2. Economic Burden of DVT, PE, PTS
Mean adjusted total annualized health care costs ranged from $31,270 for patients with a PE to $38,296 for patients with both a DVT and PE. 
The annual per-patient costs of managing PTS are estimated to be between $839 and $11,667 and an estimated 330,000 patients have PTS in the U.S.
O'Donnell, T. F., Jr., N. L. Browse, et al. (1977). "The socioeconomic effects of an iliofemoral venous thrombosis." J Surg Res 22(5):
MacDougall DA, Feliu AL, Boccuzzi SJ, Lin J. Economic burden of deep-vein thrombosis, pulmonary embolism, and post-thrombotic syndrome. Am J Health Syst Pharm. 2006;63(20 Suppl 6):S5-15.
Mahan CE, Holdsworth MT, Welch SM, Borrego M, Spyropoulos AC. Deep-vein thrombosis: a United States cost model for a preventable and costly adverse event. Thromb Haemost.106(3):

4. “While anticoagulation with heparin alone has little effect on improvement of RV size and performance within the first 24–48 hours, the extent of early RV recovery after low-dose catheter-directed thrombolysis appears comparable to that after standard dose systemic thrombolysis.
In a randomized, controlled clinical trial of 59 intermediate-risk patients, when compared with treatment by heparin alone, catheter-directed ultrasound-accelerated thrombolysis—administering 10 mg t-PA per treated lung over 15 hours—significantly reduced the subannular RV/LV dimension ratiobetween baseline and 24-hour follow-up without an increase in bleeding complications.”

7. INCIDENCE OF PE AND VTE Annual incidence Venous thromboembolism3
United States: 69 per 100,000/year1
Over 600,000 cases annually2
1-2 PE episodes per 1000 people, up to 10 per 1000 in the elderly population3-6
Venous thromboembolism3
PE commonly originates from lower limb deep vein thrombosis (DVT)
79% of patients presenting with PE have evidence of DVT
PE occurs in up to 50% of patients with proximal DVT
Overview of PE statistics
1. Silverstein et al. Arch intern Med 1998;158:
3. Tapson. N Engl J Med 2008;358(10):
5. Chunilal et al. JAMA 2003;290:2849–58
2. Wood et al. Chest 2002;121:
4. Geering et al. CMAJ 2012; 184(3):
6. Siccama et al. Ageing Res Rev 2011;10:304–13

8. 466 references

9. Definitions Submassive PE:
No systemic hypotension (systolic blood pressure>90 mm Hg) but with either RV dysfunction or myocardial necrosis.
RV dysfunction means the presence of at least 1 of the following:
RV dilation (RV / LV diameter > 0.9) or RV systolic dysfunction on echocardiography
RV dilation (RV / LV diameter > 0.9) on CT
BNP > 90 pg/mL or N-terminal pro-BNP > 500 pg/mL
Electrocardiographic changes (new complete or incomplete RBBB, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion)
Myocardial necrosis is defined as either of the following:
Elevation of troponin I (> 0.4 ng/mL) or — Elevation of troponin T (> 0.1 ng/mL)

10. Definitions Massive PE:
Sustained hypotension (SBP<90 mm Hg for 15 minutes or requiring inotropic support – no other cause)
Pulselessness, or
Persistent profound bradycardia (heart rate 40 bpm with signs or symptoms of shock).

