Pulmonary Embolism Thrombolysis Study an investigator-initiated, investigator-sponsored trial

1. Pulmonary Embolism Thrombolysis Studyan investigator-initiated, investigator-sponsored trial The PEITH Investigators ClinicalTrials.gov # NCT00639743 EudraCT # 2006-005328-18

2. Rationale: risk-adjusted treatment of acute PE Thrombolysis?

3. Primary To investigate the clinical benefits (efficacy) ofthrombolysis with tenecteplase over placebo in normotensive patients with acute intermediate-risk PE (both treatment arms receive standard heparin anticoagulation) Secondary To assess the safety of tenecteplase in patients with intermediate-risk PE PEITHO: Objectives

4. PEITHO: Primary outcome • All-cause mortality or • Hemodynamic collapse • within 7 days of randomization, defined as: • need for cardiopulmonary resuscitation • or • systolic BP < 90 mm Hg for ≥15 min ordrop by ≥ 40 mm Hg for ≥15 min with end organ hypoperfusion (cold extremities, urinary output < 30 mL/h, mental confusion) • or • need for catecholamines to maintain adequate organ perfusion and a systolic BP of >90 mm Hg

5. PEITHO: Secondary efficacy and safety outcomes • Secondary end points: • All-cause mortality within 7 days of randomization • Hemodynamic collapse within 7 days of randomization • Confirmed symptomatic pulmonary embolism recurrence within 7 days • All-cause mortality within 30 days of randomization • Safety endpoints • Non-intracranial major bleeding within 7 days • Total strokes (intracranial hemorrhage or ischemic stroke) within 7 days • Serious adverse events (SAE) within 30 days All end points were adjudicated by an independent 3-member Clinical Events Committee (CEC)

6. PEITHO: Overview of study design Confirmed acute symptomatic PE Primary Outcome, Secondary Outcomes TNK Absence of hemodynamic collapse Seconray Outomes, SAE UFH, LMWH or Fondaparinux UFH infusion DOUBLE BLIND Confirmed RV dysfunction + myocardial injury VKA <2 h R Placebo UFH, LMWH or Fondaparinux UFH infusion VKA UFH bolus i.v. Day 2 Day 7 Day 30 ClinicalTrials.gov # NCT00639743 EudraCT # 2006-005328-18 S Konstantinides for the PEITHO Steering Committee. Am Heart J 2012;163:33-38.e1

7. PEITHO: Analyzed population Tenecteplase Placebo Randomized (N=1006) 506 500 1 ICF unavail. ITT Population 506 499 Safety population* 506 499 *all ITT patients received study medication First Patient In: November 2007; Last Patient Out: August 2012 The PEITHO Investigators

8. PEITHO: Baseline characteristics The PEITHO Investigators

9. PEITHO: Diagnostic and risk stratification tests The PEITHO Investigators

10. PEITHO outcomes

11. PEITHO: Primary efficacy outcome 0.23 0.44 0.88 0 1.00 2.00 Odds ratio Thrombolysis superior ITT population The PEITHO Investigators

12. PEITHO: Analysis of primary efficacy outcome ITT population The PEITHO Investigators

13. PEITHO: Other clinical outcomes (within 7 days) ITT population The PEITHO Investigators

14. PEITHO: Safety outcomes (within 7 days of randomization) ITT population The PEITHO Investigators

15. PEITHO: Safety outcomes (2) ITT population The PEITHO Investigators

16. PEITHO: Causes of death (within 30 days of randomization) ITT population The PEITHO Investigators

17. PEITHO: Primary end point according to age Age ≤ 75 years 0.12 0.33 0.85 0 1.00 2.00 Odds ratio Age >75 years 0.63 1.66 0.23 0 1.00 2.00 Odds ratio ITT population The PEITHO Investigators

18. PEITHO: Efficacy versus safety according to age ≤ 75 years >75 years Death or hemodynamiccollapse (primary EP) % Strokewithoutprimary EP (notleadingtodeathorhemodynamiccollapse) placebo TNK placebo TNK N 335 344 164 162 ITT population The PEITHO Investigators

