Gregory Piazza, MD, MS on behalf of the SEATTLE II Investigators March 30, 2014

1. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II) Gregory Piazza, MD, MS on behalf of the SEATTLE II Investigators March 30, 2014 Sponsored by the EKOS Corporation

2. Acute Pulmonary Embolism: A Spectrum of Risk In-Hospital Death or Clinical Deterioration 32% In-Hospital Mortality RV Dysfunction with +Troponin Unstable 3.4% In-Hospital Mortality RV Dysfunction OR +Troponin Stable Normal RV and Troponin Casazza F, et al. Thromb Res 2012;130:847 Becattini C, et al. CHEST 2013;144: 1539

3. Increased RV/LV Ratio on CT and PE-Related Mortality Trujillo-Santos J, et al. J Thromb Haemost 2013;11: 1823-1832

4. Intracranial Hemorrhage: Efficacy at the Cost of Safety

5. Objectives A prospective, single-arm, multicenter trial to: • Evaluate the efficacy of ultrasound-facilitated, catheter-directed low-dose fibrinolysis to reverse RV dysfunction as measured by CT-determined RV/LV diameter ratio in patients with acute massive and submassive PE • Assess the safety of ultrasound-facilitated, catheter-directed low-dose fibrinolysis in patients with acute massive and submassive PE

6. Patient Selection Main Inclusion Criteria: • Proximal PE on CT (filling defect in ≥ 1 main, lobar, or segmental pulmonary artery) AND • Age ≥ 18 years AND • PE symptom duration ≤ 14 days AND • Massive PE (syncope, systemic arterial hypotension, cardiogenic shock, or resuscitated cardiac arrest) OR • Submassive PE (RV/LV diameter ≥ 0.9 on contrast-enhanced chest CT) Main Exclusion Criteria: • Stroke/TIA, head trauma, or intracranial or intraspinal disease within 1 year • Active or recent (within 1 month) bleeding from a major organ • Major surgery within 7 days • Hematocrit < 30%, platelets < 100k/μL, INR > 3, aPTT > 50 seconds on no anticoagulation • Serum creatinine > 2 mg/dL • Clinician-determined high-risk for catastrophic bleeding • Hemodynamic instability despite medical therapy • Pregnancy

7. Study Overview Study Sites = 21 Total Trial Population = 150

8. Intervention Monitoring in intermediate care or ICU setting

9. Study Outcomes • Primary Efficacy: Change in core lab-measured RV/LV ratio from baseline to 48 hours as assessed by chest CT • Secondary Efficacy: Change in invasively measured PA systolic pressure from baseline to device removal and as estimated on 48-hour echocardiogram • Primary Safety: Adjudicated major bleeding within 72 hours of the start of the procedure • Secondary Safety: Adjudicated recurrent PE or death within 30 days of the procedure, or major technical procedural complications

10. Study Enrollment Patients

11. Baseline Characteristics

12. Characteristics of PE *Patients could have received more than one anticoagulant.

13. Procedural Characteristics *N = 150 patients (1 patient died before devices could be placed) **N = 285 devices attempted ***N = 278 devices placed

14. Outcomes: RV/LV Ratio p < 0.0001 1.55 1.13 RV/LV Ratio

15. Outcomes: PA Systolic Pressure p < 0.0001 p < 0.0001 51.4 37.5 36.9 Mean PA Systolic Pressure (mmHg)

16. Massive vs. Submassive PE p = 0.31 p = 0.61 0.51 14.3 0.43 12.6

17. Outcomes: Modified Miller Score p < 0.0001 22.5 15.8 Mean Modified Miller Score

18. Clinical Outcomes *All death, serious adverse, and bleeding events were adjudicated by an independent safety monitor. **N = 149 (1 patient lost to follow-up)

19. Discussion • We observed a 30% decrease in CT-measured RV/LV ratio over 48 hours in patients with massive and submassive PE treated with ultrasound-facilitated catheter-directed low-dose fibrinolysis. • Ultrasound-facilitated catheter-directed low-dose fibrinolysis rapidly relieved pulmonary artery obstruction and reduced pulmonary hypertension. • Ultrasound-facilitated catheter-directed low-dose fibrinolysis minimized the risk of intracranial hemorrhage.

20. Overcoming the Hurdle of Intracranial Hemorrhage

21. Limitations • The single-arm study design precluded direct comparison with the efficacy and safety of systemic fibrinolysis or anticoagulation alone. • Our study design did not allow for evaluation of clinical end points such as hemodynamic collapse or mortality.

22. Conclusions • Ultrasound-facilitated catheter-directed low-dose fibrinolysis for acute PE improves RV function and decreases pulmonary hypertension and angiographic obstruction. • By minimizing the risk of intracranial bleed, ultrasound-facilitated catheter-directed low-dose fibrinolysis represents a potential “game-changer” in treatment of high-risk PE patients.

23. SEATTLE II Investigators • Gregory Piazza, M.D., M.S. • Tod C. Engelhardt, M.D. • Keith M. Sterling, M.D. • Noah J. Jones, M.D. • John C. Gurley, M.D. • RohitBhatheja, M.D. • Robert Kennedy, M.D. • Nilesh Goswami, M.D. • Kannan Natarajan, M.D. • John Rundback, M.D. • ImmadSadiq, M.D. • Stephen K. Liu, M.D. • NarinderBhalla, M.D. • M. Laiq Raja, M.D. • Barry S. Weinstock, M.D. • Jacob Cynamon, M.D. • Fakhir F. Elmasri, M.D. • Mark J. Garcia M.D. • Mark Kumar, M.D. • Juan Ayerdi, M.D. • Peter Soukas, M.D. • William Kuo, M.D. • Samuel Z. Goldhaber, M.D. • Special thanks to: • Benjamin Hohlfelder, B.S. (Thrombosis Research Group)

24. Back-Up Slides

25. Rationale for Study Design • Timely enrollment in randomized controlled trials for PE has historically been problematic. • A single-arm design allowed for efficient evaluation of the safety and efficacy of ultrasound-facilitated, catheter-directed low-dose fibrinolysis for treatment of PE. • Our study provided clinicians performing ultrasound-accelerated catheter-directed low-dose fibrinolysis with a standardized protocol for the procedure, which had been performed with little standardization among operators. • Our study design allowed for more rigorous monitoring and reporting of adverse events. Meyer G, et al. N Engl J Med 2014; in press Kucher N, et al. Circulation 2014;129:479