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ON-TIME-2 On going- T irofiban I n M yocardial Infarction E valuation

ON-TIME-2 On going- T irofiban I n M yocardial Infarction E valuation. Presenter Disclosure Information. Christian W. Hamm, MD, FESC, FACC. The following relationships exist related to this presentation:. Consulting Fees Merck, GSK, Lilly, Modest Level

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ON-TIME-2 On going- T irofiban I n M yocardial Infarction E valuation

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  1. ON-TIME-2Ongoing-Tirofiban In MyocardialInfarction 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. ON-TIME-Studies Prehospital Tirofiban in AMI History ON-TIME 1: No significant benefit for low bolus dose Tirofiban in AMI ON-TIME 2Registry 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 Infarction Evaluation Multicenter, prospective, randomized, double-blind, placebo-controlled Analysis: ITT End-points adjudicated (CEC) Investigator initiated and driven Unrestricted grant from Merck & Co Inc.

  5. Trial Leadership Ongoing Tirofiban In Myocardial Infarction Evaluation Co-Principle Investigators Arnoud van t´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. 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 Participating Centers Ongoing Tirofiban In Myocardial Infarction Evaluation

  7. ON-TIME -2 Acute myocardial infarction diagnosed in ambulance or referral center ASA + 600 mg Clopidogrel + UFH N=984 6/2006-11/2007 Placebo Tirofiban * Transportation Angiogram Angiogram PCI center Tirofiban provisional PCI Tirofiban cont’d *Bolus: 25 µg/kg & 0.15 µg/kg/min infusion

  8. Ongoing Tirofiban In Myocardial Infarction 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 Infarction Evaluation Baseline Data

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

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

  12. Placebo Tirofiban p- value n=493 n=491 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 Infarction Evaluation Angiography and Reperfusion

  13. Ongoing Tirofiban In Myocardial Infarction 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. Ongoing Tirofiban In Myocardial Infarction 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. Ongoing Tirofiban In Myocardial Infarction Evaluation Residual ST-Deviation and Mortality P<0.001

  16. 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. Residual ST > 3 mm (combined) Tirofiban better Placebo better TIMI pre 0,1 Primary Endpoint Subgroups 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. Ongoing Tirofiban In Myocardial Infarction Evaluation Clinical Secondary Endpoints: 30 days Recurrent MI 0.013

  19. Ongoing Tirofiban In Myocardial Infarction Evaluation Event-free Survival P = 0.013

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

  21. Ongoing Tirofiban In Myocardial Infarction Evaluation Safety Endpoint: Bleeding 4.0% 0.115

  22. Ongoing Tirofiban In Myocardial Infarction Evaluation Exploratory Endpoints: Biomarkers

  23. Ongoing Tirofiban In Myocardial Infarction 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 Infarction 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. Thank you ! Ongoing Tirofiban In Myocardial Infaction Evaluation

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

  27. Ongoing Tirofiban In Myocardial Infarction 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 Infarction 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 Infarction 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 48-72 hours after PCI) • Distal Embolisation • MRI infarct Size • Spect Salvage index • Platelet Aggregation

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