1. Ultrasound Assisted Thrombolysis for Massive and Submassive Pulmonary Embolism Scott M Lilly, MD PhD Interventional Cardiology Fellows School August 15 th, 2014

2. Acknowledgements  Peter Bittenbender, MD  Ray Magorien, MD  Michael Bray, EKOS Corporation

3. Outline  Background and Definitions  How to Determine Risk  Treatment of High Risk patients  Practical Points and Program Experience

4. Background and Definitions  300k-600k per year  1-2 per 1000 people, or as high as 1 in 100 if > 80  10-30% overall 30 day mortality  Sudden death is presenting symptom in ~ 25%  2012: 166,665 primary admissions for PE  In-hospital mortality ~ 3%  Most commonly from lower extremity DVT  Evidence of DVT in > 50% 4 cdc.gov; Agency for Healthcare Research and Quality

5. Massive PESubmassive PEMinor/Nonmassive PE High riskModerate/intermediate riskLow risk Sustained hypotension (systolic BP <90 mmHg for  15 min) Inotropic support Pulseless Persistent profound bradycardia (HR <40 bpm with signs or symptoms of shock) Systemically normotensive (systolic BP  90 mmHg) RV dysfunction Myocardial necrosis Systemically normotensive (systolic BP  90 mmHg) No RV dysfunction No myocardial necrosis RV dysfunction RV/LV ratio > 0.9 or RV systolic dysfunction on echo RV/LV ratio > 0.9 on CT Elevation of BNP (>90 pg/mL) Elevation of NTpro-BNP (>500 pg/mL) ECG changes: new complete or incomplete RBBB anteroseptal ST elevation or depression anteroseptal T-wave inversion Jaff et al. Circulation 2011;123(16):1788-1830. LV RV Jaff et al. Circulation 2011;123(16):1788-1830. Background and Definitions

6. Massive PE [High risk] 5% PE population Submassive PE [Moderate risk] 40% PE population Minor PE [Low risk] 55% PE population Massive PE [High risk] 5% PE population Minor PE [Low risk] 55% PE population

7. Outline  Background and Definitions  How to Determine Risk  Treatment of High Risk patients  Practical Points and Program Experience

8. Massive PESubmassive PEMinor/Nonmassive PE High riskModerate/intermediate riskLow risk Sustained hypotension (systolic BP <90 mmHg for  15 min) Inotropic support Pulseless Persistent profound bradycardia (HR <40 bpm with signs or symptoms of shock) Systemically normotensive (systolic BP  90 mmHg) RV dysfunction Myocardial necrosis Systemically normotensive (systolic BP  90 mmHg) No RV dysfunction No myocardial necrosis Jaff et al. Circulation 2011;123(16):1788-1830. How to Determine Risk Mortality In hospital ~ 25% (MAPPET) 90-day ~ 50% (ICOPER) ?

9. Massive PESubmassive PEMinor/Nonmassive PE High riskModerate/intermediate riskLow risk Sustained hypotension (systolic BP <90 mmHg for  15 min) Inotropic support Pulseless Persistent profound bradycardia (HR <40 bpm with signs or symptoms of shock) Systemically normotensive (systolic BP  90 mmHg) RV dysfunction Myocardial necrosis Systemically normotensive (systolic BP  90 mmHg) No RV dysfunction No myocardial necrosis Jaff et al. Circulation 2011;123(16):1788-1830. How to Determine Risk

10. 10 −Registry of 1,416 patients −Mortality rate: 1.9% if RV/LV ratio < 0.9 6.6% if RV/LV ratio ≥ 0.9 Fremont et al. CHEST 2008;133:358-362 How to Determine Risk

11. 11 −Retrospective analysis of 120 patients with hemodynamically stable PE based on chest CT −PE-related mortality at 3 months:  17% if RV/LV ≥ 1.5  8% if 1.0 ≤ RV/LV < 1.5  0% if RV/LV < 1.0 Van der Meer et al. Radiology 2005; 235:798-803. How to Determine Risk

12. 12 −Retrospective analysis of 63 patients with chest CT −Adverse event rate at 30 days:  80.3% if RV/LV ratio > 0.9  51.3% if RV/LV ratio ≤ 0.9 Quiroz et. al. Circulation. 2004;109:2401-2404 How to Determine Risk

13. Risk Stratification *ACC/AHA Guidelines 2011Circulation 2006;113:577-82

14. Outline  Background and Definitions  How to Determine Risk  Treatment of High Risk patients  Practical Points and Program Experience

15. Degree of PETreatment*Bleeding Risk Non-MassiveHeparin (I)Less Sub-MassiveLytics (IIb) MassiveLytics (IIa)More 20% risk of major bleeding 3% risk of intracranial hemorrhage *ACC/AHA Guidelines 2011Circulation 2006;113:577-82 Treatment of High Risk patients

