on-time-2 ongoing-tirofiban in myocardial infarction evaluation
TRANSCRIPT
ON-TIME-2ON-TIME-2OnOngoing-going-TTirofiban irofiban IIn n
MMyocardialyocardialInfarction Infarction EEvaluationvaluation
ON-TIME-2ON-TIME-2OnOngoing-going-TTirofiban irofiban IIn n
MMyocardialyocardialInfarction Infarction EEvaluationvaluation
Presenter Disclosure Information
Christian W. Hamm, MD, FESC, FACC
The following relationships exist related to this presentation:
Consulting Fees Merck, GSK, Lilly, Modest Level& speakers honoraria The Med.Comp., Sanofi,
Medtronic, Cordis, Braun,CVT, Abbott, Roche
ON-TIME-StudiesON-TIME-StudiesON-TIME-StudiesON-TIME-Studies
ON-TIME 1:No significant benefit for low bolus dose Tirofiban in AMI
ON-TIME 2 RegistryOpen label Tirofiban, high bolus dose
( N=416, Zwolle + Nieuwegein)( N=416, Zwolle + Nieuwegein)
ON-TIME 2 Randomized StudyTirofiban high bolus dose double-blind + 600 mg clopidogrel
Prehospital GPIIb/IIIa in AMI Prehospital GPIIb/IIIa in AMI HistoryHistory
Prehospital GPIIb/IIIa in AMI Prehospital GPIIb/IIIa in AMI HistoryHistory
Trial DesignTrial Design(Registration: ISRCTN 06195297)
Trial DesignTrial Design(Registration: ISRCTN 06195297)
Ongoing Tirofiban In Myocardial Infaction Evaluation
Multicenter, prospective, randomized, double-blind, placebo-controlled
Analysis: ITTEnd-points adjudicated (CEC)
Investigator initiated and drivenUnrestricted grant from Merck & Co Inc.
Trial LeadershipTrial LeadershipTrial LeadershipTrial Leadership
Ongoing Tirofiban In Myocardial Infaction Evaluation
Co-Principle InvestigatorsArnoud van ´HofChristian W. HammJurriën M. ten Berg
Steering CommitteeP. StellaL. van den MerckhoffM. ScheperT. Dill (Germany, MRI)G. Giannitsis (biomarker)J. BrachmannS. Guptha
CRODiagram B.V., J. Klijn
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 CentersParticipating CentersParticipating Centers
Ongoing Tirofiban In Myocardial Infaction 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
Transportation
PCI centreAngiogramAngiogram
TirofibanTirofibanprovisionalprovisional
Tirofiban Tirofiban cont’dcont’d
ON-TIME -2 ON-TIME -2 ON-TIME -2 ON-TIME -2
N=9846/2006-11/2007
PCI
*Bolus: 25 µg/kg & 0.15 µg/kg/min infusion
PrimaryPrimary
• Residual ST segment deviation (>3mm) Residual ST segment deviation (>3mm) 1 hour after PCI1 hour after PCI
Key SecondaryKey Secondary
• Combined occurrence of death, recurrent MI, urgent TVR or Combined occurrence of death, recurrent MI, urgent TVR or
thrombotic bailout at 30 days follow-up thrombotic bailout at 30 days follow-up
• Safety ( major bleeding)Safety ( major bleeding)
EndpointsEndpointsEndpointsEndpoints
Ongoing Tirofiban In Myocardial Infaction Evaluation
Baseline Data Baseline Data
Ongoing Tirofiban In Myocardial Infaction Evaluation
Placebo Tirofiban p- value
Patients (n) 493 491
Age (yrs) 62.0 ± 12.0 61.6 ± 11.8 0.599
TIMI - risk> 3 32.2% 27.7% 0.124
Pre - hospital Randomisation
95.7% 94.5% 0.367
No AMI 5.9% 6.3% 0.777
Inclusion SiteInclusion SiteInclusion SiteInclusion Site
AmbulanceAmbulance 95%95%
Referral CenterReferral Center 3%3%
PCI center (ER)PCI center (ER) 2%2%
Ongoing Tirofiban In Myocardial Infaction Evaluation
76 20 25 19 16
0 60 120 180
Ischemic Time (min)
SO-1st Contact Preparation Transportation
Door-Angio Angio-Balloon
Ischemic TimeIschemic Time
Ongoing Tirofiban In Myocardial Infaction Evaluation
60 min
d-t-b 35 min
[ Mean transport distance: 25 km/ 17 miles ]
Angiography and Angiography and ReperfusionReperfusion
Ongoing Tirofiban In Myocardial Infaction Evaluation
Placebo n=493
Tirofiban n=491
p- value
Angio performed 99.0% 98.2% 0.278
PCI 90.0% 87.6% 0.235
CABG 2.7% 2.9% 0.225
Conservative 7.4% 9.5% 0.82
Ongoing Tirofiban In Myocardial Infaction Evaluation
Results: Primary EndpointResults: Primary EndpointResidual ST deviation at 60 min.Residual ST deviation at 60 min.