19. PEITHO: Conclusions In patients with intermediate-risk pulmonary embolism, intravenous bolus tenecteplase significantly reduced the primary end point of death or hemodynamic collapse within 7 days of randomization. The results of PEITHO justify the concept of risk stratification of normotensive patients with acute PE. They confirm the notion that early “advanced” (recanalization) treatment prevents clinical deterioration in patients with evidence of right ventricular dysfunction and myocardial injury. In PEITHO, the benefits of thrombolysis came at the cost of a significantly increased risk of major, particularly intracranial, hemorrhage. The patient’s age should be taken into account when weighing the expected benefits versus risks of systemic thrombolysis in clinical practice.

20. PEITHO: Organization Irene M. Lang Austria Franck Verschuren Belgium Hélène Bouvaist France Thierry Danays (non-voting) France Nicolas Meneveau France Gerard Pacouret France Mustapha Sebbane France Jan Beyer-Westendorf Germany Claudia Dellas Germany Klaus Empen Germany Annette Geibel Germany Christian Kupatt Germany Sebastian Schellong Germany Holger Thiele Germany Benjamin Brenner Israel Co-Chairmen (Principal Investigators) • Stavros Konstantinides, Germany/Greece • Guy Meyer, France Data Safety Monitoring Board • Thomas Meinertz, Germany (Chair) • Frans van de Werf, Belgium • Arnaud Perrier, Switzerland Trial Statistician • Eric Vicaut, France Critical Events Adjudication Committee • MareikeLankeit, Germany (Chair) • Philippe Girard, France • Olivier Sanchez, France Sponsor’s Representative: • Philippe Gallula, France Steering Committee Members • Giancarlo Agnelli Italy • Cecilia Becattini Italy • NazzarenoGaliè Italy • MatteoRugolotto Italy • Aldo Salvi Italy • Piotr PruszczykPoland • Adam Torbicki Poland • Ana Franca Portugal • AntoniuPetris Romania • Gabriel Tatu-Chitoiu Romania • BranislavStefanovic Serbia • MatijaKozak Slovenia • David Jiménez Castro Spain • Nils KucherSwitzerland • Samuel Z. Goldhaber United States

21. PEITHO: Investigators PEITHO Investigators

22. PEITHO: Acknowledgements Study CRO • Pierrel Research Special thanks to: • Laurence Guery, France • Erich Bluhmki, Germany • Gudrun Heinrichs, Germany • AnkeHallmann, Germany • Anja Kronenberg, Germany • Raoul Stahrenberg, Germany • Jeannette Veuhoff, Germany • Cinzia Nitti, Italy • Marco Villa, Italy • MaciejKostrubiec, Poland

24. PEITHO: Inclusion criteria • Age ≥ 18 years • Acute PE confirmed by: ù • lung scan, or • spiral CT, or • pulmonary angiogram • RV dysfunction plus myocardial injury: a) echocardiography or CT PLUS b) positive troponin I or T test

25. PEITHO: Key exclusion criteria Hemodynamic collapse at presentation (high-risk PE); Known significant bleeding risk Administration of thrombolytic agents within the 4 previous days Vena cava filter insertion or pulmonary thrombectomy within the 4 previous days Known coagulation disorder (including vitamin K antagonist) Treatment with an investigational drug under another study protocol in the 7 previous days Previous enrollment in this study Any other condition that the investigator feels would place the patient at increased risk of the investigational therapy is initiated

26. Weight-adapted bolus of TNK (or placebo) Weight (kg)Dose in mgDose in unitsDose in ml <60 30 mg 6000 U 6 ml >60 to <70 35 mg 7000 U 7 ml >70 to <80 40 mg 8000 U 8 ml >80 to <90 45 mg 9000 U 9 ml >90 50 mg 10000 U 10 ml

27. PEITHO: Causes of death (within 7 days of randomization) ITT population The PEITHO Investigators