Economic Burden of DVT, PE, PTS - PowerPoint Presentation

1.

2. Economic Burden of DVT, PE, PTSMean 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): 483-8.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):405-415.

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.”

5.

6.

7. Annual incidenceUnited States: 69 per 100,000/year1 Over 600,000 cases annually21-2 PE episodes per 1000 people, up to 10 per 1000 in the elderly population3-6Venous thromboembolism3PE 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 DVTINCIDENCE OF PE AND VTE1. Silverstein et al. Arch intern Med 1998;158:585-93.2. Wood et al. Chest 2002;121:877-905. 3. Tapson. N Engl J Med 2008;358(10):1037-1052.4. Geering et al. CMAJ 2012; 184(3):305-3105. Chunilal et al. JAMA 2003;290:2849–586. Siccama et al. Ageing Res Rev 2011;10:304–137

8. Incidence of clinical venous thromboembolismResponsible for the hospitalization of 250,000 Americans annually.Thomson Reuters national MarketScan(®) Commercial and Medicare databases (January 2002-December 2006)12.7 Million patients studiedOverall prevalence grew by 33.1% from 2002 – 2006. 950,000 in 2006 1.82 million in 205010% of hospital deaths can be attributed to PE.   Lloyd-Jones D, Adams RJ, Brown TM, et al; on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics: 2010 update: a report from the American Heart Association [published cor- rection appears in Circulation. 2010;121:e260]. Circulation. 2010;121: e46–e215. Deitelzweig SB, Johnson BH, Lin J, Schulman KL. Prevalence of clinical venous thromboembolism in the USA: current trends and future projections. Am J Hematol.86(2):217-220. Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):338S-400S.

9. 466 references

10. DefinitionsSubmassive 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/mLElectrocardiographic 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)

11. DefinitionsMassive 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).

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

13. Mortality from Pulmonary EmbolismLow – risk PE : 1%Submassive PE: 3%Massive PE: 9 – 14%

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

15. Prognostic importance of RV dysfunction at time of presentation2454 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% diedGoldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353(9162):1386-1389.

16. “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 moreintensive anticoagulation was used. ”

17. 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 RVD87 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; 166:2151-2156.

18. Importance of RV/LV ratio in submassive PE950 / 1416 echo RV / LV ratios obtainedIn 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):358-362.

19. Mortality risk increases with stepwise increase in RV/LV RatioRetrospective 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; 235:798-803.

20. Prospective Evaluation of RV function and Functional Status 6 months after acute submassive PEKline 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; 136:1202-1210.

21. Breakup200 initial presentation  162 at six months144/162 – Heparin only18/162 – Heparin + tPA 50/144 had RVSP>40 at diagnosis39/50 had RVSP> baseline at six months18/39 NYHA 318/162 – Heparin + tPA11/18 RVSP>40 at diagnosis0/18 RVSP> baseline at six months

22. UFH vs. tPA39 / 144 (27%) demonstrated an increase in RVSP at 6-month follow- up18 (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

23. Thrombolysis treatment in submassive PE results in trend towards improved clinical outcomes and RV FunctionProspective 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 - 5.4% 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.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 2011. 341(1):33-39.

24.

25. Long term follow-up of patients with PE treated with IV thrombolytics40 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 exerciseExercise 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.

26. PEITHO1006 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/placeboHemodynamic collapse: 1.6% - TNK versus 5.0% for placeboMore 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)Meyer G, et al. for the PEITHO Investigators. Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism. N Engl J Med 2014;370(15):1402-1411.

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

28.

29.

30. Contraindications to systemic fibrinolysis Absolute Prior ICH Known structural intracranial cerebrovascular disease (eg, arteriovenous malformation)Known malignant intracranial neoplasmIschemic stroke within 3 monthsSuspected aortic dissection, active bleeding or bleeding diathesisRecent surgery encroaching on the spinal canal or brain, and Recent significant closed-head or facial trauma with radiographic evidence of bony fracture or brain injuryRelativeAge > 75 yearsCurrent use of anticoagulation PregnancyNoncompressible vascular puncturesTraumatic or prolonged cardiopulmonary resuscitation (>10 minutes)Recent internal bleeding (within 2 to 4 weeks)History of chronic, severe, and poorly controlled hypertensionSevere uncontrolled hypertension on presentation (systolic blood pressure >180 mmHg or diastolic blood pressure >110 mm Hg)DementiaRemote (>3 months) ischemic stroke;Major surgery within 3 weeks.

