- 66 centres over 16 countries in Europe, Middle-East, Africa and Asia-Pacific- Endpoints are in-hospital, 30-day and 6-month MACE

- Results available at JIM 2004

First registry of DexametTM : SAFE

DEXAMETHASONE-ELUTING STENTS IMPROVE SIGNS OF INFLAMMATION IN PATIENTS

WITH UNSTABLE CORONARY SYNDROMES UNDERGOING PERCUTANEOUS CORONARY

INTERVENTION

G. Patti, A. D’Ambrosio, A. Carcagni’, M. Cortes-Morichetti,P. Carminati, G. Di Sciascio

CAMPUS BIOMEDICO UNIVERSITY OF ROME

Study design: case-control study with prospective evaluation

Population: 60 pts receiving dexamethasone-eluting stent (Dexamet, N=30) or Biodivysio phosphorylcholine-coated stent (N=30)

Inclusion criteria: - unstable angina (IIB-IIIB) or angina post recent (< 1 mo) myocardial infarction

- angiographic evidence of “complex” coronary lesions that could be covered by a single stent

Plasma levels of CRP were measured at: - 3 to 6 hours before PCI - 6, 24, 48 hours and 7 days after PCI

Follow-up assessment: occurrence of MACE (myocardial infarction, death, repeat revascularization)

DEXAMETHASONE-ELUTING STENTS IN UNSTABLE CORONARY SYNDROMES

Methods

3.7**5.4 * 3.6

5.2

2.8

2.33.2

5.8

9.8

11.4

0

3

6

9

12

15

18

Pre 6 h post 24 h post 48 h post 7 days post

CR

P m

g/l

DexametTM

Non DES

* P=0.041 vs non DES** P=0.026 vs non DES

DEXAMETHASONE-ELUTING STENTS

IN UNSTABLE CORONARY SYNDROMES

0

50

100

150

200

250

300

350

400

24 h 48 h 7 days

Non DES

DexametTM152

85

396

93

326

32

P=0.03

P=0.01

CR

P %

incr

ease

from

bas

elin

e

DEXAMETHASONE-ELUTING STENTS

IN UNSTABLE CORONARY SYNDROMES

Baseline CRP <3 mg/l

(N=19)

Baseline CRP 3 mg/l (N=11)

0

40

80

120

160

200

24 h 48 h 7 days

CR

P p

e rc e

n t i n

c re a

s efr

om b

a se l

ine

P=0.009

121

69

199

40

96

14

DEXAMETHASONE-ELUTING STENTS

IN UNSTABLE CORONARY SYNDROMES

0

20

40

60

80

100

0 1 2 3 4

% o

f pa

tien

ts

Dexamet Non DES

months after stenting

6

P=0.06

Event-free survival curves

DEXAMETHASONE-ELUTING STENTS

IN UNSTABLE CORONARY SYNDROMES

CONCLUSIONS

Dexamethasone-eluting stents improve early inflammatoryresponse after PCI; this effect is more evident in pts with higher baseline CRP status

The sustained attenuation of CRP values at 7 days may suggestearly plaque stabilization with dexamethasone-eluting stentsin pts with unstable coronary syndromes

Clinical follow-up at 6 months shows a trend towards favorableintermediate-term results

Will steroid-eluting stents be the treatment of choice for ptswith unstable coronary syndromes?

MA

CE

du

rin

g th

e fo

llow

-up

(%

)

1 2 3 4

Pre-procedural CRP Quartiles

0

5

10

15

20

25

30

16%

P = 0.09

5

27

RESULTS Patti, Di Sciascio et al. – Am J Cardiol

             

                                                       

From morphology ................ To plaque “biology”

CR

P (

mg

/dl)

0

0,40

0,80

1,20

ControlsN=12

Stable anginaN=49

Unstable anginaN=57

P=0.046

P=0.66

P=0.07

Distribution of CRP plasma levels

Patti, Di Sciascio et al. – IL-1Ra: a sensitive marker of instability in patients with coronary artery disease J Thromb Thrombol 2002; 14: 139