11. Definitions Low-risk PE: Normotensive with Normal biomarker levels and
No RV dysfunction
Short- term mortality rates approaching <1%

12. Mortality from Pulmonary Embolism
EMPEROR: national, prospective, multicenter, observational registry 
30-day outcomes
 22 community and academic EDs
Low – risk PE : 1%
Submassive PE: 3%
Massive PE: 9 – 14%

13. Why treat sub-massive PE with anything more than anti-thrombins?
Pulmonary Artery Pressure
Persistent RV dysfunction

14. Prognostic importance of RV dysfunction at time of presentation
2454 consecutive pulmonary embolism patients at 52 hospitals in seven countries.
RV hypokinesis on baseline echo - 57% higher mortality rate at 3 months, even though most of the patients (88.9%) were hemodynamically stable.
Overall mortality rate at three months was 17.4%
7.9% of patients had recurrent PE within 3 months and of these, 46.8% died
Of the 2349 patients who were treated for PE, 2274 (97%) patients received heparin and 1782 (76%) oral anticoagulation. 304 (13%) were treated with
thrombolytic therapy, and 243 (10%) received inferior vena- cava filters. Catheter embolectomy and surgical embolectomy were each done in 15 patients.
Overall crude mortality rate at 3 months was 17·4%
Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353(9162):

15. “Despite modern methods for diagnosis and treatment, PE continues to have a high mortality rate at 3 months. 75% of the deaths occurred during the initial hospital admission for PE. These deaths are most probably due to recurrent PE, and the frequency might be lowered if more
intensive anticoagulation was used. ”

16. Prognostic Importance of Persistent RV dysfunction (RVD)
Retrospective Analysis of 301 Patients with first episode acute PE
146 (48.5%) of patients had evidence of RVD
87 of these patients showed complete RVD regression at discharge (23 underwent thrombolysis)
59 patients retained 1 or more signs of RVD at discharge (7 underwent thrombolysis).
Mean Follow-up was 3.1 ± 2.7 years with the following observations:
8 PE related deaths
6 of the 8 PE related deaths were in the persistent RVD group
Persistent RVD group mortality rate = 6/59 = 10.2%
No RVD group mortality rate = 2/155 = 1.3%
Patients with RVD persistence had increased likelihood of recurrent VTE (14/59, 24%) compared to those without RVD (15/155, 10%) or with RVD regression (3/87, 3%)
Patients with RVD not resolved prior to hospital discharge were 8-times more likely to have a recurrent PE and suffered more than 4-times the mortality rate than patients whose RVD resolved prior to discharge.
Grifoni S, Vanni S, Magazzini S, et al. Association of persistent right ventricular dysfunction at hospital discharge after acute pulmonary embolism with recurrent thromboembolic events. Arch Intern Med 2006; 166:

17. Importance of RV/LV ratio in submassive PE
950 / 1416 echo RV / LV ratios obtained
In patients with systolic BP ≥ 90 mmHg, the mortality rate was 3.3% in patients whose RV/LV ratio was ≥ 0.6 and 1.1% for those whose RV/LV ratio was < 0.6 (OR 2.66, p = 0.01)
Fremont B, Pacouret G, Jacobi D, Puglisi R, Charbonnier B, de Labriolle A. Prognostic value of echocardiographic right/left ventricular end-diastolic diameter ratio in patients with acute pulmonary embolism: results from a monocenter registry of 1,416 patients. Chest. 2008;133(2):

18. Mortality risk increases with stepwise increase in RV/LV Ratio
Retrospective analysis of 120 patients with hemodynamically stable PE and helical CT available for review.
CT signs of right ventricular dysfunction (RVD) (defined as RV/LV > 1.0) were seen in 69 patients (57.5%).
All were administered intravenous unfractionated heparin for at least 5 days
At three months, 18 (15%) patients had died, of which seven were PE related.
Risk of PE-related death correlated to an RV/LV ratio > 1.0
Van der Meer et al. Right Ventricular Dysfunction and Pulmonary Obstruction Index at Helical CT: Prediction of Clinical Outcome during 3-month Follow-up in Patients with Acute Pulmonary Embolism. Radiology 2005; 235:

