Challenges from Drug Eluting Stent (DES) Studies - Future DES Study Design
Peter S. Lam, Ph.D.
Director, Biostatistics, Medical Sciences
Future DES IssuesSept 16 2005
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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
Future DES IssuesSept 16 2005
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Zone for TLR
stented segmentproximal
edgedistaledge
5 mm 5 mm
Zone for Target Lesion Revascularization (TLR)
Future DES IssuesSept 16 2005
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Background: breakthrough technologies
5%
BMSPTCA DES
Ne
ed
for
reva
scu
lari
zatio
n
Driver of restenosis
recoil
neointima formation
implantation technique
mechanical stabilization of acute result
local delivery of anti-proliferative agents
40%
20%
‘fool-proof’ delivery system ?
Future DES IssuesSept 16 2005
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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)
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Which needs have not been addressed so far ?
Cardiac death
Myocardial infarction
Need for revascularization
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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 7% vs. 6% 6% vs. 5% 5% vs. 4%N/group* 9700 8400 7000
*80% power with 2 sided alpha of 5%
Future DES IssuesSept 16 2005
8Silber (Sept 6, 2005, ESC)
Future DES IssuesSept 16 2005
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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, …
Future DES IssuesSept 16 2005
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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.
Future DES IssuesSept 16 2005
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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.
H. Wang, JSM 2005 Correlation of QCA parameters and TLR
QCA Measures as Predictors of QCA Measures as Predictors of TLRTLRAll Patients in pooled TAXUS studiesAll Patients in pooled TAXUS studies
ROC c-statistic
TLR % (n/N)
MLD (mm)
In-stent 0.904 12.6 (330/2624)
In-segment 0.946 12.7 (333/2627)
%DS
In-stent 0.899 12.5 (329/2623)
In-segment 0.954 12.7 (333/2627)
Late Loss (mm)
In-stent 0.871 12.6 (330/2620)
In-segment 0.899 12.7 (333/2623)
H. Wang, JSM 2005 Correlation of QCA parameters and TLR
ROC AnalysisROC AnalysisAll Patients in pooled TAXUS studies All Patients in pooled TAXUS studies
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 0.2 0.4 0.6 0.8 1
In-stent late loss has the lowest AUC, while in-segment %DS has the highest AUC
In-segment % Diameter
StenosisIn-stent Late Loss
c-statistic = 0.871
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 0.2 0.4 0.6 0.8 1
Sensi
tivit
y
Sensi
tivit
y
1-Specificity 1-Specificity
c-statistic = 0.954
Future DES IssuesSept 16 2005
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Regulatory approach
Pharmaceutical environment
DES device environment
high risk patient population
low risk patient population
proof-of-principle
expansion
workhorse(low risk)
high risk patient population
proof-of-principle
expansion
TAXUS ARRIVE – Usage PatternsTAXUS ARRIVE – Usage Patterns Which needs have not been addressed so far?Which needs have not been addressed so far?
50 Sites50 Sites
319 Physicians
2585 Patients2585 Patients
3070 Vessels3070 Vessels
3769 Lesions3769 Lesions
4204 Stents4204 Stents
TAXUS IV-like
Long Lesions
(>26 mm)AMI
OstialLesions
Bifurcations
Expanded Use Observed in 58% of patients treated
ISR
SVG
Small vessels(<2.5 mm)LM
Total
Occlusions
Future DES IssuesSept 16 2005
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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