mean ± SD Placebo Tirofiban p- value
Readable ECG 94.1% 95.5% 0.358
ResidualST - deviation (mm)
4.8 ±6.3 3.3 ± 4.3 0.002
> 3 mm ST-deviation 44.3% 36.6% 0.026
normal ECG 30.2% 37.3% 0.031
Cumulative ST- Deviation over Cumulative ST- Deviation over TimeTime
Ongoing Tirofiban In Myocardial Infaction Evaluation
0
4
8
12
16
Diagnosis pre Angio 60min 90 min
Placebo Tirofiban 14.3±9.1
12.1±9.4
5.9±8.1
4.8±6.3
14.5±9.1
10.9±9.2
4.4±5.3
3.3±4.3
0.0020.0220.028p=0.84
[mm]
Residual ST-Deviation Residual ST-Deviation and Mortalityand Mortality
Residual ST-Deviation Residual ST-Deviation and Mortalityand Mortality
Ongoing Tirofiban In Myocardial Infaction Evaluation
0,6
4,1
0
1
2
3
4
5
30 d
ay M
orta
lity
(%
)
ST dev <3mm ST dev >3mm
P<0.001
Residual ST > 3 mm (combined)
Placebo betterTirofiban better
All patients (PCI)
Male gender
Female gender
Diabetes
No diabetes
TIMI risk > 3
TIMI risk ≤ 3
Age < median value
Age > median value
0.1 1 10
Primary
Endpoint
Subgroups
TIMI pre 0,1
TIMI pre 2,3
Angio < 55 min
Angio > 55 min
Onset of Pain ≤ 76 min
Onset of pain > 76 min
Bail out tirofiban
No bail out tirofiban
0,1 1 10
Residual ST > 3 mm (combined)
Placebo betterTirofiban better
Primary
Endpoint
Subgroups
Clinical Secondary Endpoints: 30 Clinical Secondary Endpoints: 30 daysdays
Ongoing Tirofiban In Myocardial Infaction Evaluation
Placebon=477
Tirofibann=473
p-value
Death 19 (4.0%) 11(2.3%) 0.144
Reccurent MI 14 (2.9%) 13 (2.7%) 0.863
Stroke 7 (1.5%) 1 (0.2%) 0.069
Urgent TVR 23 (4.8%) 19 (4.0%) 0.546
Death/MI/TVR/Stroke 47 (9.9%) 34 (7.2%) 0.141
Thromb. Bail out 140 (28.5%) 97(19.9%) 0.002
Combined 159 (33.3%) 123 (26.0%) 0.013
Recurrent MI
0.013
Event-free SurvivalEvent-free SurvivalEvent-free SurvivalEvent-free Survival
Time (days)302520151050
Ev
en
t fr
ee s
urv
iva
l
90%
80%
70%
60%
50%
40%
Tirofiban
Placebo
P value 0,012
Ongoing Tirofiban In Myocardial Infaction Evaluation
P = 0.012
Thrombotic Bail-out and Thrombotic Bail-out and AngiographyAngiography
Ongoing Tirofiban In Myocardial Infaction Evaluation
Placebo (n = 493)
Tirofiban(n = 491)
p-value
Bail- out 28.5% 19.9% 0.002
TIMI-Flow 0-2 9.1% 5.9% 0.058
Abrupt closure 2.2% 0.2% 0.004
Distal embolisation 11.8% 9,0% 0.155
Safety Endpoint: Safety Endpoint: BleedingBleeding
Ongoing Tirofiban In Myocardial Infaction Evaluation
Placebon=477
Tirofibann=473
p-value
Major 2.9% 4,00% 0.363
Non-CABG 1.5% 1.9% 0.41
Minor 4.4% 6.1% 0.233
Non- CABG 2.7% 4.6% 0.807
Exploratory Endpoints: Exploratory Endpoints: BiomarkersBiomarkers
Ongoing Tirofiban In Myocardial Infaction Evaluation
Median [Q1 -Q3] Placebo Tirofiban p-value
Troponin T(72-96 hrs) (n=590)
1.8 µg/L[0.0009 -11.31]
1.87 µg/L[0.009-17.73]
0.916
NT- proBNP(72-96/ 18-24 hrs)(n=785)
1066 µg/L[485 - 2664]
891 µg/L[424 - 1671]
0.026
NT- proBNP>median
225/404 (55.7%) 177/386 (45.9%) 0.006
SummarySummarySummarySummary
• Pre-Hospital initiation of tirofiban (HDB) improves Pre-Hospital initiation of tirofiban (HDB) improves
ST resolution before and after primary PCIST resolution before and after primary PCI
• Combined secondary clinical endpoint reducedCombined secondary clinical endpoint reduced
• No increase in bleeding riskNo increase in bleeding risk
• Pre-Hospital initiation of tirofiban (HDB) improves Pre-Hospital initiation of tirofiban (HDB) improves
ST resolution before and after primary PCIST resolution before and after primary PCI
• Combined secondary clinical endpoint reducedCombined secondary clinical endpoint reduced
• No increase in bleeding riskNo increase in bleeding risk
Ongoing Tirofiban In Myocardial Infaction Evaluation
ConclusionsConclusionsConclusionsConclusions
• High dose tirofiban on top of clopidogrel (600mg) High dose tirofiban on top of clopidogrel (600mg)
in the prehospital setting is safein the prehospital setting is safe
• Improves outcome of primary PCI for AMIImproves outcome of primary PCI for AMI
• Long term mortality benefit ?Long term mortality benefit ?