19. Prospective Evaluation of RV function and Functional Status 6 months after acute submassive PE
Prospective observation of 200 normotensive patients with acute PE (CT angiography)
144 of 162 patients that returned for follow up at 6 months had been treated with heparin only and 18 had been treated with heparin plus alteplase
50 of the heparin only treated patients followed up at 6 months had RSVP ≥ 40 mmHg at diagnosis; 39 of those 50 had higher RVSP at 6 months than at baseline (27%)
Of these 39 patients with higher RVSP at 6 months, 18 (46%) had either dyspnea at rest or exercise intolerance
11 of the heparin plus alteplase treated patients followed up at 6 months had RVSP ≥40mm Hg at diagnosis; The RVSP at follow up was not higher than at time of diagnosis in any of the heparin plus alteplase treated patients
Kline J, Steuerwal M, Marchick M, Hernandex-Nino J, Rose G. Prospective Evaluation of Right Ventricular Function and Functional Status 6 Months after acute submassive pulmonary embolism. Chest 2009; 136:

20. Breakup 200 initial presentation  162 at six months
144/162 – Heparin only
18/162 – Heparin + tPA
50/144 had RVSP>40 at diagnosis
39/50 had RVSP> baseline at six months
18/39 NYHA 3
11/18 RVSP>40 at diagnosis
0/18 RVSP> baseline at six months

21. UFH vs. tPA
39 / 144 (27%) demonstrated an increase in RVSP at 6-month follow- up
18 (46%) of these 39 patients had either dyspnea (NYHA classification > II) or exercise intolerance (6-minute walk distance <330 m).
No patient treated with adjunctive alteplase demonstrated an increase in RVSP at 6-month follow-up.
Treat with Heparin:
1 in 4 chance of PHTN
1 in 8 chance NYHA 3

22. Thrombolysis treatment in submassive PE results in trend towards improved clinical outcomes and RV Function
Prospective study
72 Patients with first episode acute submassive PE and RV Dysfunction
Randomized to placebo versus alteplase, in addition to heparin.
tPA group showed a significant early improvement of RV function compared with heparin group as well as sustained improvement at 180 days.
tPA group % combined adverse events (mortality, RVD, major bleeding and DVT) vs. 45.7% in the heparin group (p < 0.005)
Thrombolysis treatment was associated with an increase in minor non-fatal bleeding events.
Echocardiogram was performed at admission, at 24, 48 and 72 hours, at discharge and at 3 and at 6 months after randomization.
Fasullo S, Scalzo S, Maringhini G, Ganci F, Cannizzaro S, Basile I, Cangemi D, Terrazzino G, Parrinello G, Sarullo F, Baglini R, Paterna S, Pasquale P. The American Journal of Medical Sciences (1):33-39.

24. Long term follow-up of patients with PE treated with IV thrombolytics
40 patients. Prospective Randomized Trial
Randomized to heparin or IV urokinase or streptokinase
Follow-up mean 7.4 years
At rest:
Mean PA pressure and PVR significantly higher in heparin treated group (22 vs 17 mmHg (P<0.05) and 351 vs 171 dynes s-1 cm-5 (p<0.02), respectively)
During exercise
Exercise PA pressure rose from 22 to 32 mmHg (p<0.01) and PVR rose from 351 to 437 dynes s-1 cm-5 (p<0.01) but not in the thrombolytic treated group
Sharma G, Folland E, McIntyre K, et al. Long-term benefit of thrombolytic therapy in patients with pulmonary embolism Vascular Medicine 2000; 5:91-95.

25. PEITHO
1006 normotensive patients with acute intermediate-risk PE (characterized by RV dysfunction) randomized to tenecteplase or placebo.
At 7-days
All-cause mortality: 1.2 % heparin/TNK vs. 1.8% heparin/placebo
Hemodynamic collapse: 1.6% - TNK versus 5.0% for placebo
More patients in the placebo-treated group required open-label thrombolysis than in the tenecteplase-treated group (4.6% versus 0.8%)
Non-intracranial major bleeding was 6.3% in the treatment group compared to 1.5% in the placebo group (p<0.001),
Hemorrhagic stroke occurred in 2% of tenecteplase-treated patients compared to 0.2% of placebo patients (p=0.003)
Randomized multicenter trial
Meyer G, et al. for the PEITHO Investigators. Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism. N Engl J Med 2014;370(15):

