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

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Presentation on theme: "ON-TIME-2 Ongoing-Tirofiban In Myocardial Infarction Evaluation"— Presentation transcript:

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

2 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

3 Prehospital GPIIb/IIIa in AMI History
ON-TIME-Studies Prehospital GPIIb/IIIa in AMI History ON-TIME 1: No significant benefit for low bolus dose Tirofiban in AMI ON-TIME 2 Registry Open label Tirofiban, high bolus dose ( N=416, Zwolle + Nieuwegein) ON-TIME 2 Randomized Study Tirofiban high bolus dose double-blind + 600 mg clopidogrel

4 Trial Design (Registration: ISRCTN 06195297)
Ongoing Tirofiban In Myocardial Infaction Evaluation Trial Design (Registration: ISRCTN ) Multicenter, prospective, randomized, double-blind, placebo-controlled Analysis: ITT End-points adjudicated (CEC) Investigator initiated and driven Unrestricted grant from Merck & Co Inc.

5 Ongoing Tirofiban In Myocardial Infaction Evaluation
Trial Leadership Co-Principle Investigators Arnoud van ´Hof Christian W. Hamm Jurriën M. ten Berg Steering Committee P. Stella L. van den Merckhoff M. Scheper T. Dill (Germany, MRI) G. Giannitsis (biomarker) J. Brachmann S. Guptha CRO Diagram B.V., J. Klijn

6 Participating Centers
Ongoing Tirofiban In Myocardial Infaction Evaluation 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 4. Klinikum Coburg Prof. Dr. J. Brachmann 5. Klinikum Lüdenscheid Dr. Lemke 6. Segeberger Kliniken Prof. Dr. G. Richardt 7. Philipps Universität Marburg Prof. Maisch 8. Allgemeines Krankenhaus Celle Prof. Dr. W. Terres 9. Uni-klinik Giessen Prof. Dr. H. Tillmanns 10. Imtalklinik Pfaffenhofen Prof. C. Firschke 11. Med. Hochschule Hannover Prof. Dr. Schieffer 12. Uniklinik Mannheim Dr. T. Süselbeck 13. Uniklinik Lübeck Prof. Dr. H. Schunkert 14. Stätisches Klinikum Lüneburg Prof. Dr. W. Kupper 15. Zentralklinikum Suhl Prof. W. Haberbosch 16. Uni-Klinik Rostock Prof. Dr. C.Nienaber 17. Kreiskrankenhaus Bergstrasse Dr. W. Auch-Schwelk 18. Asklepios Klinik St. Georg Prof. Dr. K.H. Kuck 19. Klinikum Darmstadt Prof Dr. G. Werner 20. Evangelisches Krankenhaus Holzminden Dr. C. Beythien Belgium: 1. AZ Sint-Jan AV Brugge Dr. P. Coussement

7 Acute myocardial infarction diagnosed in ambulance or referral center
ON-TIME -2 Acute myocardial infarction diagnosed in ambulance or referral center ASA+600 mg Clopidogrel N=984 6/ /2007 Placebo Tirofiban * Transportation Angiogram PCI centre Angiogram Tirofiban provisional PCI Tirofiban cont’d *Bolus: 25 µg/kg & 0.15 µg/kg/min infusion

8 Ongoing Tirofiban In Myocardial Infaction Evaluation
Endpoints Primary Residual ST segment deviation (>3mm) 1 hour after PCI Key Secondary Combined occurrence of death, recurrent MI, urgent TVR or thrombotic bailout at 30 days follow-up Safety ( major bleeding)

9 Ongoing Tirofiban In Myocardial Infaction Evaluation
Baseline Data

10 Ongoing Tirofiban In Myocardial Infaction Evaluation
Inclusion Site Ambulance 95% Referral Center 3% PCI center (ER) 2%

11 Ongoing Tirofiban In Myocardial Infaction Evaluation
Ischemic Time 60 min d-t-b 35 min [ Mean transport distance: 25 km/ 17 miles ]

12 Angiography and Reperfusion
Ongoing Tirofiban In Myocardial Infaction Evaluation Angiography and Reperfusion 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

