1

Advanced AngioplastyLondon, England27 January, 2006

Jörg Michael Rustige,MDMedical Director

Lilly Critical Care Europe, Geneva

2

Results: Inhibition of Platelet AggregationResults: Inhibition of Platelet Aggregation(IPA) at 24 Hours(IPA) at 24 Hours

-20.0-20.0

0.00.0

20.020.0

40.040.0

60.060.0

80.080.0

100.0100.0

Inhi

bitio

n of

Pla

tele

t Agg

rega

tion

(%)

Inhi

bitio

n of

Pla

tele

t Agg

rega

tion

(%)

Response to Response to

Drug 1Drug 1

Drug 1 ResponderDrug 1 Non-responder

*Responder = *Responder = 25% IPA at 4 and 24 h 25% IPA at 4 and 24 h

3

-20.0-20.0

0.00.0

20.020.0

40.040.0

60.060.0

80.080.0

100.0100.0

Inhi

bitio

n of

Pla

tele

t Agg

rega

tion

(%)

Inhi

bitio

n of

Pla

tele

t Agg

rega

tion

(%)

Response to Response to Drug 2Drug 2

Response to Response to

Drug 1Drug 1*Responder = *Responder = 25% IPA at 4 and 24 h 25% IPA at 4 and 24 h

Results: Inhibition of Platelet AggregationResults: Inhibition of Platelet Aggregation(IPA) at 24 Hours(IPA) at 24 Hours

4

-20.0-20.0

0.00.0

20.020.0

40.040.0

60.060.0

80.080.0

100.0100.0

Inhi

bitio

n of

Pla

tele

t Agg

rega

tion

(%)

Inhi

bitio

n of

Pla

tele

t Agg

rega

tion

(%)

Response to Response to Drug 2Drug 2

Response to Response to

Drug 2Drug 2*Responder = *Responder = 25% IPA at 4 and 24 h 25% IPA at 4 and 24 h

Results: Inhibition of Platelet AggregationResults: Inhibition of Platelet Aggregation(IPA) at 24 Hours(IPA) at 24 Hours

5

IPA

-20 -10 0 10 20 30 40 50 60 70 80 90 100

Per

cent

of s

ubje

cts

(%)

0

10

20

30

40

50

60

Clopidogrel 300 mg

Prasugrel 60 mg

Comparative IPA (20 M ADP), 4 h Post Loading Dose

n = 66

6

0

20

40

60

80

100

0 2 4 6 8 10 12Time (Hr)

% IP

A (2

0 M

AD

P)Thienopyridines: Speed of onset of actionThienopyridines: Speed of onset of action

Eli Lilly and Company, Data on file

Drug 1 Drug 1 Resp Drug 1 Non-Resp

Drug 1

Drug 2 Drug 2 in 1 Resp Drug 2 in 1 Non-resp

Drug 2

7

10 EP: Significant Non-CABG Bleeding 30 D

1.2%

2.0%1.5%1.7% 1.6%

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

Clop Pras 40/7.5 60/10 60/15

P= NS

3/254 11/650 3/199 4/200 4/251R/N

P = 0.77

Prasugrel LD/MDTreatment Group

Dose RangingClop. vs Prasugrel

8

MACE: Time to EventDeath, MI, CTVT, Stroke, and Recurrent Ischemia

CLOPIDOGREL

PRASUGREL

Kap

lan-

Mei

er E

stim

ate

0%

2%

4%

6%

8%

10%

Time since PCI (days)0 5 10 15 20 25 30 35

p = 0.26

9.4%

7.2%

RR=0.77 [0.5, 1.2]

9

STUDY DESIGNACS (STEMI or UA/NSTEMI) & Planned PCIACS (STEMI or UA/NSTEMI) & Planned PCI

PRASUGRELPRASUGREL60 mg LD/ 10 mg MD60 mg LD/ 10 mg MD

CLOPIDOGRELCLOPIDOGREL300 mg LD/ 75 mg MD

11oo endpoint: endpoint: CV death, MI, StrokeCV death, MI, Stroke22oo endpoints: endpoints: CV death, MI, Stroke, Rehosp-Rec IschCV death, MI, Stroke, Rehosp-Rec Isch

CV death, MI, UTVRCV death, MI, UTVR

Median duration of therapy 12 months

10

Early invasive treatment in NSTE-ACSEarly invasive treatment in NSTE-ACS

11

NSTE-ACSTrop T pos Death, MI, or ACS

Abciximab during all PCI procedures

Selective invasive

Early invasive

AspirinEnoxaparinClopidogrel

Statins

CAG Medical Rx

PCI / CABG

Medical Rx

CAG / PCI / CABG

ETT

Chest pain

- 24 hrs

Random.