26. Intracranial Hemorrhage: Efficacy at the Cost of Safety
Study
Intracranial Hemorrhage (Fibrinolysis Group)
ICOPER
(Goldhaber SZ, et al. 1999)
9/304 (3%)
PEITHO
(Meyer G, et al. 2014)
10/506 (2%)

29. Contraindications to systemic fibrinolysis
Absolute
Relative
Age > 75 years
Current use of anticoagulation
Pregnancy
Noncompressible vascular punctures
Traumatic or prolonged cardiopulmonary resuscitation (>10 minutes)
Recent internal bleeding (within 2 to 4 weeks)
History of chronic, severe, and poorly controlled hypertension
Severe uncontrolled hypertension on presentation (systolic blood pressure >180 mmHg or diastolic blood pressure >110 mm Hg)
Dementia
Remote (>3 months) ischemic stroke;
Major surgery within 3 weeks.
Prior ICH
Known structural intracranial cerebrovascular disease (eg, arteriovenous malformation)
Known malignant intracranial neoplasm
Ischemic stroke within 3 months
Suspected aortic dissection, active bleeding or bleeding diathesis
Recent surgery encroaching on the spinal canal or brain, and
Recent significant closed-head or facial trauma with radiographic evidence of bony fracture or brain injury

30. First RCT for a catheter-based modality
ULTIMA: EKOS® to heparin in intermediate risk PE therapy
First RCT for a catheter-based modality
Primary Objective: Is fixed low-dose catheter-directed ultrasound accelerated thrombolysis superior to heparin alone in reversal of RV dilatation in submassive / intermediate risk PE
Kucher et al. Circulation. 2014;129:

31. EKOS® vs. heparin for the treatment of intermediate risk PE
Kucher et al. Circulation. 2014;129:

32. Greater RVD reduction with EKOS® with tPA + heparin than with heparin alone
Kucher et al. Circulation. 2014;129:

33. Echo findings with EKOS® with tPA + heparin than heparin alone
Kucher et al. Circulation. 2014;129:

34. No statistical difference in safety outcomes with EKOS® with tPA + heparin than heparin alone
Kucher et al. Circulation. 2014;129:

35. 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

36. SEATTLE II Ultrasound-facilitated fibrinolysis using EKOS®
If unilateral PE: tPA 1 mg/hr using one device for 24 hours
If bilateral PE: tPA 1 mg/hr per device (using two simultaneously) for 12 hours
Follow up at 48 +/- 6 hours
CT measurement of RV/LV ratio
Echocardiogram to estimate PA systolic pressure
Piazza G. “A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II).” American College of Cardiology 63rd Annual Scientific Session, Washington DC, March 30, 2014.

37. Patient Selection Main Inclusion Criteria: Main Exclusion 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

38. 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.

39. The SEATTLE II Study
Patient characteristics and treatment details N %
Total enrollment
150*
100%
Massive / Submassive PE
31 / 119
21% / 79%
History of previous DVT 30
20%
History of previous PE 15
10%
Concomitant use of antiplatelet agents 51
34%
Unilateral / Bilateral PE
20 / 130
13% / 87%
Total rtPA dose
23.7 ± 2.9 mg
* Denotes 1 patient died prior to treatment
Piazza G. “A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II).” American College of Cardiology 63rd Annual Scientific Session, Washington DC, March 30, 2014.

40. Reduced RV/LV ratio and Modified Miller Score at 48 hours post-EKOS®
Piazza G. “A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II).” American College of Cardiology 63rd Annual Scientific Session, Washington DC, March 30, 2014.

41. Reduced pulmonary artery pressure immediately post-procedure
Piazza G. “A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II).” American College of Cardiology 63rd Annual Scientific Session, Washington DC, March 30, 2014.

