Transcript in the real world

Drug –eluting stents
Where are we now and what can we expect in 2003?
Tony Gershlick
Leicester
Trials
Real World
What we need
i. Prevent restenosis – cost effective
Either :
- Treat all – at equivalent cost (DES @ £450)
- Select those at higher risk
- Treat those who develop ISR
ii.
Trials to reflect the patients undergoing PCI
iii.
Trials to continue to show benefit (o late adverse events )
iv.
N.I.C.E.
All or only in those @ higher risk ?
68 yr non-insulin
dependant diabetic
Bifurcations ?
Are the DES trials moving with the need ?
trial update
trial evaluation
what is new ?
PACLITAXEL
TLR 4.6% versus 12% (<0.05)
Non –polymer
Guidant Achieve stent
paclitaxel in ELUTES dose
In segment BR
TVF
22
20%
17
12
12
10%
C
treated
C
treated
GIUDANT / Cook … paclitaxel
DES Trials and real life
1 Single Lesion < 25 mm
Plus complicating factor
DELIVER 2
Trial
* CTO, Bifurcation, ISR
2 single lesions < 25 mm
de novo or *
1 long lesion > 25 mm
PACLITAXEL
DELIVER II – Lesion characteristics(n = 500)
Intended treatment
One <25mm lesion with complicating factor *
47%
Two <25mm lesions
26%
One very long lesion (> 25 mm)
27%
In-stent restenosis
(25%)
Bifurcations
Chronic total/sub-total occlusions
(28%)
(19%)
Death
3 (0.6%)
TLR (PCI)
2 (0.4%)
TLR (CABG)
None
Q-wave MI
3 (0.6%)
Non Q-wave MI
7 (1.4%)
Total
15 (3.0%)
TAXUS III
In-Stent Restenosis Registry
28 out of 30 patients available for follow-up
Preliminary Results
MI (Q & non-Q-wave)
TVR (non-target lesion)
TLR
CABG
Death
Stent Thrombosis
MACE
30-day
3.6%
0%
0%
0%
0%
0%
3.6%
6 month
3.6%
0%
21.4%
3.6%
0%
0%
28.6%
Note: These results apply to this study only and are not necessarily representative.
Caution: Investigational device: Limited by federal law to investigational use. Not available for sale in the US.
II
TAXUS IV
To demonstrate safety and performance of
TAXUS Express SR compared to uncoated
express control TAXUS V
Prospective randomised double blinded
80 U.S. Sites
6 Sites in US
Anticipated Start Q1 2003
1326 patients presenting
with deFormulation
novo
Slow Release
lesions (10 to 28mm)
TAXUS V
Destratified
novo armby treated
Randomisation was
In Stent Restenosis arm
diabetes and vessel
diameter
1,000
Patients
500 Patients
10 - 40 mm Lesion Lengths
TAXUS Stent versus
Primary endpoint Stents:
- 9 months
2.25TVR
- 4.0rate
mm,Brachytherapy
Lengths: 8 - 32 mm
Multiple Stents Allowed
Recruitment complete currently in
follow up phase.
TAXUS VI
European Study designed
evaluate safety and efficacy of TAXUS
MR
formulation (1mcg/mm2)
De Novo lesions
vessel diameter >2.5mm to <3.75mm
Lesion Length >18mm and <40mm
448 patients randomised in 2 groups
Primary endpoint TVR at 6 months
Patients will be followed up for 5 years
Enrollment commenced June 2002 will close Jan 2
Non polymer
dead in the water ?? Lesion/patient risk & stent risk
Await DELIVER 2 ?
TAXUS
to date some reflection of real life but on-going real test
- % events in control group
(poor stent , mix of risks)
- overall (in-segment effect)
SIROLIMUS
Mean lesion length 14.4mm
SIRUS – how like real life was
it ??
