1. F. Van de Werf, ACC 2013 STREAM STRATEGIC REPERFUSION EARLY AFTER MYOCARDIAL INFARCTION

2. F. Van de Werf, ACC 2013 Study grant from Boehringer Ingelheim to perform the STREAM trial, paid to the University of Leuven, Belgium Honoraria from Boehringer Ingelheim for membership of advisory board related to studies with dabigatran in patients with mechanical heart valves Frans Van de Werf: Disclosures

3. F. Van de Werf, ACC 2013 Large contemporary international registries continue to demonstrate persisting delays to primary PCI in STEMI patients first presenting to EMS or non-cath capable hospitals Subsequent transfer for primary PCI commonly results in reperfusion times exceeding current guideline recommendations These delays are associated with commensurate increases in morbidity and mortality BACKGROUND

4. F. Van de Werf, ACC 2013 A strategy of early fibrinolysis followed by coronary angiography within 6-24 hours or rescue PCI if needed was compared with standard primary PCI in STEMI patients with at least 2 mm ST-elevation in 2 contiguous leads presenting within 3 hours of symptom onset and unable to undergo primary PCI within 1 hour. STUDY AIM

5. F. Van de Werf, ACC 2013 SAMPLE SIZE AND STATISTICAL ANALYSES 1000 patients per group was planned Primary endpoint in PPCI group projected to be 15.0% No formal primary hypothesis / all analyses explorative Data reported on ITT basis with 95% CI Analysis performed independently KU Leuven, Belgium

6. F. Van de Werf, ACC 2013 no lytic STUDY PROTOCOL RANDOMIZATION 1:1 by IVRS, OPEN LABEL Ambulance/ER Primary endpoint: composite of all cause death or shock or CHF or reinfarction up to day 30 ECG at 90 min: ST resolution ≥ 50% Standard primary PCI Aspirin Clopidogrel: LD 300 mg + 75 mg QD Enoxaparin: 30 mg IV + 1 mg/kg SC Q12h Aspirin Clopidogrel: LD 300 mg + 75 mg QD Enoxaparin: 30 mg IV + 1 mg/kg SC Q12h Antiplatelet and antithrombin treatment according to local standards Antiplatelet and antithrombin treatment according to local standards angio >6 to 24 hrs PCI/CABG if indicated angio >6 to 24 hrs PCI/CABG if indicated immediate angio + rescue PCI if indicated YES NO Strategy A: pharmaco-invasive Strategy B: primary PCI Aspirin Clopidogrel: 75 mg QD Enoxaparin: 0.75 mg/kg SC Q12h Aspirin Clopidogrel: 75 mg QD Enoxaparin: 0.75 mg/kg SC Q12h PCI Hospital STEMI <3 hrs from onset symptoms, PPCI <60 min not possible, 2 mm ST-elevation in 2 leads ≥75y: ½ dose TNK <75y:full dose After 20% of the planned recruitment, the TNK dose was reduced by 50% among patients ≥75 years of age.

7. F. Van de Werf, ACC 2013 ENROLMENT AND KEY DATES 1892 patients randomized by 99 sites in 15 countries First patient in: March 19, 2008 Last patient in: July 26, 2012 Last patient out: Sep 7, 2012 Enrolment setting

8. F. Van de Werf, ACC 2013 PATIENTS PER COUNTRY

9. F. Van de Werf, ACC 2013 BASELINE CHARACTERISTICS (1) Data are mean (SD) or %

10. F. Van de Werf, ACC 2013 BASELINE CHARACTERISTICS (2) Data are %

11. F. Van de Werf, ACC 2013 62 Sx onset 1st Medical contact 61 1 Hour 2 Hours n=1892 29 Randomize IVRS 9 Rx TNK 3186 Sx onset Rx PPCI 100 min 178 min MEDIAN TIMES TO TREATMENT (min) 1st Medical contact 78 min difference Randomize IVRS

12. F. Van de Werf, ACC 2013 62 Sx onset 61 1 Hour 2 Hours 299 Rx TNK 3186 Sx onset Rx PPCI 100 min 178 min MEDIAN TIMES TO TREATMENT (min) 36% Rescue PCI at 2.2h n=1892 64% non-urgent cath at 17h 1st Medical contact Randomize IVRS 1st Medical contact Randomize IVRS

