1. ©2015 MFMER | slide-1 Less Lytic Ultrasound-assisted catheter-directed thrombolysis in the treatment of pulmonary embolism Brianne M. Ritchie, PharmD MBA BCPS Pharmacy Grand Rounds July 12, 2016

2. ©2015 MFMER | slide-2 Objectives Describe the mechanism by which UACDT acts in the treatment of pulmonary embolism Review the evidence supporting UACDT in the treatment of pulmonary embolism Describe important pharmacotherapy considerations for patients receiving UACDT UACDT – Ultrasound-assisted catheter-directed thrombolysis

3. ©2015 MFMER | slide-3 Epidemiology DVT and PE represent the spectrum of VTE Annual incidence United States: 600,000 + Europe: 1,000,000 + Annual mortality United States: 300,000 DVT – deep vein thrombosis PE – pulmonary embolism VTE – venous thromboembolism Tapson V. N Engl J Med. 2008;358:1037-1052.

4. ©2015 MFMER | slide-4 Pathophysiology Tapson V. N Engl J Med. 2008;358:1037-1052.

5. ©2015 MFMER | slide-5 Pathophysiology Agnelli G. N Engl J Med. 2010;363:266-274. RV:LV – right ventricular to left ventricular ratio RV – right ventricle LV – left ventricle

6. ©2015 MFMER | slide-6 Definitions Massive PE High Risk Hemodynamically unstable RV dysfunction Myocardial necrosis Jaff MR. Circulation. 2011;123:1788-1830. Konstantinides S. Eur Heart J. 2014;35(43):3033-3069. PE – pulmonary embolism RV – right ventricular Nonmassive PE Low Risk Hemodynamically stable No RV dysfunction No myocardial necrosis Submassive PE Intermediate Risk Hemodynamically stable RV dysfunction Myocardial necrosis

7. ©2015 MFMER | slide-7 Treatment Clinical outcomes vary with patient characteristics Tailor medical and interventional therapies Advanced therapies may reduce RV pressure overload and prevent further morbidity and mortality Surgical embolectomy Systemic thrombolysis Pharmacomechanical therapy Jaff MR, McMurtry S, et al. Circulation. 2011;123:1788-1830. Konstantinides S, Torbicki A, et al. Eur Heart J. 2014;35(43):3033-3069. PE – pulmonary embolism RV – right ventricular DefinitionRecommendation Nonmassive PEHeparin (I) Submassive PELytics (IIb) Massive PELytics (IIa)

8. ©2015 MFMER | slide-8 Treatment Risk vs. Benefit Systemic thrombolysis significantly reduces RV strain and prevents hemodynamic collapse Net benefit nearly completely eliminated by increased risk of major bleeding Intracranial hemorrhage 3-5% Utilization of systemic thrombolysis in the United States is low Jaff MR, McMurtry S, et al. Circulation. 2011;123:1788-1830. Konstantinides S, Torbicki A, et al. Eur Heart J. 2014;35(43):3033-3069. Meyer G N Engl J Med. 2014;370:1402-1411. Goldhaber SZ. Lancet. 1999;353(9162):1386-1389. PE – pulmonary embolism RV – right ventricular P = 0.02 P < 0.001 P = 0.003 N = 1005

9. ©2015 MFMER | slide-9 Mechanism of Action Describe the mechanism by which UACDT acts in the treatment of pulmonary embolism UACDT – Ultrasound-assisted catheter-directed thrombolysis

10. ©2015 MFMER | slide-10 Mechanism of Action EKOS – EkoSonic® Endovascular System with Acoustic Pulse Thrombolysis™ https://www.btg-im.com/EKOS/US/Products EKOS

11. ©2015 MFMER | slide-11 Mechanism of Action https://www.btg-im.com/EKOS/US/Products 1.Ultrasonic fibrin separation 2.Acoustic streaming active drug delivery 3.Plasminogen-activated thrombolysis EKOS – EkoSonic® Endovascular System with Acoustic Pulse Thrombolysis™

12. ©2015 MFMER | slide-12 Mechanism of Action EKOS – EkoSonic® Endovascular System with Acoustic Pulse Thrombolysis™ https://www.btg-im.com/EKOS/US/Products

13. ©2015 MFMER | slide-13 Which of the following is not a mechanism of action of UACDT in the treatment of PE? A.Ultrasonic fibrin separation B.Acoustic streaming active drug delivery C.Plasminogen-activated thrombolysis D.All of the above aPTT – activated partial thromboplastin time UACDT – ultrasound-assisted catheter-directed thrombolysis Assessment Question Mechanism of Action

14. ©2015 MFMER | slide-14 Which of the following is not a mechanism of action of UACDT in the treatment of PE? A.Ultrasonic fibrin separation B.Acoustic streaming active drug delivery C.Plasminogen-activated thrombolysis D.All of the above aPTT – activated partial thromboplastin time UACDT – ultrasound-assisted catheter-directed thrombolysis Assessment Question Mechanism of Action

15. ©2015 MFMER | slide-15 Clinical Evidence Review the evidence supporting UACDT in the treatment of pulmonary embolism UACDT – Ultrasound-assisted catheter-directed thrombolysis Jaff MR, McMurtry S, et al. Circulation. 2011;123:1788-1830. Konstantinides S, Torbicki A, et al. Eur Heart J. 2014;35(43):3033-3069.

