Ongoing Tirofiban In Myocardial Infarction Evaluation ON-TIME-2 Ongoing-Tirofiban In Myocardial...

Ongoing Tirofiban In Myocardial Infarction Evaluation

ON-TIME-2Ongoing-Tirofiban In Myocardial

Infarction Evaluation

1 Year Follow-Up

ON-TIME-2Ongoing-Tirofiban In Myocardial

Infarction Evaluation

1 Year Follow-Up

Conflicts of interest

Conflicts of interest

Speaker’s name: Christian W. Hamm

I have the following potential conflicts of interest to report:

Consulting & speaker honoraria:GSK, Sanofi-Aventis, The Med. Comp.,Merck, Lilly, Iroko, Pfizer, Boehringer

Ingelheim


Trial Design(Registration: ISRCTN 06195297)

Trial Design(Registration: ISRCTN 06195297)

Multicenter, prospective, randomized, international

Analysis: ITTEnd-points adjudicated (CEC)

Investigator initiated and drivenUnrestricted grant from Merck and Iroko


Trial LeadershipTrial Leadership

Co-Principle InvestigatorsArnoud van t´HofChristian W. HammJurriën M. ten Berg

Steering CommitteeP. StellaL. van den MerckhoffT. Dill (Germany, MRI)G. Giannitsis (biomarker)J. BrachmannS. Guptha

CRODiagram B.V., J. Klijn


Study PhasesStudy Phases

Open Label• June 2004 – June 2006• N=414• 2 centres• Netherlands• HBD Tirofiban or no Tirofiban• 600 mg Clopidogrel,

heparine, ASA

Double Blind• June 2006 – Nov 2007• N=984• 24 centres• Netherlands, Germany, Belgium• HBD Tirofiban or Placebo• 600 mg Clopidogrel, heparine,

ASA


Inclusion criteria• Chest pain > 30 min but less

than 24 hours

• ST in 2 contiguous leads: > 0.2 mV (anterior MI) or 0.1 mV (non-anterior MI)

Exclusion criteria• Age > 85 yrs• Women < 50 yrs• Lytic therapy < 24 hrs• Acenocoumarol < 7 days• C.I to 2b/3a blockade• Killip IV• Hemodialysis


Acute myocardial infarctionAcute myocardial infarctiondiagnosed in ambulance or referral centerdiagnosed in ambulance or referral center

ASA+600 mg ClopidogrelASA+600 mg Clopidogrel

AngiogramAngiogram

Tirofiban *Tirofiban *PlaceboPlacebo

TransportationTransportation

PCI centrePCI centreAngiogramAngiogram

TirofibanTirofibanprovisionalprovisional

Tirofiban Tirofiban cont’dcont’d

PCIPCI

*Bolus: 25 µg/kg & 0.15 µg/kg/min infusion


Primary

• Residual ST segment deviation (>3mm) 1

hour after PCI

Key Clinical Secondary

• Combined occurrence of death, recurrent MI, urgent

TVR or thrombotic bailout at 30 days follow-up

• Safety ( major bleeding)

• Death at 1 year follow-up

EndpointsEndpoints


Baseline DataBaseline Data

Open LabelOpen Label Double BlindDouble Blind

(n=414)(n=414) (n=984)(n=984)

Age (mean, yr)Age (mean, yr) 6262 6262

Male gender (%)Male gender (%) 7777 7676

Prev MI (%)Prev MI (%) 1111 9 9

Diabetes (%)Diabetes (%) 1111 1212

Hypertension (%)Hypertension (%) 3434 3434

Smoking (%)Smoking (%) 4848 4747

Anterior MI (%)Anterior MI (%) 4545 4242

Killip > 1 (%)Killip > 1 (%) 1313 1212

Ambulance RX (%)Ambulance RX (%) 9898 9595


Ischemic TimeIschemic Time


ON-TIME 2The Lancet 2008; 372: 537-46


Residual ST Deviation after PCI

Residual ST Deviation after PCI


All-Cause Mortality 30 DaysAll-Cause Mortality 30 Days

open label & double-blind, n = 1398


All-Cause Mortality 1-YearAll-Cause Mortality 1-Year

P = 0.077

open label & double-blind, n = 1398


7.0

4.4

0

1

2

3

4

5

6

7

Placebo Tirofiban

5.3

3.4

0

1

2

3

4

5

6

7

Placebo Tirofiban

All cause Mortality 1 YearAll cause Mortality 1 Year

RR: 0.78 (95% CI: 0.53-1.14, p=0.157) RR: 0.77 (95% CI: 0.46-1.29, p=0.276)

N=984 N=414Double Blind Open Label

-36%-37%


9.1

5.4

0

2

4

6

8

10

Placebo Tirofiban

8.1

6.6

0

2

4

6

8

10

Placebo Tirofiban

All cause Mortality and AMI 1 YearAll cause Mortality and AMI 1 Year

N=984 N=414

Double Blind Open Label

-19%-41%


1 Year Survival: Patients with Primary PCI

1 Year Survival: Patients with Primary PCI

P = 0.007

open label & double-blind, n = 1.155


Summary: HD Tirofiban in the AmbulanceSummary: HD Tirofiban in the Ambulance

• Strong trend to reduced mortality continues over

1 year follow-up in open label and double blind

cohorts.

