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New Treatment Options for Pulmonary Embolism

New Treatment Options for Pulmonary Embolism. EKOS and EkoSonic are registered trademarks and Acoustic Pulse Thrombolysis is a trademark of EKOS Corporation, a BTG International group company. BTG and the BTG roundel logo are registered trademarks. CE-EKO-1800045.

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New Treatment Options for Pulmonary Embolism

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  1. New Treatment Options for Pulmonary Embolism EKOS and EkoSonic are registered trademarks and Acoustic Pulse Thrombolysis is a trademark of EKOS Corporation, a BTG International group company. BTG and the BTG roundel logo are registered trademarks. CE-EKO-1800045

  2. EKOS Control Unit 4.0 + Clinical Evidence =Simplifying Thrombolysis with EKOS therapy • EKOS CU4.0 • Manage 2 EKOS™ DevicessimplifyingBilateral PE1 • It integrateseasilyintohospital workflow1 • Speeds up set up time as uses step-by-step instructions1 • Zero interruption in therapywithbuilt-in batterymakesiteasier to transport the patient fromlab to ward1 • Only proven solution with long term evidence • Over 40k PE patients treated with EKOS1 • 866 patients treated in 21 EKOS PE studies2 • Very low mortality & bleeding rates3 • Very low tPA dose & short duration3 • Significant improvements in QoL3 • Bilateral PE (VTE) treatment, Simplified • Flexibility • Safety • Economic Efficiencies 1Data on file. 2Mangi M et al. Cureus 2017;9:e1492. 3Sterling, K. “Long-term Results of the OPTALYSE PE trial” as presented at the International Symposium on Endovascular Therapy (ISET) meeting, Hollywood, FL Feb 2018.

  3. EkoSonic™ Endovascular SystemFDA clearance • THE EKOSONIC™ENDOVASCULAR SYSTEM IS INDICATED FOR: • Controlled and selective infusion of physician-specified fluids, including thrombolytics, into the peripheral vasculature • Infusion of solutions into the pulmonary arteries • The ultrasound facilitated, controlled and selective infusion of physician-specified fluids, including thrombolytics, into the vasculature for the treatment of pulmonary embolism Warnings, precautions, and potential complications, and contraindications, can be found in the Instructions For Use (IFU)Caution: Federal (USA) law restricts these devices to sale by or on the order of a physician.

  4. EkoSonic™ Endovascular SystemCE Mark • THE EKOSONIC™ENDOVASCULAR SYSTEM IS INDICATED FOR: • Controlled and selective infusion of physician-specified fluids, including thrombolytics, into the peripheral vasculature • Intended for the treatment of pulmonary embolism patients with ≥ 50% clot burden in one or both main pulmonary arteries or lobar pulmonary arteries, and evidence of right heart dysfunction based on right heart pressures (mean pulmonary artery pressure ≥ 25 mmHg) or echocardiographic evaluation. Warnings, precautions, and potential complications, and contraindications, can be found in the Instructions For Use (IFU)Caution: Federal (USA) law restricts these devices to sale by or on the order of a physician.

  5. EkoSonic™ Endovascular SystemFeatures • 5.4 Fr catheter • 106 and 135 cm working length • 6, 12, 18, 24, 30, 40 and 50 cm treatment zones Central Coolant Lumen Infusion Catheter Radiopaque marker Therapy Optimization Sensor Ultrasound transducer Ultrasonic Core Drug Lumen (x 3) Guidewire or Ultrasonic Core (0.035” diameter)

  6. EKOS™ Control System 4.0 Components • EKOS™ Control Unit4.0 • Connector Interface Cables (CICs) • Power cord Features • Manages two EKOS ™ devices simultaneously. • Touchscreen displays clear instructions and color coded screens for easy set-up, operation & troubleshooting. • Controls & monitors output power and temperature of the ultrasound transducers. EKOS™ Control Unit 4.0 with built-in battery and mounting bracket