42. Zero cases of intracranial hemorrhage reported in the study
Clinical outcomes*
N = 150
Mean length of stay ± SD, days
8.8 ± 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 (%)
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)
Piazza G. “A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II).” American College of Cardiology 63rd Annual Scientific Session, Washington DC, March 30, 2014.

43. Infusion Catheter Ultrasonic Core Features 5.4 Fr catheter
EkoSonic® Endovascular System
Infusion Catheter
Ultrasonic Core
Central Coolant Lumen
Features
5.4 Fr catheter
106 and 135 cm working length
6, 12, 18, 24, 30, 40 and 50 cm treatment zones
Therapy Optimization Sensor
Drug Lumen
Guidewire or MSD (0.035” diameter)

44. Effect of Ultrasound on Thrombus
How ultrasonic energy unlocks the clot
Ultrasonic energy causes fibrin strands to thin, exposing plasminogen receptor sites and fibrin strands to loosen
Thrombus permeability and lytic penetration are dramatically increased
Ultrasound pressure waves force lytic agent deep into the clot and keep it there
WITHOUT ULTRASOUND
ENERGY
WITH ULTRASOUND
ENERGY
ULTRASOUND ENERGY
& THROMBOLYTIC
Braatan et al. Thrmob Haemost 1997;78:
Francis et al. Ultrasound in Medicine and Biology, 1995;21(5):
Soltani et al. Physics in Medicine and Biology, 2008; 53:

45. Overcoming the Hurdle of Intracranial Hemorrhage
Study
Intracranial 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%)

46. Limitations
Single-arm study design precluded direct comparison with the efficacy and safety of systemic fibrinolysis or anticoagulation alone.

47. Ekos vs. CDT
EKOS or CDT was performed in 15 (45%) and 18 (55%) procedures.
In the EKOS group, complete thrombus removal was achieved in 100% cases.
In the CDT cohort, complete or partial thrombus removal was accomplished in 7 (50%) and 2 (14%) cases, respectively.
Comparing treatment success based on thrombus removal, EKOS treatment resulted in an improved treatment outcome compared with the CDT group (p < .02). The mean time of thrombolysis in EKOS and CDT group was / and / hours, respectively (p = .03).
The mortality rate in the EKOS and CDT group was 9.1% and 14.2%, respectively (not significant).
Treatment-related hemorrhagic complication rates in the EKOS and CDT group were 0% and 21.4%, respectively . A significant reduction in Miller scores was noted in both groups following catheter-based interventions.
No significant difference in relative Miller score improvement was observed between groups.
Ultrasound-accelerated thrombolysis using the EkoSonic system is an effective treatment modality in patients with acute massive PE. 
Vascular Nov-Dec;17 Suppl 3:S Comparison of percutaneous ultrasound-accelerated thrombolysis versus catheter-directed thrombolysis in patients with acute massive pulmonary embolism. Lin PH1, Annambhotla S, Bechara CF, et al.

48. Ultrasound-assisted CDT is superior to anticoagulation alone in reversing RV dilatation in patients with intermediate-risk PE.
Available data suggest a low major bleeding rate following ultrasound-assisted thrombolysis, but clinical outcome studies are warranted to confirm a favourable safety profile.
For unstable patients with high-risk PE, ultrasound-assisted thrombolysis is a potentially promising technique.
In practice, ultrasound-assisted CDT may be indicated in selected patients with intermediate or high-risk PE if the bleeding risk under systemic thrombolysis is increased.
Ideally, these procedures are performed in experienced centres with around-the-clock availability of catheter therapy and surgical embolectomy

57. PE Programs Duke Wake Forest Rex Washington Hospital Center Columbia
UCLA Ronald Reagan
Prairie Heart and Vascular
University of Iowa
Detroit Medical Center / Wayne State University
Wash U
Christiana Healthcare, DE