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Moderating the risk of ACS patients
by early decisions on platelet inhibition
Jörg M Rustige, MD Correvio International, Switzerland
MY CONFLICTS OF INTEREST IS
I am an employee of Correvio.
P=0.27 p<0.001
Pharmacodynamic comparison of GP IIb/IIIa Inhibitors
•
Danzietal.AJC2006;97:489-493
Open-label study, high-risk PCI with planned use of GP IIb/IIIa inhibitor, N=114
DANZI
High Dose Bolus of 25 microgram/kg
Developed by research from European Academic centres, mainly in Italy and Netherlands
4 van ‘t Hof AWJ, et al. Lancet 2008;16;372(9638):537-46
Dosing of Aggrastat for high risk patients going to PCI
Van‘tHofetalLancet2008;372:537-546TenBergetalJACC2010;55:2446-2455
15' 30' 1 H 2 H 6 H 18-24 H0
25
50
75
100
125
Prasugrel 60 mg
Tirofiban 25µg/kg bolus± 2 H infusion
* * * *
P<0.0001 for the trend
Time after Start of the Treatment
*%
IPA
to
20µ
mol
/L A
DP
Fabolus PRO Study
Valgimigli M et al, J Am Coll Cardiol Intv 2012;5:268–77
1° Efficacy Endpoint - (PCI Patients)
Days From First Dose
0 5 10 15 20 25 30
Endp
oint
(%)
0
5
10
15
20
Pre-treatment14.1
CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout
PCI Cohort
No Pre-treatment13.8
HR, 1.03(95% 0.84, 1.26)P=0.77
HR, 1.01(95% 0.82, 1.24)P=0.93
Pre-treatment13.1
No Pre-treatment13.1
13721389
11911206
11871202
11831194
11791189
11771186
11771172
No. at Risk, EfficacyEnd Point:No pre-treatmentPre-treatment
©2012CorrevioConfidenJal7
Angiogram(N=696)
HDBTirofiban*(N=709)Placebo(N=689)
TransportaJon
PCIcenterAngiogram(N=681)
PrimaryPCI(N=601)HDBTirofibanbailout
PrimaryPCI(N=602)TirofibanInfusion*PCI
*Bolus: 25 µg/kg and 0.15 µg/kg/min infusion.
STEMIpaKentsdiagnosedinambulanceorreferralcenterASA+600mgclopidogrel+UFH
van ‘t Hof AWJ, et al. Lancet 2008;16;372(9638):537-46 Ten Berg et al, JACC 2010; 55:2446-55
*Bolus:25µg/kg;Infusion:0.15µg/kg/minfor18hours
Open-labelphaseJune2004-June2006,N=414
Double-blindphaseJune2006-Nov.2007,N=984
On-TIME2:StudyDesignandFlowchart
TenBergetalJACC2010;55:2446-2455
Patients with STEMI who were to undergo primary PCI and met the following criteria:
• Symptoms >30 minutes but <24 hours, and • ST-segment elevation of >1 mV in 2 adjacent ECG leads
8 van ‘t Hof AWJ, et al. Lancet 2008;16;372(9638):537-46
On-TIME 2: Inclusion Criteria
Van‘tHofetalLancet2008;372:537-546TenBergetalJACC2010;55:2446-2455
• Known severe renal failure (GFR <30 mL/min) or serum creatinine >200 mmol/L
• Cardiogenic Shock • Persistent severe hypertension (systolic pressure >180 mm
Hg or diastolic pressure >110 mm Hg) • Left Bundle Branch Block (LBBB) • Contraindication to anticoagulation or increased risk of
bleeding
9 van ‘t Hof AWJ, et al. Lancet 2008;16;372(9638):537-46
On-TIME 2: Major Exclusion Criteria
Van‘tHofetalLancet2008;372:537-546
Primary Endpoint: Double Blind Phase