  7. Acoustic Pulse Thrombolysis™ treatmentMechanism of action Active Drug Delivery Drug is actively driven into clot by “Acoustic Streaming” Fibrin Separation Ultrasound separates fibrin without fragmentation of emboli Acoustic streaming drives lytic into clot Fibrin without Ultrasound Fibrin With Ultrasound EKOS™ Acoustic Pulse Thrombolysis™ treatment is a minimally invasive system for accelerating thrombus dissolution. 1. Braaten JV et al. Ultrasound reversibly disaggregates fibrin fibers.ThrombHaemost 1997;78:1063-8. 2. Francis CW et al. Ultrasound accelerates transport of recombinant tissue plasminogen activator into clots. Ultrasound in Medicine and Biology,1995;21(5):419-24. 3. Siddiqi F et al. Ultrasound increases flow through fibrin gels. ThrombHaemost 1995; 73(3) 495-8.

  8. EkoSonic™ Endovascular SystemMechanism of action 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 ULTRASOUND ENERGY & THROMBOLYTIC WITHOUT ULTRASOUND ENERGY WITH ULTRASOUND ENERGY Braaten JV et al. Ultrasound reversibly disaggregates fibrin fibers.ThrombHaemost 1997;78:1063-8. Francis CW et al. Ultrasound accelerates transport of recombinant tissue plasminogen activator into clots. Ultrasound in Medicine and Biology, 1995;21(5):419-24. Siddiqi F et al. Ultrasound increases flow through fibrin gels. ThrombHaemost 1995; 73(3) 495-8.

  9. Incidence of Pulmonary Embolism (PE) • Annual incidence • United States: 69 per 100,000/year1 • Over 600,000 cases annually in US2 and approximately 300,000 cases annually in European Union7 • 1-2 PE episodes per 100 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 Silverstein MD et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism. Arch intern Med 1998;158:585-93. Wood KE et al. Major pulmonary embolism: review of a pathphysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest 2002;121:877-905. Tapson VF. Acute pulmonary embolism. N Engl J Med 2008;358(10):1037-1052. Geering et al. CMAJ 2012; 184(3):305-310 Chunilal et al. JAMA 2003;290:2849–58 Siccama et al. Ageing Res Rev 2011;10:304–13 Goldhaber. Deep-vein thrombosis: Advancing awareness to protect patient lives. American Public Health Association White Paper. 2003

  10. Risk-adjusted management algorithm ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J (2014) 35 (43): 3033-3073

  11. Who are these patients?Risk Stratification of Pulmonary Embolism Patients 1 Goldhaber SZ, Visani L, De Rosa M, et al. for ICOPER. Acute pulmonary embolism; clinical outcomes in the International Cooperative Pulmonary Embolism Registry. Lancet 1999;353:1386-1389 2 Bova,EurRespir J 2014; 44: 694–703 3 Beccatini CHEST 2013; 144(5):1539–1545 4 Konstantinides, Meyer, ESC Guidelines 2014, 5 Jiminez, Riete trial JACC jan 2016 6 Epidemiology, Pathophysiology, Stratification, and Natural History of Pulmonary Embolism, Techniques in Vascular and Interventional RadiologyVolume 20, Issue 3, September 2017, Pages 135-140

  12. PE patient population profile MASSIVEPE[High risk] 5% PE population 58%1 mortality @ 3 months SUBMASSIVEPE [Moderate/Intermediate risk] 40% PE population 2-3%2,3 mortality to 21%1 mortality @ 3 months MINORPE [Low risk] 55% PE population Good prognosis Low mortality rate Goldhaber SZ et al. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386-1389 Meyer G et al. Fibrinolysis for Patients with Intermediate Risk Pulmonary Embolism. New Engl J Med 2014; 370: 1402-11 Casazza F et al. Clinical features and short term outcomes of patients with acute pulmonary embolism. The Italian Pulmonary Embolism Registry (IPER). Thrombosis Research 2012; 130:847-852