CYPHER (%)
Control (%)
(n=533)
(n=525)
14.4 ± 5.7
21.6 ± 6.7
14.4 ± 5.8
21.2 ± 5.7
Diabetes Mellitus
24.6
28.2
AHA/ACC A
7.4
7.8
B1
B2
34.0
32.6
38.1
33.5
C
26.0
20.6
Mean Lesion length
Stented length
CYPHER (%)
Control (%)
19.3
45.6
35.1
17.2
45.8
37.0
28.6
29.5
Mean stents per patient (n)
1.4 ± 0.7
1.4 ± 0.6
Patients with overlapping
stents
28.5
26.9
Diameter
2.5
3.0
3.5
> 2 stents
SIRIUS - Diabetic sub-group
CYPHER
Control
n=131
n=148
8.3
17.6
6.9
9.2
48.5
50.5
22.3
25.0
P
Restenosis
In-stent
In-segment
TLR (%)
MACE (%)
< 0.001
< 0.001
< 0.001
< 0.001
SIRIUS: TLR Events
Sirolimus Control
P-value
Overall
4.1
16.6
0.0001
124
Male
4.4
16.6
0.0001
122
Female
3.4
16.5
0.0007
130
Diabetes
6.9
22.3
0.0006
154
No Diabetes
3.2
14.3
0.0001
111
LAD
5.1
19.8
0.0001
147
Non-LAD
3.4
14.3
0.0001
109
Small Vessel (<2.75) 6.3
18.7
0.0001
125
Large Vessel
1.9
14.8
0.0001
128
Short Lesion
3.2
16.1
0.0001
129
Long Lesion (>13.5) 5.2
17.4
0.0001
122
Overlap
4.5
17.7
0.0003
131
No Overlap
3.9
16.1
0.0001
121
Hazards Ratio 95% CI
0
0.1
0.2
0.3
0.4
0.5 0.6 0.7 0.8 0.9 1.0 0.9 0.8 0.7
CYPHER better
BIFURCATION
DES + DES
Main Branch
(N = 63)
Late Loss:
In-lesion (mm)
Binary Restenosis
in-stent %
Binary
Restenosis:
In-lesion (%)
% Pts with at
least one
Restenosis (MB
or SB)
Side Branch
(N = 65)
DES + PTCA
Main Branch
(N = 22)
Side Branch
(N = 22)
0.28
0.63
0.16
0.33
0
15.9
0
N/A
2.3
25.0
5.0
10.0
21.9
Overall Stent Thrombosis rate was 3.6%
SIROLIMUS
FREEDOM trial:
Diabetic MVD randomised - Cypher or CABG
E-SIRIUS 250 patients De
novo single vessel,15mm35mm long, 2.5 - 3.5mm
diameter : reporting
Q4/ACC
Cypher Registry
‘real life’ cases
10 000 Web based
(2680)
RESOLVE ISR
ISR
VBT versus DES
UK … Europe
Start .. Spring 03
‘
What else is happening ??
Conor Stent:
Drug delivery from large, discrete,
non-deforming reservoirs
Ductile Hinges
Allow struts to open
Without deformation
Cap Layer
Drug Layer
Barrier Layer
100%
90%
Cumulative Percent
• The Conor Stent releases
all of the stent contents in
approximately 2 weeks invitro.
Release of Paclitaxel
80%
70%
60%
50%
40%
30%
20%
10%
0%
• The TAXUS stent releases
about 10% of total loading
in 10 days (about 10 ug),
the remaining 90%
remains on the stent
permanently.
0
2
4
6
Time (days)
8
10
12
Porcine Stent Injury Study
PACLITAXEL 30 DAY QCA
Late Loss
2
1.8
Clear dose response
All p<0.05 vs. metal
1.6
1.4
mm
1.2
1
0.8
0.6
0.4
16 ug @ 30d
0.2
0
METAL
POLYMER
16 ug FR
64 ug FR
64 ug SR
180 ug SR
Proximal LAD
16 ug
metal @ 30d
Proximal LAD
metal
SCEPTER
• Study of
• Controlled
•
•
•
•
•
Elution of
Paclitaxel for
The
Elimination of
Restenosis
Spring 2003 260 two doses 15 ug and 75 ug cf bare metal Connor
Rapamycin analogues
Why ?