• Residual ST segment deviation (>3 mm)
Pooled Analysis (Double blind & open label phase) • MACE (death, recurrent MI, or uTVR at 30-
days) Secondary :
• Mortality at 1-year • Safety
10 van ‘t Hof AWJ, et al. Lancet 2008;16;372(9638):537-46
On-TIME 2 Endpoint
Van‘tHofetalLancet2008;372:537-546TenBergetalJACC2010;55:2446-2455
©2012CorrevioConfidenJal11
TotalPooledCohort(n=1398)
11
n=656 n=670 n=662 n=662 n=677 n=677
On-TIME2PooledAnalysis:Short-andLong-TermEfficacy
TenBergetalJACC2010;55:2446-2455
PrimaryEndpoint SecondaryEndpoint
©2012CorrevioConfidenJal1212
PooledCohortPrimaryPCISubgroup(n=1203)
n=515 n=477 n=583 n=586
On-TIME2:30Day-MACEand1Year-MortalityinPaJentsUndergoingPrimaryPCI(86%)
TenBergetalJACC2010;55:2446-2455
©2012CorrevioConfidenJal13
2.9
4.4
3.4
5.9
0
2
4
6
8
TIMI MajorBleeding
TIMI MinorBleeding
% o
f Pat
ient
s
Placebo (n=662)HDB Tirofiban (n=677)
p=0.580
13
p=0.206
TenBergetalJACC2010;55:2446-2455
On-TIME2PooledAnalysis:Safetyat30-Days
©2012CorrevioConfidenJal14
3.0
0.2
0.0
1.0
2.0
3.0
4.0 %
Pat
ient
s
Placebo Tirofiban
AcuteStentThrombosis(<24hours)
ReducKonofacutestentthrombosisbypre-hospitalKrofibaninprimaryPCIforSTEMI
N=1073
On-TIME2PooledAnalysis:AcuteStentThrombosis
Heestermansetal.JThrombHaemost.2009;7:1612-1618
p<0.001
p=0.007
Pat
ient
s (%
)
EUROMAX & HORIZONS
AcuteStentThrombosis(<24hrs)
p<0.001
EUROMAX HORIZONS G. Steg et al October 2013, NEJM. DOI: 10.1056/NEJMoa1311096 G. Stone et al NEJM 2008;358:2218-30.
Confirmation of randomized trial in real world data sets
The reduction of mortality by the adjunctive tirofiban platelet
blockade was also observed in three independent large registries
in Germany, France and the Netherlands
17
Multivariate Analysis for in-hospital Mortality
ALKK PCI Registry; p = 0.026
Clinical Outcome at 6 Months
18
3531
1
11
1920 20
24
14
0
10
20
30
40
Placebo (n=101) HDB Tirofiban (n=101)
% o
f Pat
ient
s
Death, MI, or uTVR
Death MI uTVR
p=0.052
p=0.048
p=0.01
p=0.60
p=0.29
ADVANCE
Valgimigli M, et al. J Am Coll Cardiol. 2004;44(1):14-19.
Death, MI, uTVR, or bail-out
Conclusion
• Early platelet inhibition by administering tirofiban iv with a high dose bolus reduces major cardiovascular events at 30 days and 1 year in STEMI and high-risk NSTE-ACS patients
• Early platelet inhibition reduces stent thrombosis
• Bleeding complications are increased modestly
Verwijzers Regio
Ambulance personeel:
RAV IJssel Vecht BV & RAD NW Veluwe En Ambulance diensten On-TIME 2
Why Tirofiban in the Ambulance?
Verwijzers Regio
Ambulance personeel:
RAV IJssel Vecht BV & RAD NW Veluwe En Ambulance diensten On-TIME 2
Not necessarily in the Ambulance –
Verwijzers Regio
Ambulance personeel:
RAV IJssel Vecht BV & RAD NW Veluwe En Ambulance diensten On-TIME 2
...make decisions early....
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