  13. Why treat intermediate risk PE patients aggressively? • Various studies report presence of right ventricular dysfunction (RVD) as a predictor of poor clinical outcomes • Mortality • Adverse events • VTE recurrence

  14. The significance of RV dysfunction • The presence of RV hypokinesis was associated with a 57% higher mortality rate at 3 months - even though most of the patients (88.9%) were hemodynamically stable • Goldhaber S, Visani L, DeRosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). The Lancet; Apr 24,1999; 353,9162; Health Module pg. 1386. • RV:LV >0.9 shown to be an independent predictor of mortality • Fremont et al. Prognostic Value of Echocardiographic Right/Left Ventricular End-Diastolic Diameter Ratio in Patients with Acute Pulmonary Embolism. CHEST 2008; 133:358-362. • Mortality risk increased with stepwise increase in RV:LV • 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.

  15. The significance of RV dysfunction • PE pts with RV enlargement had a significantly higher chance of adverse events within 30 days • Quiroz R, Kucher N, Schoepf J, et. al. Right Ventricular Enlargement on Chest Computed Tomography: Prognostic Role in Acute Pulmonary Embolism. Circulation. 2004;109:2401-2404. • PE pts with RVD which wasn’t resolved prior to discharge were 8-times more likely to have a recurrent VTE than patients whose RVD was 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..

  16. Rationale for thrombolysis in acute PE • Reduce RV Dysfunction (not achievable by AC alone) • Reverse RV afterload/failure toward prevention of hemodynamic collapse • Improve pulmonary reperfusion/capillary blood flow/gas exchange • Restore systemic arterial perfusion pressure • Decrease the risk of developing chronic pulmonary hypertension Piazza G and Goldhaber SZ. Finbrinolysis for acute pulmonary embolism. Vascular Medicine 2010 15(5):419-428

  17. Why Intermediate PE patients are at risk: key factors contributing to hemodynamic collapse in acute PE Konstantinides SV et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. European Heart Journal 2014. 35: 3033-3080.

  18. ULTIMA study compared EKOS™ to heparin in intermediate risk PE therapy The first RCT for an advanced catheter-based modality Primary Objective • Determine whether fixed low-dose catheter-directed ultrasound accelerated thrombolysis is superior to heparin alone in reversal of RV dilatation in submassive/intermediate risk PE Kucher N et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129:479-486

  19. More improved echo findings from EKOS™ with tPA + heparin than heparin alone SYSTOLIC RV DYSFUNCTION SIGNIFICANTLY IMPROVED P=0.003* P<0.001 P<0.001** 100% 80% 60% Systolic RV Dysfuntion 40% 20% 0% Baseline 24 Hours 90 Days Baseline 24 Hours 90 Days EKOS™ with tPA + Heparin Heparin Normal Moderate Mild Severe *Two-sided exact Mantel-Haenzel test | **Wilcoxon rank sum test Kucher N et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129:479-486

  20. No statistical difference in safety outcomes with EKOS™ with tPA + Heparin than Heparin alone No Deaths Or Significant Bleeding Complications *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 bleeding following endoscopic removal of colon polyp Kucher N et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129:479-486

  21. ULTIMA study:Demonstrated that EKOS™ is superior to AC in reducing RV/LV ratio at 24 hours. CONCLUSION ULTIMA confirmed that a fixed-dose, ultrasound-assisted catheter-directed thrombolysis EKOS™ regimen was superior to anticoagulation alone in improving RV dysfunction at 24 hours without an increase in bleeding complications. Kucher N et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129:479-486

  22. SEATTLE II examined EKOS™ benefit in a clinical trial setting in the US Evaluate ultrasound-facilitated fibrinolysis using EKOS™ for massive and submassive PE (n=150; 22 centers): • Efficacy – as measured by reduction in RV/LV ratio • Safety – as measured by major bleeding within 72 hours 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 et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism. The SEATTLE II Study. J Amer Coll Cardiol: Cardiovasc Interventions 2015; 8(10):1382-1392.

