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

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


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


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


Baseline Data Baseline Data


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%


76 20 25 19 16

0 60 120 180

Ischemic Time (min)

SO-1st Contact Preparation Transportation

Door-Angio Angio-Balloon

Ischemic TimeIschemic Time


60 min

d-t-b 35 min

[ Mean transport distance: 25 km/ 17 miles ]

Angiography and Angiography and ReperfusionReperfusion


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


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


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


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


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


P = 0.012

Thrombotic Bail-out and Thrombotic Bail-out and AngiographyAngiography


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


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


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


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 ?


Thank you !Thank you !



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


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


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


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