• High dose tirofiban on top of clopidogrel (600mg) High dose tirofiban on top of clopidogrel (600mg)
in the prehospital setting is safein the prehospital setting is safe
• Improves outcome of primary PCI for AMIImproves outcome of primary PCI for AMI
• Long term mortality benefit ?Long term mortality benefit ?
Ongoing Tirofiban In Myocardial Infaction Evaluation
Thank you !Thank you !
Ongoing Tirofiban In Myocardial Infaction Evaluation
Ongoing Tirofiban In Myocardial Infaction Evaluation
Baseline Data 2Baseline Data 2Time lines + TransportationTime lines + Transportation
mean ± Q1-Q3Placebo (n=493)
Tirofiban(n=496)
p- value
Symptom- to -Diagnosis (min)
79 [45 - 155.8] 72 [44 - 141] 0.377
Study medication-to- angio (min)
55 [43-70] 55 [43-70] 0.844
TransportDistance (km)
25 [12-41] 25 [12-41] 0.931
Placebo Controlled study (N=958)Placebo Controlled study (N=958)
Primary End PointPrimary End Point
• Relative 20% reduction: 50 to 40%Relative 20% reduction: 50 to 40%
• N=814 (N=814 (Alpha 0.05, power 80%)Alpha 0.05, power 80%), 20% loss, N=958 , 20% loss, N=958
Key Secondary End PointKey Secondary End Point
• 68% power to detect a Relative 40% difference (13 to 8%)68% power to detect a Relative 40% difference (13 to 8%)
Open label + Plac controlled (N=1.400)Open label + Plac controlled (N=1.400)
• 55% power to detect a relative 40% difference in combined death/re-55% power to detect a relative 40% difference in combined death/re-
MI/urg TVRMI/urg TVR (7.5 to 4.5%)(7.5 to 4.5%)
StatisticsStatisticsStatisticsStatistics
Ongoing Tirofiban In Myocardial Infaction Evaluation
Placebo Controlled study (N=958)Placebo Controlled study (N=958)
Primary End PointPrimary End Point
• Relative 20% reduction: 50 to 40%Relative 20% reduction: 50 to 40%
• N=814 (N=814 (Alpha 0.05, power 80%)Alpha 0.05, power 80%), 20% loss, N=958 , 20% loss, N=958
Key Secondary End PointKey Secondary End Point• 90 % power to detect a relative 30% difference (35 to 25%)90 % power to detect a relative 30% difference (35 to 25%)
• 80% power to detect a relative 40% difference in 80% power to detect a relative 40% difference in
combined death/re-MI/urg TVRcombined death/re-MI/urg TVR (11.5 to 7.5%)(11.5 to 7.5%)
StatisticsStatisticsStatisticsStatistics
Ongoing Tirofiban In Myocardial Infaction Evaluation
Secondary OtherSecondary Other
• Incidence of TIMI 3 flow of the IRV at initial angiographyIncidence of TIMI 3 flow of the IRV at initial angiography
• Incidence of normal MBGIncidence of normal MBG
ExploratoryExploratory
• Enzymatic Infarct size ( single cTnT 48-72 hours after PCI)Enzymatic Infarct size ( single cTnT 48-72 hours after PCI)
• Distal EmbolisationDistal Embolisation
• MRI infarct SizeMRI infarct Size
• Spect Salvage indexSpect Salvage index
• Platelet AggregationPlatelet Aggregation
Endpoints - 2Endpoints - 2Endpoints - 2Endpoints - 2
Ongoing Tirofiban In Myocardial Infaction Evaluation