Challenges from Drug Eluting Stent (DES) Studies - Future DES Study Design

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Challenges from Drug Eluting Stent (DES) Studies
- Future DES Study Design

• Peter S. Lam, Ph.D.
• Director, Biostatistics, Medical Sciences

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Topics

• Background (History, Definition of MACE/TVR)
• Challenges in future study design/planning
• Clinical Endpoint -gt future use of TLR
• QCA Surrogate Endpoint -gt more works need to be
  done
• Post-approval study ARRIVE to show real world
  stent use (heterogeneity)
• Address these off-label uses
• Summary

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Zone for Target Lesion Revascularization (TLR)
Zone for TLR
5 mm
5 mm
stented segment
proximaledge
distaledge
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Background breakthrough technologies
Driver of restenosis
recoil
40
mechanical stabilization of acute result
Need for revascularization
neointima formation
20
local delivery of anti-proliferative agents
5
implantation technique
fool-proof delivery system ?
PTCA
BMS
DES
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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 ?
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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
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Silber (Sept 6, 2005, ESC)
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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,

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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(N529) TAXUS II(N529) TAXUS IV(N1314) TAXUS IV(N1314) TAXUS VI(N446) TAXUS VI(N446) TAXUS V(N1156) TAXUS V(N1156) Pooled(N3445) Pooled(N3445)
9-M Event Rate () 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.
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QCA Surrogate Endpoints for Clinical Endpoint

• choice of QCA surrogate endpoints
• minimum lumen diameter
• percent diameter stenosis
• binary restenosis (DS 50)
• late loss
• Currently it is up to the sponsor to justify the
  choice of QCA.

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QCA Measures as Predictors of TLRAll 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)
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ROC AnalysisAll Patients in pooled TAXUS studies
In-segment Diameter Stenosis
In-stent Late Loss
Sensitivity
Sensitivity
c-statistic 0.871
c-statistic 0.954
1-Specificity
1-Specificity
In-stent late loss has the lowest AUC, while
in-segment DS has the highest AUC
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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
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TAXUS ARRIVE Usage Patterns Which needs have
not been addressed so far?
Long Lesions (gt26 mm)
AMI
Ostial Lesions
50 Sites 319 Physicians 2585 Patients
3070 Vessels
3769 Lesions
4204 Stents
Bifurcations
ISR
SVG
TAXUS IV-like
Small vessels (lt2.5 mm)
LM
Total Occlusions
Expanded Use Observed in 58 of patients treated
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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