ONTIME2 OngoingTirofiban In Myocardial Infarction Evaluation 1 Year FollowUp

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ON-TIME-2Ongoing-Tirofiban In MyocardialInfarcti
on Evaluation1 Year Follow-Up
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Conflicts of interest

• Speakers 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

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Trial Design(Registration ISRCTN 06195297)
Multicenter, prospective, randomized,
international Analysis ITT End-points
adjudicated (CEC) Investigator initiated and
driven Unrestricted grant from Merck and Iroko
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Trial Leadership
Co-Principle Investigators Arnoud van
tHof Christian W. Hamm Jurriën M. ten
Berg Steering Committee P. Stella L. van den
Merckhoff T. Dill (Germany, MRI) G. Giannitsis
(biomarker) J. Brachmann S. Guptha CRO Diagram
B.V., J. Klijn
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Study Phases

• Open Label
• June 2004 June 2006
• N414
• 2 centres
• Netherlands
• HBD Tirofiban or no Tirofiban
• 600 mg Clopidogrel,
• heparine, ASA

• Double Blind
• June 2006 Nov 2007
• N984
• 24 centres
• Netherlands, Germany, Belgium
• HBD Tirofiban or Placebo
• 600 mg Clopidogrel, heparine,
• ASA

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• Inclusion criteria
• Chest pain gt 30 min but less than 24 hours
• ST ? in 2 contiguous leads gt 0.2 mV (anterior
  MI) or 0.1 mV (non-anterior MI)

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

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Acute myocardial infarction diagnosed in
ambulance or referral center ASA600 mg
Clopidogrel
Tirofiban
Placebo
Transportation
PCI centre
Angiogram
Angiogram
Tirofiban provisional
Tirofiban contd
PCI
Bolus 25 µg/kg 0.15 µg/kg/min infusion
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Endpoints

• Primary
• Residual ST segment deviation (gt3mm) 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

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Baseline Data

• Open Label Double Blind
• (n414) (n984)
• Age (mean, yr) 62 62
• Male gender () 77 76
• Prev MI () 11 9
• Diabetes () 11 12
• Hypertension () 34 34
• Smoking () 48 47
• Anterior MI () 45 42
• Killip gt 1 () 13 12
• Ambulance RX () 98 95

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Ischemic Time
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ON-TIME 2The Lancet 2008 372 537-46
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Residual ST Deviation after PCI
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All-Cause Mortality 30 Days
open label double-blind, n 1398
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All-Cause Mortality 1-Year
open label double-blind, n 1398
P 0.077
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All cause Mortality 1 Year
Double Blind
Open Label
N984
N414
-37
-36
RR 0.78 (95 CI 0.53-1.14, p0.157)
RR 0.77 (95 CI 0.46-1.29, p0.276)
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All cause Mortality and AMI 1 Year
Double Blind
Open Label
N984
N414
-41
-19
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1 Year Survival Patients with Primary PCI
open label double-blind, n 1.155
P 0.007
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(No Transcript)
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Summary 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 (gt 65 yrs), in Killip
  class ? 2 and in early presenters.

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Conclusion

• Prehospital HD Tirofiban
• A Promising Option for AMI Networks

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Thank You !
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1 Year Survival Patients with Primary PCI
double-blind, n 826
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All-Cause Mortality 1-Year
double-blind, n 984
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1-Year Cardiac Mortality
double-blind, n 984
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Double Blind Phase

• further platelet aggregation inhibition besides
  high-dose
• clopidogrel improves ST resolution both before
  and after PCI
• On-TIME 2 study, Lancet 2008372537-46

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Initial TIMI flow
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Pooled AnalysisOpen Label and Double Blind

• N1398 Tirofiban Placebo P-value (n709) (n
  689)
• Age (mean, yr) 62 62 NS
• Male gender () 77 76 NS
• Prev MI () 9 9 NS
• Diabetes () 12 11 NS
• Hypertension () 34 34 NS
• Smoking () 46 49 NS
• Anterior MI () 43 43 NS
• Killip gt 1 () 11 14 NS
• Ambulance triage () 96 97 NS

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Pooled AnalysisResidual ST deviation
Plac/no Tiro N689
Tirofiban N709
mean SD
p- value
14.6 9.1
Baseline ST-deviation (mm)
14.2 8.6
0.645
Residual ST-deviation
4.8 6.04
3.7 5.2
0.001
1 hr post PCI (mm)
normal ECG 1 hr post PCI
30.0
36.1
0.003
gt 3 mm ST-deviation
45.0
38.7
0.024
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Effect on different End Points
Surrogate End Points
Clinical End Points
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Survival free from MACE
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Residual ST-Deviation and Mortality
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Why in ambulance?
Surrogate End Points
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Why in ambulance?
Pain-diagnosislt75 min
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Participating Centers

• The Netherlands
• 1. Isala klinieken Zwolle Dr. A.W.J. van t Hof
• 2. Antonius Ziekenhuis Nieuwegein Dr. J. ten Berg
• 3. UMC Utrecht Drs. P.R. Stella
• 4. Medisch Spectrum Twente Dr. K. van
  Houwelingen
• Germany
• 1. Kerckhoff-Klinik Prof. Dr. C. Hamm
• 2. Universitätsklinikum Heidelberg Prof. Dr. H
  Katus
• 3. St. Johannes Hospital Dortmund Prof. Dr.
  Heuer