Challenges from Drug Eluting Stent
(DES) Studies
- Future DES Study Design
Peter S. Lam, Ph.D.
Director, Biostatistics, Medical Sciences
Topics
Background (History, Definition of MACE/TVR)
Challenges in future study design/planning …
•
•
•
•
•
Clinical Endpoint -> future use of “TLR”
QCA Surrogate Endpoint -> more works need to be done
Post-approval study ARRIVE to show real world stent use
(heterogeneity)
Address these off-label uses
Summary
2
Future DES Issues
Sept 16 2005
Zone for Target Lesion
Revascularization (TLR)
Zone for TLR
5 mm
proximal
edge
5 mm
stented segment
3
distal
edge
Future DES Issues
Sept 16 2005
Background: breakthrough technologies
Driver of restenosis
Need for
revascularization
recoil
40%
mechanical stabilization of
acute result
neointima formation
20%
local delivery of
anti-proliferative agents
5%
PTCA
BMS
implantation technique
‘fool-proof’ delivery
system ?
DES
4
Future DES Issues
Sept 16 2005
Safety Endpoint – MACE Definition
Major Adverse Coronary Event is a composite
endpoint of
1. Cardiac death,
2. MI (Non-Q-Wave and Q-Wave), and
3. TVR (TLR and non-TLR)
5
Future DES Issues
Sept 16 2005
Which needs have not been addressed
so far ?
Cardiac death
Myocardial infarction
Need for
revascularization
6
Future DES Issues
Sept 16 2005
Superiority over DES?
• Current technologies have reduced the
incidence of remaining safety and efficacy into
the 5%-8% rate
• Proof of superiority of attempts to further
reduce these events will require at least
14,000 patient studies with long term follow-up
Reduction
N/group*
7% vs. 6%
9700
6% vs. 5%
8400
5% vs. 4%
7000
*80% power with 2 sided alpha of 5%
7
Future DES Issues
Sept 16 2005
Silber (Sept 6, 2005, ESC)
8
Future DES Issues
Sept 16 2005
New DES study design challenges
• BMS controlled trial – no long feasible
• Active controlled trial – non-inferiority approach
• Operator technique – more aggressive to treat
more complex lesions, more direct stenting, …
9
Future DES Issues
Sept 16 2005
Efficacy Clinical Endpoint – TVR
should be replaced by TLR
Target Vessel Revascularization is a composite endpoint of
TLR and non-TLR, where non-TLR is disease progression in
the target vessel (noise)
9-M*
Event
Rate (%)
TAXUS II
(N=529)
TAXUS IV
(N=1314)
TAXUS VI
(N=446)
TAXUS V
(N=1156)
Pooled
(N=3445)
DES BMS DES BMS DES BMS DES BMS DES BMS
TLR
4.6
14.1
3.8
13.2
6.8
18.9
8.3
15.2
5.8
14.8
Non-TLR
1.9
2.0
2.0
2.1
3.7
0.9
4.7
4.1
3.1
2.7
TVR
6.5
16.0
5.7
14.7
9.6
19.4
11.8
16.8
8.4
16.2
*284 days for TAXUS II, IV and V; 300 days for TAXUS VI.
10
Future DES Issues
Sept 16 2005
QCA Surrogate Endpoints for
Clinical Endpoint
choice of QCA surrogate endpoints:
1) minimum lumen diameter
2) percent diameter stenosis
3) binary restenosis (%DS ≥ 50%)
4) late loss
Currently it is up to the sponsor to justify the
choice of QCA.
11
Future DES Issues
Sept 16 2005
QCA Measures as Predictors of TLR
All Patients in pooled TAXUS studies
MLD (mm)
In-stent
In-segment
%DS
In-stent
In-segment
Late Loss (mm)
In-stent
In-segment
H. Wang, JSM 2005
ROC
c-statistic
TLR
% (n/N)
0.904
0.946
12.6 (330/2624)
12.7 (333/2627)
0.899
0.954
12.5 (329/2623)
12.7 (333/2627)
0.871
0.899
12.6 (330/2620)
12.7 (333/2623)
Correlation of QCA parameters and TLR
ROC Analysis
All Patients in pooled TAXUS studies
In-segment
% Diameter Stenosis
1
1
0.9
0.9
0.8
0.8
0.7
0.7
Sensitivity
Sensitivity
In-stent Late Loss
0.6
0.5
0.4
0.3
c-statistic =
0.871
0.2
0.1
0.6
0.5
0.4
0.3
c-statistic =
0.954
0.2
0.1
0
0
0
0.2
0.4
0.6
1-Specificity
0.8
1
0
0.2
0.4
0.6
1-Specificity
0.8
1
In-stent late loss has the lowest AUC, while
in-segment %DS has the highest AUC
H. Wang, JSM 2005
Correlation of QCA parameters and TLR
Regulatory approach
Pharmaceutical
environment
DES device
environment
high risk patient
population
workhorse
(low risk)
proof-of-principle
proof-of-principle
expansion
expansion
low risk patient
population
high risk patient
population
14
Future DES Issues
Sept 16 2005
TAXUS ARRIVE – Usage Patterns
Which needs have not been addressed so far?
Long Lesions
(>26 mm)
AMI
Ostial
Lesions
50 Sites
319 Physicians
2585 Patients
Bifurcations
3070 Vessels
3769 Lesions
ISR
4204 Stents
SVG
TAXUS IV-like
Small vessels
LM (<2.5 mm)
Total
Occlusions
Expanded Use Observed in 58% of patients treated
Summary - challenges
• Future DES studies most likely to be “non-inferiority trial”
– choice of gold standard DES/margin
• Change of primary efficacy endpoint from TVR to TLR
• QCA surrogate endpoints (advantage, choice)
• Studies to address DES use in high risk patients
16
Future DES Issues
Sept 16 2005