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 FeesMerck, GSK, Lilly, Modest Level & speakers honorariaThe Med.Comp., Sanofi, Medtronic, Cordis, Braun, CVT, Abbott, Roche

3. ON-TIME-StudiesON-TIME-Studies 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 Prehospital Tirofiban in AMI History

4. Trial Design 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 ZwolleDr. A.W.J. van ’t Hof 2. Antonius Ziekenhuis NieuwegeinDr. J. ten Berg 3. UMC UtrechtDrs. P.R. Stella 4. Medisch Spectrum TwenteDr. K. van Houwelingen Germany: 1. Kerckhoff-KlinikProf. Dr. C. Hamm 2. Universitätsklinikum HeidelbergProf. Dr. H Katus 3. St. Johannes Hospital DortmundProf. Dr. Heuer 4. Klinikum CoburgProf. Dr. J. Brachmann 5. Klinikum LüdenscheidDr. Lemke 6. Segeberger KlinikenProf. Dr. G. Richardt 7. Philipps Universität MarburgProf. Maisch 8. Allgemeines Krankenhaus CelleProf. Dr. W. Terres 9. Uni-klinik GiessenProf. Dr. H. Tillmanns 10. Imtalklinik PfaffenhofenProf. C. Firschke 11. Med. Hochschule HannoverProf. Dr. Schieffer 12. Uniklinik MannheimDr. T. Süselbeck 13. Uniklinik LübeckProf. Dr. H. Schunkert 14. Stätisches Klinikum LüneburgProf. Dr. W. Kupper 15. Zentralklinikum SuhlProf. W. Haberbosch 16. Uni-Klinik RostockProf. Dr. C.Nienaber 17. Kreiskrankenhaus BergstrasseDr. W. Auch-Schwelk 18. Asklepios Klinik St. GeorgProf. Dr. K.H. Kuck 19. Klinikum DarmstadtProf Dr. G. Werner 20. Evangelisches Krankenhaus HolzmindenDr. C. Beythien Belgium: 1. AZ Sint-Jan AV BruggeDr. P. Coussement Participating Centers Ongoing Tirofiban In Myocardial Infarction Evaluation

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

8. Primary Residual ST segment deviation (>3mm) 1 hour after PCIResidual 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-upCombined occurrence of death, recurrent MI, urgent TVR or thrombotic bailout at 30 days follow-up Safety ( major bleeding)Safety ( major bleeding) EndpointsEndpoints Ongoing Tirofiban In Myocardial Infarction Evaluation

9. Baseline Data Ongoing Tirofiban In Myocardial Infarction Evaluation

10. Inclusion Site Ambulance95% Referral Center3% PCI center (ER)2% Ongoing Tirofiban In Myocardial Infarction Evaluation

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

12. Angiography and Reperfusion Ongoing Tirofiban In Myocardial Infarction Evaluation Placebo n=493 Tirofiban n=491 p- value Angio performed99.0%98.2%0.278 PCI90.0%87.6%0.235 CABG2.7%2.9%0.225 Conservative7.4%9.5%0.82

13. Ongoing Tirofiban In Myocardial Infarction Evaluation Results: Primary Endpoint Residual ST deviation at 60 min. mean ± SDPlaceboTirofibanp- value Readable ECG94.1%95.5%0.358 Residual ST - deviation (mm) 4.8 ±6.33.3 ± 4.30.002 > 3 mm ST-deviation44.3%36.6%0.026 normal ECG30.2%37.3%0.031

14. Cumulative ST- Deviation over Time Ongoing Tirofiban In Myocardial Infarction Evaluation 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 0.0020.0220.028 p=0.84 [mm]

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

16. 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 0.1110 Primary Endpoint Subgroups

17. 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 0,11 10 Residual ST > 3 mm (combined) Placebo betterTirofiban better Primary Endpoint Subgroups

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

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

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

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

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

23. SummarySummary Pre-Hospital initiation of tirofiban (HDB) improves ST resolution before and after primary PCIPre-Hospital initiation of tirofiban (HDB) improves ST 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 Infarction Evaluation

24. ConclusionsConclusions High dose tirofiban on top of clopidogrel (600mg) in the prehospital setting is safeHigh dose tirofiban on top of clopidogrel (600mg) in 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 Infarction Evaluation

25. Thank you ! Ongoing Tirofiban In Myocardial Infaction Evaluation

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

27. Placebo Controlled study (N=958) Primary End Point Relative 20% reduction: 50 to 40%Relative 20% reduction: 50 to 40% N=814 ( Alpha 0.05, power 80%), 20% loss, N=958N=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%)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%)55% power to detect a relative 40% difference in combined death/re- MI/urg TVR (7.5 to 4.5%) StatisticsStatistics Ongoing Tirofiban In Myocardial Infarction Evaluation

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

29. Secondary 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 MBGExploratory 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 - 2 Ongoing Tirofiban In Myocardial Infarction Evaluation