• In patients undergoing primary PCI (84%)

mortality is significantly lower.

• Highest efficacy in elderly (> 65 yrs), in Killip class

2 and in early presenters.


ConclusionConclusion

Prehospital HD Tirofiban:Prehospital HD Tirofiban:

A Promising Option for AMI NetworksA Promising Option for AMI Networks

Prehospital HD Tirofiban:Prehospital HD Tirofiban:

A Promising Option for AMI NetworksA Promising Option for AMI Networks


Thank You !Thank You !


1 Year Survival: Patients with Primary PCI1 Year Survival: Patients with Primary PCI

double-blind, n = 826


All-Cause Mortality 1-Year All-Cause Mortality 1-Year



1-Year Cardiac Mortality1-Year Cardiac Mortality



Double Blind PhaseDouble Blind Phase

‘further platelet aggregation inhibition besides high-dose

clopidogrel improves ST resolution both before and after PCI’

On-TIME 2 study, Lancet 2008;372:537-46


Initial TIMI flowInitial TIMI flow


Pooled AnalysisOpen Label and Double Blind

Pooled AnalysisOpen Label and Double Blind

N=1398 Tirofiban Placebo P-value(n=709) (n=689)

Age (mean, yr) 62 62 NSMale gender (%) 77 76 NSPrev MI (%) 9 9 NSDiabetes (%) 12 11 NSHypertension (%) 34 34 NSSmoking (%) 46 49 NSAnterior MI (%) 43 43 NSKillip > 1 (%) 11 14 NSAmbulance triage (%) 96 97 NS


mean ± SDPlac/no Tiro

N=689Tirofiban

N=709p- value

Baseline ST-deviation (mm) 14.2 ± 8.6 0.645

Residual ST-deviation1 hr post PCI (mm)

4.8 ± 6.04 3.7 ± 5.2 0.001

> 3 mm ST-deviation 45.0% 38.7% 0.024

normal ECG 1 hr post PCI 30.0% 36.1% 0.003

14.6 ± 9.1

Pooled AnalysisResidual ST deviation

Pooled AnalysisResidual ST deviation


Effect on different End Points Effect on different End Points

Clinical End Points

Surrogate End Points


Survival free from MACESurvival free from MACE


Residual ST-Deviation and Mortality

Residual ST-Deviation and Mortality


Why in ambulance? Why in ambulance? Surrogate End Points

Pain-diagnosis>75 minPain-diagnosis<75 min


Why in ambulance? Why in ambulance?

Pain-diagnosis>75 minPain-diagnosis<75 min


The Netherlands:1. Isala klinieken Zwolle Dr. A.W.J. van ’t Hof2. Antonius Ziekenhuis Nieuwegein Dr. J. ten Berg3. UMC Utrecht Drs. P.R. Stella4. Medisch Spectrum Twente Dr. K. van Houwelingen

Germany:1. Kerckhoff-Klinik Prof. Dr. C. Hamm2. Universitätsklinikum Heidelberg Prof. Dr. H Katus3. St. Johannes Hospital Dortmund Prof. Dr. Heuer4. Klinikum Coburg Prof. Dr. J. Brachmann5. Klinikum Lüdenscheid Dr. Lemke6. Segeberger Kliniken Prof. Dr. G. Richardt7. Philipps Universität Marburg Prof. Maisch 8. Allgemeines Krankenhaus Celle Prof. Dr. W. Terres9. Uni-klinik Giessen Prof. Dr. H. Tillmanns10. Imtalklinik Pfaffenhofen Prof. C. Firschke11. Med. Hochschule Hannover Prof. Dr. Schieffer12. Uniklinik Mannheim Dr. T. Süselbeck13. Uniklinik Lübeck Prof. Dr. H. Schunkert14. Stätisches Klinikum Lüneburg Prof. Dr. W. Kupper15. Zentralklinikum Suhl Prof. W. Haberbosch16. Uni-Klinik Rostock Prof. Dr. C.Nienaber17. Kreiskrankenhaus Bergstrasse Dr. W. Auch-Schwelk18. Asklepios Klinik St. Georg Prof. Dr. K.H. Kuck19. Klinikum Darmstadt Prof Dr. G. Werner20. Evangelisches Krankenhaus Holzminden Dr. C. Beythien

Belgium:1. AZ Sint-Jan AV Brugge Dr. P. Coussement

Participating CentersParticipating Centers

Ongoing Tirofiban In Myocardial Infarction Evaluation ON-TIME-2 Ongoing-Tirofiban In Myocardial...

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