0 hrs

Refractory angina

-

+

24-48 hrs

1 year

ICTUS Study Design

12

10%

20%

30%

100 200 300

Early invasive

Selective invasive

Death, MI*, Rehospitalisation for ACS

21.7%

20.4%

Relative Risk: 1.0695% CI: 0.85 – 1.32

P = 0.59

Time (days)

*Peak CK-MB > 1 x ULN; serial sampling every 6 hrs In patients with elevated CK-MB at randomization,

at least 50% decrease with subsequent rise > 1 x ULN

1-year results of ICTUS

13

Benefit of GP 2b/3a Agents in ACS Benefit of GP 2b/3a Agents in ACS TrialsTrials

All patients with ACS

Patients with ACS, undergoing PCI within 5 days

Boersma E et al. Lancet 2002

0.5 0.6 0.7 1.1Anti GPIIb/IIIa better

0.8 0.9 1.0

Relative 30-Day Risk of Death and MI

Meta-analysis of 6 major trials: Combined n = 31,402 Boersma et al Lancet 2002

14

Trials of 2b/3a inhibition in PCITrials of 2b/3a inhibition in PCI

PCI Studies Abciximab EPIC (bolus arm)EPILOGEPISTENT (stent arms)

Eptifibatide IMPACT-IIESPRIT

Tirofiban RESTORE

PCI Subgroups Eptifibatide PURSUIT(death&MI) Tirofiban PRISM-PLUS

Comparison Abciximabvs. Tirofiban TARGET

Odds Ratio for 30-DayDeath, MI & Urg. TVR

0.5 1.0 2.0

15 Kong D, et al. Am J Cardiol. 2003; 92:651-655.

Placebo BetterIIb/IIIa Better

Trial Control TreatmentN

0.1 1 10

RESTORE 1.1% 0.9%12,940

EPILOG 1.2% 0.9%4891

RAPPORT 1.3% 1.0%5374

CAPTURE 1.3% 1.0%6639

EPIC 1.7% 1.5%2099

1.3%IMPACT I 1.0%6789

1.2%IMPACT II 0.9%10,799

ESPRIT 1.0% 0.8%17,403

ISAR-2 1.1% 0.8%17,804

ADMIRAL 1.2% 0.8%18,104

EPISTENT 1.1% 0.8%15,339

1.3%CADILLAC 0.9%20,186

Odds Ratio and 95% CI

0.73 (0.55, 0.96)P=0.024

Meta-analysis of Survival with Platelet Meta-analysis of Survival with Platelet GP IIb/IIIa Antagonists for PCIGP IIb/IIIa Antagonists for PCI

16

Mortality in Primary PCI TrialsMortality in Primary PCI Trials

n = 400ACE

Circ 2004; 109:1704

4,5

7,3

3,7

10,5

4,13,3 3,3

5

8,5

6

0

2

4

6

8

10

12

14No Abciximab Abciximab

% o

f Pat

ient

s AHA2002, Oral Presentation

CADILLAC Registry:In-hospital Mortality8.3% without Abx;4.7% with Abx

Circ 1998; 98:734n = 483

RAPPORT

JACC 2000; 35:915n = 401ISAR-2

NEJM 2001; 41:1895n = 300

ADMIRALn = 2082

CADILLAC

NEJM 2002; 346:957

6 Month 1 Year 6 Month 6 Month 1 Year

p = 0.82

p = 0.13 p = 0.23 p = 0.04p = NS

Primary PCI for AMI

17

FINESSE: Study DesignFINESSE: Study Design

Abciximab bolus

ASA, unfractionated heparin 40U/kg (max 3000u) or enoxaparin (0.5 mg/kg IV + 0.3 mg/kg SC) – substudy only

Abciximab bolus Combo Rx

Primary PCI; Begin Abciximab Infusion

Primary endpoint at 90 days: all-cause mortality, resuscitated VFoccurring > 48H, cardiogenic shock, or readmission/ED visit for HF

Doo

r to

Bal

loon

(inc

ludi

ng tr

ansf

er)

> 60

min

but

< 4

hou

rs

Primary PCI withconcomittant Abx

Reteplase / Abciximab“facilitated PCI”

Pre-PCI Abciximab“facilitated PCI”

Acute MI patients with ST Elevation or New LBBB, < 6 hours of pain to qualifying ECG (N = 3000); Randomized 1:1:1