16. *ACC/AHA Guidelines 2011Circulation 2006;113:577-82 Treatment of High Risk patients

17. 17Study Intracranial Hemorrhage (Fibrinolysis Group) ICOPER (Goldhaber SZ, et al. 1999) 9/304 (3%) PEITHO (Meyer G, et al. 2014) 10/506 (2%) Treatment of High Risk patients

18. Status of Trials Treatment of High Risk patients

21. The ULTIMA Trial A Prospective, Randomized, Controlled Study of Ultrasound Accelerated Thrombolysis for the Treatment of Acute Pulmonary Embolism Annual Meeting of the American College of Cardiology, March 9, 2013 Treatment of High Risk patients

22. 22 Hypothesis: Ultrasound-assisted, catheter-directed thrombolysis is superior to treatment with heparin alone for reversing RV enlargement within 24 hours ULTrasound Accelerated ThrombolysIs of PulMonAry Embolism The ULTIMA Trial Treatment of High Risk patients

23. 23 Symptoms < 14 days No hemodynamic collapse at presentation No active bleeding Acute symptomatic PE confirmed by contrast-enhanced chest CT with embolus located in at least one main or proximal lower lobe pulmonary artery RV/LV ratio > 1 on echocardiography Enrollment Criteria The ULTIMA Trial Treatment of High Risk patients

24. EKOS + HeparinHeparin p-value N = 30N = 29 Age, mean ± SD64 ± 1562 ± 13 0.33 Body mass index, mean ± SD31 ± 729 ± 7 0.28 Women1963%1241% 0.12 Coronary artery disease27%13% 1.00 Tobacco use414%724% 0.50 Diabetes mellitus620%414% 0.73 Cancer517%27% 0.42 Renal insufficiency413%517% 0.73 Previous deep vein thrombosis 413%828% 0.21 Previous pulmonary embolism413%27% 0.67 24 The ULTIMA Trial Treatment of High Risk patients Nils Kutcher, ACC.13

25. 25 EKOS + HeparinHeparin p-value N = 30N = 29 Troponin test positive, n (%) 16/20 (80%)17/22 (77%) 1.00 Pulmonary occlusion score (CT) 1, mean ± SD 26 ± 724 ± 8 0.24 Pulmonary occlusion score (CT) 1, median (min-max) 26 (9-36)22 (13-38) 1 Qanadli Am J Roentgenology 2001;176:1415-20 Pulmonary occlusion score 1 Multiply score points for non- occlusive embolus by one Multiply score points for occlusive embolus by two Maximum score is 40. 20 10 3 2 5 1 1 2 1 1 1 1 1 1 1 1 1 1 1 1 5 3 11 1 1 1 1 1 The ULTIMA Trial Treatment of High Risk patients Nils Kutcher, ACC.13

26. EKOS + Heparin N = 30 Heparin N = 29 p-value Total heparin dose from randomization to 24 hours, IU30939 ± 790734277 ± 56320.08 Technical success device placement100%- Device placement time, minutes, median (min-max) 42 (15 – 102) - Dual device procedure25 (83%)- Total rt-PA dose two devices, mg20.7 ± 2.5- Single device procedure5 (17%)- Total rt-PA dose single device, mg12.2 ± 3.8- Length of stay in ICU/IMC, days2.6 ± 1.31.7 ± 1.30.01 Length of hospital stay, days8.8 ± 3.58.7 ± 3.90.88 26 The ULTIMA Trial Treatment of High Risk patients Nils Kutcher, ACC.13

27. 27 RV/LV Ratio (Echocardiography) EKOS + Heparin Heparin Alone The ULTIMA Trial Treatment of High Risk patients Nils Kutcher, ACC.13

28. Right Ventricular Dysfunction The ULTIMA Trial Treatment of High Risk patients Nils Kutcher, ACC.13

29. 29 Clinical outcomes at 90 days EKOS + HeparinHeparin p-value N = 30N = 29 Death00%1*3% 0.49 Recurrent venous thromboembolism00%0 1.00 Major bleeding00%0 1.00 Minor bleeding 3**10%1§1§ 3% 0.61 rehospitalization and death from advanced pancreatic cancer ** two patients with transient mild hemoptysis without medical intervention, one patient with groin hematoma requiring manual compression § one patient with transient anal bleeding following endoscopic removal of colon polyp The ULTIMA Trial Treatment of High Risk patients

30. Systemic Lytics vs EKOS Systemic Lytics v Heparin EKOS v Heparin Total Lytics Dose100mg20.7mg (12.2mg) Mortality5.9% -> 4.3%1/29 -> 0/30 RV SizeImproved RV FunctionImproved Major Bleeding20%0/30 ICH3%0/30

31. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II) The SEATTLE II Trial Treatment of High Risk patients

32. The SEATTLE II Trial Treatment of High Risk patients 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

33. 33 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 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 The SEATTLE II Trial Treatment of High Risk patients

34. 34 The SEATTLE II Trial Treatment of High Risk patients Procedure Completion Post-Procedure Right Heart Catheter Measurements Catheter Removal Ultrasound-Facilitated, Low-Dose, Catheter-Directed Fibrinolysis t-PA Infusion Activation of high frequency, low power ultrasound Baseline Right Heart Catheter Measurements Including pulmonary artery systolic pressure Catheter Placement and Treatment Based on Extent of Disease Unilateral: 1 catheter infusing t-PA 1 mg/hour for 24 hours Bilateral: 2 catheters infusing t-PA 1 mg/hour/catheter for 12 hours Standard Anticoagulation for PE UFH goal PTT 40-60 sec during procedure

35. 35 The SEATTLE II Trial Treatment of High Risk patients Procedural Characteristics Mean dose of t-PA ± SD*, mg23.7 ± 2.9 Successful device placement**, n (%)278 (97.5) Access sites***, n (%) Right femoral vein Left femoral vein Right internal jugular vein Other 177 (63.7) 61 (21.9) 31 (11.2) 9 (3.2) Number of devices per patient*, n (%) 0 1 2 1 (0.7) 20 (13.3) 129 (86) Completed infusion of t-PA***, n (%)272 (97.8) *N = 150 patients (1 patient died before devices could be placed) **N = 285 devices attempted ***N = 278 devices placed

36. 36 The SEATTLE II Trial Treatment of High Risk patients Characteristics of PE, n (%)N = 150 Duration of symptoms ≤14 days >14 days 149 (99.3) 1 (0.7) Any symptoms of PE150 (100) PE subtype Submassive Massive 119 (79.3) 31 (20.7) Pre-procedure anticoagulation* Intravenous unfractionated heparin Enoxaparin Warfarin Other None 76 (50.7) 54 (36) 16 (10.7) 7 (4.7) 24 (16) *Patients could have received more than one anticoagulant.

37. 37 The SEATTLE II Trial Treatment of High Risk patients RV to LV Ratio

38. 38 0.43 p = 0.31 p = 0.61 14.3 12.6 0.51 The SEATTLE II Trial Treatment of High Risk patients

39. 39 The SEATTLE II Trial Treatment of High Risk patients Clinical outcomes*N = 150 Mean length of stay ± SD, days8.8 ± 5 In-hospital death, n (%)3 (2) 30-day mortality**, n (%)4 (2.7) Serious adverse events due to device, n (%)2 (1.3) Serious adverse events due to t-PA, n (%)2 (1.3) IVC filter placed, n (%)24 (16) Major bleeding within 30 days**, n (%) GUSTO moderate** GUSTO severe** 17 (11.4) 16 (10.7) 1 (0.7) Intracranial hemorrhage, n (%)0 (0) *All death, serious adverse, and bleeding events were adjudicated by an independent safety monitor. **N = 149 (1 patient lost to follow-up)

40. 40 StudyIntracranial Hemorrhage (Fibrinolysis Group) ICOPER (Goldhaber SZ, et al. 1999) 9/304 (3%) PEITHO (Meyer G, et al. 2014) 10/506 (2%) SEATTLE II (Piazza G, et al. 2014) 0/150 (0%) The SEATTLE II Trial Treatment of High Risk patients

41.  Lysis vs Placebo  13 placebo controlled, randomized trials of lysis vs placebo  Minority for massive PE, total 480 patients.  Variable drugs, dosing, timing and adjunctive therapies  No independent mortality effect  Meta-analyses reduction in death/recurrent PE  Improvement in RV size/function, mPA pressures  EKOS v Heparin  No study large enough to evaluate death/recurrent PE  Improved RV size/function at 24hrs, catch up at 90days  Improved RV function at 90 days Status of Trials Treatment of High Risk patients

42. Outline  Background and Definitions  How to Determine Risk  Treatment of High Risk patients  Practical Points, Program Experience

43. Who is an EKOS Candidate?  Large, Central PE – symptoms <14 days  SBP<90 (not responsive to fluids)  Need for inotrope  HR<40 w/ s/s Shock  PEA (after return of circulation)  RV:LV ratio > 1.0 (CTPE)  RV:LV ratio > 1.0 (TTE)  Signs of RV dysfxn (TTE) MASSIVE SUBMASSIVE Activate a PE Alert by dialing the Transfer Center Hotline phone number: 366-8111

44. 44 The PE Guideline is Located on One Source Listed under “Venous Thromboembolism”