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

Future DES IssuesSept 16 2005

2

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


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Zone for TLR

stented segmentproximal

edgedistaledge

5 mm 5 mm

Zone for Target Lesion Revascularization (TLR)


4

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 ?


5

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%


8Silber (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, …


10

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.


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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


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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


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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

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

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