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....