I. Commercial
2. Alter potency .. Modifying affinity for binding proteins
3. Modify physical properties
* Lipophilic, tissue penetration, residence time
* Stability
* Release kinetics
4. Alter metabolic elimination
5. Overcome edge effect
6. Higher risk populations
Tacrolimus
Cyclosporin
Binding protein:
Effector protein:
Tacrolimus
Cyclophilin
Calcineurin
• Blocks T-cell activation
Actions:
• No effect on smooth muscle
• Toxic to kidneys
Sirolimus
FKBP12
TOR
• Blocks T-cell proliferation
(anti-inflammatory effect)
• Blocks SMC proliferation
Sirolimus R=H
Everolimus R= CH2CH2OH
Everolimus and Guidant programme
Biosensors Int FUTURE 1
Preliminary data
16 patients !!
TAXUS
FUTURE 1
RAVEL
0.08 mm
control
-0.01 mm
0.84 mm
Late loss
0.31 mm
% Diameter stenosis
3%
control
Binary restenosis
control
39%
0%
20%
IVUS % intimal suppression
65%
No edge effect
88%
95%
Everolimus Drug Eluting Stent GUIDANT
SS + EVAL
Pig at 28 Days
Everolimus 2
Everolimus 3 =
Everolimus 3
Everolimus 2 =
Percent stenosis at 28 and 90 Days Following
Everolimus-Eluting Stent Implanation in Pig
Coronary Arteries
35
18%
% Stenosis
30
control
Everolimus 4
41%
25
20
15
10
5
0
30 days
90 days
Everolimus 4 - 245 mg +104 mg top coat
Everolimus 5 - 337 mg +169 mg top coat
Everolimus and Guidant programme
VISION –E studies SPIRIT 1 (etc etc)
dosing,
CE marking
US pivotal
n.b. no UK !!! (regulatory)
Similarities of ABT-578 and Rapamycin
Structural Domains Binding to FKBP-12 and mTOR
H O
42
O
O
O
O
N
Rapamycin
O
O
H O
N
H O
O
O
N
O
O
N
N
42
O
O
O
O
ABT-578
N
O
H O
O
H O
O
O
O
O
FKBP Binding
Domain
mTOR Effector
Domain
MEDTRONIC
In Vitro Inhibition of Human Coronary Artery
Smooth Muscle Cell Proliferation
100
A
% Inhibition
80
60
40
Rapamycin
ABT-578
20
0
-20
0.01
0.1
1
10
Concentration (nM)
100
A Randomized Controlled Trial to Evaluate
the Safety and Efficacy of the Medtronic AVE
ABT-578 Coated Driver Coronary Stent
in De Novo Native Coronary Artery Lesions
•Approx 70 Sites in Europe, Canada, Asian Pacific, Australia
•Approx 1100 subjects
•Double blind, two arm, randomized controlled trial of ABT-578 coated
Driver stent vs. bare Driver stent
•Follow-up at 30 days, 6, 9, 12 months, yearly to 5 years
•First 400 (approx) subjects enrolled also participate in subset with
angiographic follow-up at 8 months
•IVUS sub-study at 15-20 selected centers, IVUS at index and 8 months
•Initial Enrolment: March 2003
Everolimus plus
Sirolimus R=H
Everolimus R= CH2CH2OH
Everolimus plus R= CH2CH2R
4
5
6
7
8
9
Future developments
2 or more drugs
Anti-restenotic
Local Simvastatin Delivery After
Vascular Injury
(mm)
140
120
*
= 0.07
Neointimal PThickness
P<0.05 vs CON
106
14 days
28 days
100
80
60
40
*
32
Anti-thrombotic
87
P=
0.53
33
45
*
20
0
Simvastatin Rapamycin Simvastatin Rapamycin
Control
Paclitaxel
Small vessels , edge effect
40ug /balloon …. Vessel wall
Trials
2003
RAPAMYCIN ANALOGUES
JOMED
TACROLIMUS
GUIDANT
EVEROLIMUS
MEDTRONIC
ABT 578
EVEROLIMUS PLUS
MPA
TAXUS II + ,
SIRIUS ,
DELIVER 2
Real World
D.E.S. (current or ‘ improved’ ) are likely to impact on restenosis
in the real world
‘the Limus effect’“Lyticitis”
Qs . Can we afford them ?
Will N.I.C.E approve them?