13 Ongoing Tirofiban In Myocardial Infaction Evaluation
Results: Primary Endpoint Residual ST deviation at 60 min. mean ± SD Placebo Tirofiban p- value Readable ECG 94.1% 95.5% 0.358 Residual 4.8 ±6.3 3.3 ± 4.3 0.002 ST - deviation (mm) normal ECG 30.2% 37.3% 0.031 > 3 mm ST-deviation 44.3% 36.6% 0.026

14 Cumulative ST- Deviation over Time
Ongoing Tirofiban In Myocardial Infaction Evaluation Cumulative ST- Deviation over Time [mm] 14.5±9.1 14.3±9.1 12.1±9.4 10.9±9.2 5.9±8.1 4.8±6.3 4.4±5.3 3.3±4.3 p=0.84 0.028 0.022 0.002

15 Residual ST-Deviation and Mortality
Ongoing Tirofiban In Myocardial Infaction Evaluation Residual ST-Deviation and Mortality P<0.001

16 Primary Endpoint Subgroups Residual ST > 3 mm (combined)
Tirofiban better Placebo better All patients (PCI) Primary Endpoint Subgroups Male gender Female gender Diabetes No diabetes TIMI risk > 3 TIMI risk ≤ 3 Age < median value Age > median value 0.1 1 10

17 Primary Endpoint Subgroups 10 0,1 1 Residual ST > 3 mm (combined)
Tirofiban better Placebo better 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 10 0,1 1

18 Clinical Secondary Endpoints: 30 days
Ongoing Tirofiban In Myocardial Infaction Evaluation Clinical Secondary Endpoints: 30 days Recurrent MI 0.013

19 Ongoing Tirofiban In Myocardial Infaction Evaluation
Event-free Survival P = 0.012

20 Thrombotic Bail-out and Angiography
Ongoing Tirofiban In Myocardial Infaction Evaluation Thrombotic Bail-out and Angiography

21 Safety Endpoint: Bleeding
Ongoing Tirofiban In Myocardial Infaction Evaluation Safety Endpoint: Bleeding

22 Exploratory Endpoints: Biomarkers
Ongoing Tirofiban In Myocardial Infaction Evaluation Exploratory Endpoints: Biomarkers

23 Ongoing Tirofiban In Myocardial Infaction Evaluation
Summary Pre-Hospital initiation of tirofiban (HDB) improves ST resolution before and after primary PCI Combined secondary clinical endpoint reduced No increase in bleeding risk

24 Ongoing Tirofiban In Myocardial Infaction Evaluation
Conclusions High dose tirofiban on top of clopidogrel (600mg) in the prehospital setting is safe Improves outcome of primary PCI for AMI Long term mortality benefit ?

25 Ongoing Tirofiban In Myocardial Infaction Evaluation
Thank you ! Ongoing Tirofiban In Myocardial Infaction Evaluation

26 Ongoing Tirofiban In Myocardial Infaction Evaluation
Baseline Data 2 Time lines + Transportation

27 Ongoing Tirofiban In Myocardial Infaction Evaluation
Statistics Placebo Controlled study (N=958) Primary End Point Relative 20% reduction: 50 to 40% N=814 (Alpha 0.05, power 80%), 20% loss, N=958 Key Secondary End Point 68% power to detect a Relative 40% difference (13 to 8%) Open label + Plac controlled (N=1.400) 55% power to detect a relative 40% difference in combined death/re-MI/urg TVR (7.5 to 4.5%)

28 Ongoing Tirofiban In Myocardial Infaction Evaluation
Statistics Placebo Controlled study (N=958) Primary End Point Relative 20% reduction: 50 to 40% N=814 (Alpha 0.05, power 80%), 20% loss, N=958 Key Secondary End Point 90 % power to detect a relative 30% difference (35 to 25%) 80% power to detect a relative 40% difference in combined death/re-MI/urg TVR (11.5 to 7.5%)

29 Ongoing Tirofiban In Myocardial Infaction Evaluation
Endpoints - 2 Secondary Other Incidence of TIMI 3 flow of the IRV at initial angiography Incidence of normal MBG Exploratory Enzymatic Infarct size ( single cTnT hours after PCI) Distal Embolisation MRI infarct Size Spect Salvage index Platelet Aggregation


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