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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
Ongoing Tirofiban In Myocardial Infarction Evaluation
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
Ongoing Tirofiban In Myocardial Infarction Evaluation
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
Ongoing Tirofiban In Myocardial Infarction Evaluation
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
Ongoing Tirofiban In Myocardial Infarction Evaluation
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
Ongoing Tirofiban In Myocardial Infarction Evaluation
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
Ongoing Tirofiban In Myocardial Infarction Evaluation
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
Ongoing Tirofiban In Myocardial Infarction Evaluation
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
Ongoing Tirofiban In Myocardial Infarction Evaluation
Ischemic TimeIschemic Time
Ongoing Tirofiban In Myocardial Infarction Evaluation
ON-TIME 2The Lancet 2008; 372: 537-46
Ongoing Tirofiban In Myocardial Infarction Evaluation
Residual ST Deviation after PCI
Residual ST Deviation after PCI
Ongoing Tirofiban In Myocardial Infarction Evaluation
All-Cause Mortality 30 DaysAll-Cause Mortality 30 Days
open label & double-blind, n = 1398
Ongoing Tirofiban In Myocardial Infarction Evaluation
All-Cause Mortality 1-YearAll-Cause Mortality 1-Year
P = 0.077
open label & double-blind, n = 1398
Ongoing Tirofiban In Myocardial Infarction Evaluation
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%
Ongoing Tirofiban In Myocardial Infarction Evaluation
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%
Ongoing Tirofiban In Myocardial Infarction Evaluation
1 Year Survival: Patients with Primary PCI
1 Year Survival: Patients with Primary PCI
P = 0.007
open label & double-blind, n = 1.155
Ongoing Tirofiban In Myocardial Infarction Evaluation
Ongoing Tirofiban In Myocardial Infarction Evaluation
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.
Ongoing Tirofiban In Myocardial Infarction Evaluation
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
Ongoing Tirofiban In Myocardial Infarction Evaluation
Thank You !Thank You !
Ongoing Tirofiban In Myocardial Infarction Evaluation
1 Year Survival: Patients with Primary PCI1 Year Survival: Patients with Primary PCI
double-blind, n = 826
Ongoing Tirofiban In Myocardial Infarction Evaluation
All-Cause Mortality 1-Year All-Cause Mortality 1-Year
double-blind, n = 984
Ongoing Tirofiban In Myocardial Infarction Evaluation
1-Year Cardiac Mortality1-Year Cardiac Mortality
double-blind, n = 984
Ongoing Tirofiban In Myocardial Infarction Evaluation
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
Ongoing Tirofiban In Myocardial Infarction Evaluation
Initial TIMI flowInitial TIMI flow
Ongoing Tirofiban In Myocardial Infarction Evaluation
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
Ongoing Tirofiban In Myocardial Infarction Evaluation
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
Ongoing Tirofiban In Myocardial Infarction Evaluation
Effect on different End Points Effect on different End Points
Clinical End Points
Surrogate End Points
Ongoing Tirofiban In Myocardial Infarction Evaluation
Survival free from MACESurvival free from MACE
Ongoing Tirofiban In Myocardial Infarction Evaluation
Residual ST-Deviation and Mortality
Residual ST-Deviation and Mortality
Ongoing Tirofiban In Myocardial Infarction Evaluation
Why in ambulance? Why in ambulance? Surrogate End Points
Pain-diagnosis>75 minPain-diagnosis<75 min
Ongoing Tirofiban In Myocardial Infarction Evaluation
Why in ambulance? Why in ambulance?
Pain-diagnosis>75 minPain-diagnosis<75 min
Ongoing Tirofiban In Myocardial Infarction Evaluation
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