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. 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.


Qca measures as predictors of tlr all patients in pooled taxus studies
QCA Measures as Predictors of TLRAll Patients in pooled TAXUS studies

H. Wang, JSM 2005


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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