0

5

10

15

20

25

30

35

MA

CE

du

rin

g th

e fo

llow

-up

(%

)

1 2 3 4 Pre-procedural IL-1Ra Quartiles

P = 0.008

33

0

Patti, Di Sciascio et al. Prognostic value of IL-1Ra in patients undergoing percutaneous coronary intervention– Am J Cardiol 2002; 89: 372

SMC ProliferationSMC Proliferation

MigrationMigration Matrix secretionMatrix secretion

SMC receptors

Arterial injuryArterial injury

Growth Factors & cytokinesGrowth Factors & cytokines

ThrombusThrombus InflammationInflammation

G0 G1 G2

S

M

Smooth muscle cell (SMC)Smooth muscle cell (SMC)

Signal transduction

Cell cycle

Dual mechanism of action of: PC coating and Dexamethasone

cell cycle

Smooth muscle cell

Growth Factors & cytokinesGrowth Factors & cytokines

Arterial InjuryArterial Injury

- Neutrophils- Monocytes- Macrophage- Lymphocytes

Reduces SMC Proliferation

Matrix secretionMigration

Reduced Receptor activation

PC reduces thrombus formation Dexamethasone reduces Inflammation:

Signal transduction

THERMOGRAPHY in ACUTE CORONARY SYNDROMES

• Temperature of the plaque is inversely correlated to cap thickness (Casscells W, Lancet 1996)

• Pts presenting with AMI and unstable angina have significantly more temperature heterogeneity in their coronary atherosclerotic plaques than pts with stable angina (Stefanadis C, Circulation 1999).

• Temperature was found to be the most powerful predictor of outcome (Stefanadis C, Circulation 2000) and to have a significant correlation with CRP levels (Stefanadis C, J Mol Cell Cardiol 2000)

Inflamed plaque

Di Sciascio et al. – Am Heart J 1994; 128: 419-26Di Sciascio, Patti – Cardiologia 1999; 44: 333-9

300 pts, 824 specimens

0.002°C sensitivity

0

10

20

30

40

50

60

70

80

90%

Recurrent ischemia In-hosp. MACE

UA and CRP<0.3 mg/dl

UA and CRP>0.3 mg/dl

Liuzzo, Maseri et al. The prognostic value of CRP and serum amyloid A protein in severe unstable angina. N Engl J Med 1994; 331: 417

IL1-

Ra

(pg/

ml)

ControlsN=12

Stable anginaN=49

Unstable anginaN=47

0

100

200

300

400

500

P=0.038

P=0.002

P=0.99

IL-1Ra in ischemic syndromes

Patti, Di Sciascio et al. – IL-1Ra: a sensitive marker of instability in patients with coronary artery disease J Thromb Thrombol 2002; 14: 139

0

20

40

60

80

100

0 3 6 12 18 months

IL-1Ra (1st quart.)

IL-1Ra (4th quart.)

MACE-free survival%

Patti, Di Sciascio et al. Prognostic value of IL-1Ra in patients undergoing percutaneous coronary intervention– Am J Cardiol 2002; 89: 372

Drug Eluting Stent Trials

0,45

0,60

0,32 0,30

0,17

0,30

0,94

0

0,2

0,4

0,6

0,8

1

Stride Stride Stride Aspect Sirius TAXUS II Distinct(stable AP)(unstable AP) (Non-drug)

Late Loss (mm)

Pepine CJ et al. A controlled trial of corticosteroids to prevent restenosis after coronary angioplasty. M-HEART Group – Circulation 1990; 81: 1753

- 915 patients undergoing PTCA randomized to placebo or 1 g methylprednisolone before the procedure

- PTCA success rate 87%

0

10

20

30

40

Placebo Steroids

% R

este

nosi

s

Versaci et al. Immunosuppressive therapy for the prevention of restenosis after coronaryArtery stent implantation (IMPRESS study) – JACC 2002; 40: 1935

Oral prednisone therapy for 45 days in pts with elevated (>0.5 mg/dl) CRP levels 72 hours post PCI