  23. The SEATTLE II Study Endpoints • 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 Piazza G et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism. The SEATTLE II Study. J Amer Coll Cardiol: Cardiovasc Interventions 2015; 8(10):1382-1392.

  24. Reduced RV/LV ratio at 48 hours post-EKOS™ treatment 25% DECREASE IN RV/LV OVER 48 HOURS P<0.0001 1.55 2.0 RV/LV Ratio 1.5 1.13 1.0 .5 Pre-Procedure 48 Hours 0 Piazza G et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism. The SEATTLE II Study. J Amer Coll Cardiol: Cardiovasc Interventions 2015; 8(10):1382-1392.

  25. SEATTLE II study CONCLUSION 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, it represents a potential “game-changer” in the treatment of high-risk PE patients Piazza G et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism. The SEATTLE II Study. J Amer Coll Cardiol: Cardiovasc Interventions 2015; 8(10):1382-1392.

  26. EKOS™PE treatment showed shorter length of stay compared to anti-coagulation alone • Single-center retrospective study to evaluate safety and efficacy of EKOS™ therapy • n=45 • Comparison to separate control group (n=45) of intermediate to high-risk PE patients treated with systemic heparin or anticoagulation alone • Average LoS: EKOS™ treated = 3.2 days versus AC = 6.7 days Nykamp M et al. Safety and efficacy of ultrasound-accelerated catheter-directed lytic therapy in acute pulmonary embolism with and without hemdynamic instability. J VascSurg: Venous and Lymphatic Disord 2015; 3(5) 251-257

  27. OPTALYSE PE study explored optimal duration and dose using EKOS™therapy *Total mg r-tPA: one/two catheters Tapson V et al. A randomized trial of the optimum duration of acoustic pulse thrombolysis procedure in acute intermediate-risk pulmonary embolism. JACC: Cardiovascular Interventions 2018; 11(14):1401-1410.

  28. Study Endpoints Tapson V et al. A randomized trial of the optimum duration of acoustic pulse thrombolysis procedure in acute intermediate-risk pulmonary embolism. JACC: Cardiovascular Interventions 2018; 11(14):1401-1410.

  29. All OPTALYSE PE cohorts showed significant reduction in RV/LV at 48 hours post-initiation of procedure * Total mg r-tPA: one/two catheters Tapson V et al. A randomized trial of the optimum duration of acoustic pulse thrombolysis procedure in acute intermediate-risk pulmonary embolism. JACC: Cardiovascular Interventions 2018; 11(14):1401-1410. * Total mg r-tPA: one/two catheters

  30. Very Low Bleeding Rate *Represents patients that were treated per the study randomization 3% Bleeding Rate for OPTALYSE Cohort 2: Anemia secondary to pre-treatment facial trauma after syncope. Cohort 4: Bleeding from a splenic pseudoaneurysm treated with coil embolization Cohort 4: ICH in a 75 year old male patient with a prior history of thrombocytopenia and labile hypertension. Tapson V et al. A randomized trial of the optimum duration of acoustic pulse thrombolysis procedure in acute intermediate-risk pulmonary embolism. JACC: Cardiovascular Interventions 2018; 11(14):1401-1410.

  31. 1-year Follow Up via EchocardiogramMean RV/LV Ratio Sterling, K. “Long-term Results of the OPTALYSE PE trial” as presented at the International Symposium on Endovascular Therapy (ISET) meeting, Hollywood, FL Feb 2018.

  32. Long-Term Data: Mean RV/LV Ratio Sterling, K. “Long-term Results of the OPTALYSE PE trial” as presented at the International Symposium on Endovascular Therapy (ISET) meeting, Hollywood, FL Feb 2018.

  33. Excellent safety and efficacy at 1yr 2% All-cause Mortality for OPTALYSE 73yo male with history of hematologic abnormality expired 11d after treatment 74yo female expired due to complications of COPD 6m after treatment Konstantinides SV et al, Impact of thrombolytic therapy on the long-term outcome of intermediate-risk pulmonary embolism. Journal of the American College of Cardiology 2017; 69:1536-1544. Baglin et al., Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient-level meta-analysis, Journal of Thrombosis and Haemostasis 2010; 8(11): 2436–2442.