13. F. Van de Werf, ACC 2013 TIMI FLOW RATES TIMI before PCI TIMI after PCI P<0.001 P=0.41

14. F. Van de Werf, ACC 2013 INVASIVE PROCEDURES

15. F. Van de Werf, ACC 2013 PRIMARY ENDPOINT TNK 12.4% PPCI 14.3% TNK vs PPCI Relative Risk 0.86, 95%CI (0.68-1.09) p=0.24 Dth/Shock/CHF/ReMI (%) The 95% CI of the observed incidence in the pharmaco-invasive arm would exclude a 9% relative excess compared with PPCI

16. F. Van de Werf, ACC 2013 SINGLE ENDPOINTS UP TO 30 DAYS

17. F. Van de Werf, ACC 2013 > Subgroup analyses for primary endpoint within 30 days Relative Risk (95%CI) OVERALL Age <75 years ≥75 years P(interaction) 0.63 0.81 0.71 0.16 0.23 0.06 Time to randomization 0 to <2h ≥2h Male Female Systolic blood pressure <100 mmHg 100 to <140 mmHg 140 to <160 mmHg ≥160 mmHg Killip class I II-IV Anterior MI Inferior MI Other MI TNK BetterPPCI Better

18. F. Van de Werf, ACC 2013 Subgroup analyses for primary endpoint within 30 days Relative Risk (95%CI) Hypertension, Yes P(interaction) 0.34 0.24 0.68 0.13 Diabetes, Yes No Place of randomization, Ambulance Community hospital Before Amendment TNK BetterPPCI Better > > No Weight, <60 kg 60 to <90 kg ≥90 kg TIMI Risk Score, <5 points ≥5 points After Amendment 0.35 0.71 p=0.07

19. F. Van de Werf, ACC 2013 STROKE RATES

20. F. Van de Werf, ACC 2013 IN-HOSPITAL BLEEDING COMPLICATIONS

21. F. Van de Werf, ACC 2013 CONCLUSIONS A strategy of fibrinolysis with bolus tenecteplase and contemporary antithrombotic therapy given before transport to a PCI-capable hospital coupled with timely coronary angiography :  circumvents the need for an urgent procedure in about two thirds of fibrinolytic treated STEMI patients.  is associated with a small increased risk of intracranial bleeding.  is as effective as primary PCI in STEMI patients presenting within 3 hours of symptom onset who cannot undergo primary PCI within one hour of first medical contact.

22. F. Van de Werf, ACC 2013

23. ACKNOWLEDGEMENTS Statistical Analysis Committee E. Lesaffre K. Bogaerts A. Belmans G. Kalema E. Bluhmki Executive Committee F Van de Werf P. Armstrong A. Gershlick P. Goldstein R. Wilcox Boehringer- Ingelheim T. Danays E. Bluhmki A. Regelin G. Goetz DSMB K. Fox G. Montalescot C. Pollack J. Tijssen W. Weaver R. Brower Operations team A. Regelin T. Danays E. Bluhmki G. Goetz R. Delbé U. Fehse K. Vandenberghe C. Luys K. Broos K. Bogaerts T. Temple L. Merlini M. Mazzoleni M. Marangione Steering Committee K. HuberW. Schreiber P. SinnaeveP. Meert L. PiegasA. Carvalho R. WelshF. Rosell G. StegY. Lambert U. ZeymerH. Arntz J. NanasM. Ostojic C. FrescoA. Pesenti L. AabergeS. Halvorsen S. GrajekV. Sulimov J. Kendall T. Quinn J Adgey ECG Core Lab P. Armstrong Y. Fu R. Welsh P. Jagasia N. Dianati Maleki A. Awad C. Price T. Temple H Siha Y. Zheng Stroke Committee G. Wilms V. Thijs

24. F. Van de Werf, ACC 2013 CLINICAL OUTCOMES After amendment (N=1503) Before amendment (N=379)

25. F. Van de Werf, ACC 2013 CLINICAL OUTCOMES Before amendment (N=379)After amendment (N=1503)