31. Primary Objective:Is fixed low-dose catheter-directed ultrasound accelerated thrombolysis superior to heparin alone in reversal of RV dilatation in submassive / intermediate risk PEULTIMA: EKOS® to heparin in intermediate risk PE therapyKucher et al. Circulation. 2014;129:479-486First RCT for a catheter-based modality31

32. EKOS® vs. heparin for the treatment of intermediate risk PEKucher et al. Circulation. 2014;129:479-48632

33. Greater RVD reduction with EKOS® with tPA + heparin than with heparin alone Kucher et al. Circulation. 2014;129:479-48633

34. Echo findings with EKOS® with tPA + heparin than heparin alone Kucher et al. Circulation. 2014;129:479-48634

35. No statistical difference in safety outcomes with EKOS® with tPA + heparin than heparin aloneKucher et al. Circulation. 2014;129:479-48635

36. Fixed-dose, ultrasound-assisted catheter-directed thrombolysis EKOS® regimen superior to anticoagulation alone in improving RV dysfunction at 24 hours without an increase in bleeding complications.ULTIMA 36

37. Acute Pulmonary Embolism: A Spectrum of RiskUnstableStable32% In-Hospital Mortality3.4% In-Hospital MortalityCasazza F, et al. Thromb Res 2012;130:847Becattini C, et al. CHEST 2013;144: 1539In-Hospital Death or Clinical DeteriorationRV Dysfunction with +TroponinRV Dysfunction OR +TroponinNormal RV and Troponin

38. Ultrasound-facilitated fibrinolysis using EKOS®If unilateral PE: tPA 1 mg/hr using one device for 24 hoursIf bilateral PE: tPA 1 mg/hr per device (using two simultaneously) for 12 hoursFollow up at 48 +/- 6 hoursCT measurement of RV/LV ratioEchocardiogram to estimate PA systolic pressureSEATTLE IIPiazza 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, 2014.38

39. Patient SelectionMain Inclusion Criteria:Proximal PE on CT (filling defect in ≥ 1 main, lobar, or segmental pulmonary artery) ANDAge ≥ 18 years AND PE symptom duration ≤ 14 days AND Massive PE (syncope, systemic arterial hypotension, cardiogenic shock, or resuscitated cardiac arrest) ORSubmassive 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 yearActive or recent (within 1 month) bleeding from a major organMajor surgery within 7 daysHematocrit < 30%, platelets < 100k/μL, INR > 3, aPTT > 50 seconds on no anticoagulationSerum creatinine > 2 mg/dLClinician-determined high-risk for catastrophic bleedingHemodynamic instability despite medical therapyPregnancy

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

41. Primary EfficacyChange in core lab-measured RV/LV ratio from baseline to 48 hours as assessed by chest CTSecondary EfficacyChange in invasively measured PA systolic pressure from baseline to device removal and as estimated on 48-hour echocardiogramPrimary SafetyAdjudicated major bleeding within 72 hours of the start of the procedureThe SEATTLE II StudyEndpointsPiazza 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

42. The SEATTLE II StudyPatient characteristics and treatment detailsN%Total enrollment150*100%Massive / Submassive PE31 / 11921% / 79%History of previous DVT3020%History of previous PE1510%Concomitant use of antiplatelet agents5134%Unilateral / Bilateral PE20 / 13013% / 87%Total rtPA dose23.7 ± 2.9 mg* Denotes 1 patient died prior to treatmentPiazza 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

43. 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, 2014.43

44. Reduced pulmonary artery pressure immediately post-procedurePiazza 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, 2014.44

45. 45Zero cases of intracranial hemorrhage reported in the studyClinical outcomes* N = 150Mean length of stay ± SD, days8.8 ± 5In-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)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.

