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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”

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challenges from drug eluting stent des studies future des study design

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

Peter S. Lam, Ph.D.

Director, Biostatistics, Medical Sciences

topics
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
zone for target lesion revascularization tlr
Zone for Target Lesion Revascularization (TLR)

Zone for TLR

5 mm

5 mm

stented segment

proximaledge

distaledge

background breakthrough technologies
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

safety endpoint mace definition
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)
which needs have not been addressed so far

Cardiac death

Myocardial infarction

Need for revascularization

Which needs have not been addressed so far ?
superiority over des
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%

new des study design challenges
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, …
efficacy clinical endpoint tvr should be replaced by tlr
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)

*284 days for TAXUS II, IV and V; 300 days for TAXUS VI.

qca surrogate endpoints for clinical endpoint
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.
roc analysis all patients in pooled taxus studies
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

H. Wang, JSM 2005

regulatory approach
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

taxus arrive usage patterns which needs have not been addressed so far
TAXUS ARRIVE – Usage PatternsWhich needs have not been addressed so far?

Long Lesions

(>26 mm)

AMI

Ostial

Lesions

Bifurcations

ISR

SVG

TAXUS IV-like

Small vessels

(<2.5 mm)

LM

Total

Occlusions

Expanded Use Observed in 58% of patients treated

summary challenges
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
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