1 advanced angioplasty london, england 27 january, 2006 jörg michael rustige,md medical director...
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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
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