46. SEATTLE II studyCONCLUSIONUltrasound-facilitated, catheter-directed, low-dose fibrinolysis for acute PE improves RV function and decreases pulmonary hypertension and angiographic obstructionPiazza 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, 2014.46

47. EkoSonic® Endovascular SystemFeatures5.4 Fr catheter106 and 135 cm working length6, 12, 18, 24, 30, 40 and 50 cm treatment zonesInfusion CatheterUltrasonic CoreCentral Coolant LumenTherapy Optimization SensorDrug LumenGuidewire or MSD (0.035” diameter)47

48. WITH ULTRASOUNDENERGYWITHOUT ULTRASOUNDENERGY How ultrasonic energy unlocks the clotUltrasonic energy causes fibrin strands to thin, exposing plasminogen receptor sites and fibrin strands to loosenThrombus permeability and lytic penetration are dramatically increasedUltrasound pressure waves force lytic agent deep into the clot and keep it thereULTRASOUND ENERGY& THROMBOLYTICBraatan et al. Thrmob Haemost 1997;78:1063-8.Francis et al. Ultrasound in Medicine and Biology, 1995;21(5):419-24.Soltani et al. Physics in Medicine and Biology, 2008; 53:6837-47.48Effect of Ultrasound on Thrombus

49. Overcoming the Hurdle of Intracranial HemorrhageStudyIntracranial 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%)

50. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II)Gregory Piazza, MD, MSon behalf of the SEATTLE II InvestigatorsMarch 30, 2014

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

52. ObjectivesA 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 PEAssess the safety of ultrasound-facilitated, catheter-directed low-dose fibrinolysis in patients with acute massive and submassive PE

53. Study OverviewStudy Sites = 21Total Trial Population = 150

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

55. Baseline CharacteristicsPatient Demographics N = 150Mean age ± SD, years59 ± 16.1Mean BMI ± SD, kg/m235.6 ± 9.1Female gender , n (%)77 (51.3)Race/Ethnicity, n (%)CaucasianAfrican AmericanHispanic119 (79.3)22 (14.7)9 (6)Co-morbid Conditions, n (%)N = 150Concomitant use of antiplatelet agents52 (34.7)Immobility within 30 days of PE45 (30)Diabetes mellitus42 (28)Previous DVT30 (20)Previous PE15 (10)

56. Characteristics of PECharacteristics of PE, n (%)N = 150Duration of symptoms≤14 days>14 days149 (99.3)1 (0.7)Any symptoms of PE150 (100)PE subtypeSubmassiveMassive119 (79.3)31 (20.7)Pre-procedure anticoagulation*Intravenous unfractionated heparinEnoxaparinWarfarinOtherNone76 (50.7)54 (36)16 (10.7)7 (4.7)24 (16)*Patients could have received more than one anticoagulant.

57. Procedural CharacteristicsProcedural CharacteristicsMean dose of t-PA ± SD*, mg23.7 ± 2.9Successful device placement**, n (%)278 (97.5)Access sites***, n (%)Right femoral veinLeft femoral veinRight internal jugular veinOther177 (63.7)61 (21.9)31 (11.2)9 (3.2)Number of devices per patient*, n (%)0121 (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

58. Outcomes: RV/LV Ratio1.551.13RV/LV Ratiop < 0.0001

59. Outcomes: PA Systolic PressureMean PA Systolic Pressure (mmHg)51.436.937.5p < 0.0001p < 0.0001

60. Massive vs. Submassive PE0.43p = 0.31p = 0.6114.312.60.51

61. Outcomes: Modified Miller Score22.515.8p < 0.0001Mean Modified Miller Score

62. Clinical OutcomesClinical outcomes*N = 150Mean length of stay ± SD, days8.8 ± 5In-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)

63. Discussion30% 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.

64. Overcoming the Hurdle of Intracranial HemorrhageStudyIntracranial 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%)

65. LimitationsSingle-arm study design precluded direct comparison with the efficacy and safety of systemic fibrinolysis or anticoagulation alone.

66. Ekos vs. CDTEKOS 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 17.4 +/- 5.23 and 25.3 +/- 7.35 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. 2009 Nov-Dec;17 Suppl 3:S137-47. 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.

67. 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

68.

69.

70.

71.

72.

73.

74.

75.

76. PE ProgramsDukeWake ForestRexWashington Hospital CenterColumbiaUCLA Ronald ReaganPrairie Heart and VascularUniversity of IowaDetroit Medical Center / Wayne State UniversityWash UChristiana Healthcare, DE