  34. Quality of Life: PEmb-QOL & PROMIS-PF6 PROMIS-PF Sterling, K. “Long-term Results of the OPTALYSE PE trial” as presented at the International Symposium on Endovascular Therapy (ISET) meeting, Hollywood, FL Feb 2018.

  35. No baseline – patients were unable to walk 6 Minute Walk Test sustained from 30 days to 1-year P value not calculated Sterling, K. “Long-term Results of the OPTALYSE PE trial” as presented at the International Symposium on Endovascular Therapy (ISET) meeting, Hollywood, FL Feb 2018.

  36. OPTALYSE Case – Two Hour Duration Pre-treatment Post-EKOS™Treatment RV/LV =.80 RV/LV =1.52 Images courtesy of Houston Methodist Sugar LandHospital • 2 hr infusion time • 8mg r-tPA* • 47% reduction in RV/LV *Two catheters at 2mg/hr/catheter

  37. OPTALYSE PE Summary Each of the OPTALYSE 2, 4 & 6 hr cohorts reduced RV/LV ratio by ~23-26%* with total tPA doses as low as 8mgs# with a very low bleeding rate, and a very low long-term mortality rate while also improving quality of life. *RV/LV taken via CTA at 48hrs post-EKOS™ treatment #Two catheters at 2mg/hr/catheter

  38. OPTALYSE PE treatment options: flexible, safe, cost-effective

  39. OPTALYSE PE: Setting the Standard, Again ACUTE RESULTS The EKOS™ treatment’s successful very-low dose and short duration regimens in the OPTALYSE PE trial point to a paradigm-changing approach for PE Treatment. LONG-TERM RESULTS The favorable mortality rates, recurrent PE rates, and quality of life results demonstrate long-term benefits of EKOS™ therapy. This data further proves the PE clinical efficacy and safety of the OPTALYSE PE treatment protocols. With these results, EKOS™ is setting the standard for PE treatment safety and efficacy, again.

  40. The Key OPTALYSE Message Same efficacy & better safety in as little as 2hrs*, with tPA doses as low as 8mgs#, and now with favorable long-term mortality & QOL data *RV/LV taken via CTA at 48hrs post-EKOS™ treatment #Two catheters at 2mg/hr/catheter

  41. FURTHER REVIEW OF 20 STUDIES (2017) ON EKOS™ ELABORATED ON SAFETY, EFFICACY, LIMITATIONS & COMPLICATIONS IN SUBMASSIVE & MASSIVE PULMONARY EMBOLISM • 14 retrospective (n=524) and 6 prospective (n=383) studies published efficacy and safety data for UACDT. • 13 Studies included patients with Massive PE (n=180) • Overall, UACDT was found to offer greater benefits with fewer major bleeding events and mortality events, suggesting better safety: • The pooled incidence of in-hospital, 30 day and 90 day mortality was 2.3%, 0.4% and 0.8% respectively. • The pooled incidence of major and other bleeding episodes were 2.8% and 7.2%, respectively. • The pooled incidence of recurrent PE was 0.4%. • One Intracranial haemorrhage (ICH) reported in Ozcinar, et al. prospective observational study. The author could not find any further ICH in any other study. • In this literature review, EKOS™ is superior in improving RV/LV ratio, pulmonary artery pressure (PAP), thrombotic burden and cardiac index with a lower risk of bleeding and other complications. • EKOS™ is emerging as an alternative revascularisation procedure to systemic thrombolysis and surgical embolectomy for PE. Mangi M A, Rehman H, Bansal V, et al. (July 19, 2017) Ultrasound Assisted Catheter-Directed Thrombolysis of Acute Pulmonary Embolism: A Review of Current Literature. Cureus 9(7): e1492. DOI 10.7759/cureus.1492

  42. Thank you

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