16. ©2015 MFMER | slide-16 ULTIMA Clinical Evidence ULTIMA Title Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism Purpose To investigate whether a fixed-dose UACDT regimen is superior to anticoagulation alone in reversal of RV dilatation in intermediate-risk PE patients Design Multicenter, open-label, randomized controlled November 2010-January 2013 Patients 59 patients with submassive PE at 8 sites in 2 countries 30 UACDT alteplase + heparin vs. 29 heparin Intervention UACDT with Alteplase 10-20mg + Heparin vs. Placebo + Heparin ULTIMA – Ultrasound Accelerated Thrombolysis of Pulmonary Embolism trial RV – right ventricle PE – pulmonary Embolism Kucher N. Circulation. 2014;129:479-486. N = 59

17. ©2015 MFMER | slide-17 Clinical Evidence ULTIMA Acute PE w/ RV:LV > 1.0 Submassive UACDT Alteplase 1 mg/hr x 5hr, 0.5 mg/hr thru 15hr + Heparin 80 u/kg, 18 u/kg/hr Placebo + Heparin 80 u/kg, 18 u/kg/hr Kucher N. Circulation. 2014;129:479-486. N = 59 PE – pulmonary embolism RV:LV – right to left ventricle ratio UACDT – ultrasound-assisted catheter-directed thrombolysis

18. ©2015 MFMER | slide-18 RV:LV – right to left ventricle ratio ΔRV:LV – change in right to left ventricle ratio UACDT – ultrasound-assisted catheter-directed thrombolysis P = 0.07 P = 0.001 P < 0.001 Clinical Evidence ULTIMA N = 59 Kucher N. Circulation. 2014;129:479-486. P = 0.36 P = 0.07

19. ©2015 MFMER | slide-19 Clinical Evidence ULTIMA Kucher N. Circulation. 2014;129:479-486. P < 0.001 N = 59 P < 0.001 P = 0.015 P = 0.005 UACDT – ultrasound-assisted catheter-directed thrombolysis PAP – pulmonary artery pressure RAP – right atrial pressure CI – cardiac index Hemodynamic Variables at 24hr after UACDT

20. ©2015 MFMER | slide-20 Clinical Evidence ULTIMA Kucher N. Circulation. 2014;129:479-486. UACDT – ultrasound-assisted catheter-directed thrombolysis N = 59 UACDT Transient hemoptysis (n=2) Access site hematoma (n=1) Heparin Muscular hematoma (n=1) P = 0.61

21. ©2015 MFMER | slide-21 SEATTLE-II Clinical Evidence SEATTLE II Title Prospective, single-arm, multicenter trial of UACDT for acute massive and submassive PE Purpose To evaluate the safety and efficacy of UACDT using EKOS Design Multicenter, single-arm, randomized controlled June 2012 – February 2013 Patients 149 patients with submassive and massive PE at 22 sites in the US 149 UACDT alteplase + heparin Intervention Alteplase 24mg + Heparin SEATTLE II – Prospective, single-arm, multicenter trial of UACDT for acute PE PE – pulmonary Embolism EKOS – EkoSonic® Endovascular System with Acoustic Pulse Thrombolysis N = 150 Piazza G. J Am Coll Cardiol Intv. 2015;8:1382-1392.

22. ©2015 MFMER | slide-22 Clinical Evidence SEATTLE II Acute PE w/ RV:LV > 1.0 Submassive + Massive UACDT Alteplase 24mg + Heparin goal aPTT 60-80 N = 150 PE – pulmonary embolism RV:LV – right ventricular to left ventricular ratio UACDT – ultrasound-assisted catheter-directed thrombolysis Piazza G. J Am Coll Cardiol Intv. 2015;8:1382-1392.

23. ©2015 MFMER | slide-23 Clinical Evidence SEATTLE II Piazza G. J Am Coll Cardiol Intv. 2015;8:1382-1392. RV:LV – right to left ventricle ratio PAP – pulmonary artery pressure UACDT – ultrasound-assisted catheter-directed thrombolysis P < 0.0001 N = 150 P < 0.0001

24. ©2015 MFMER | slide-24 Clinical Evidence SEATTLE II Piazza G. J Am Coll Cardiol Intv. 2015;8:1382-1392. RV:LV – right to left ventricle ratio PAP – pulmonary artery pressure UACDT – ultrasound-assisted catheter-directed thrombolysis N = 150

25. ©2015 MFMER | slide-25 OPTALYSE PE Study of the Optimum Duration of Acoustic Pulse Thrombolysis Procedure in the Treatment of Acute Submassive Pulmonary Embolism Patients PE confirmed by CTA with RV:LV > 0.9 Design Randomized, multi-arm of varying durations and doses of UACDT Primary Endpoint Reduction in RV:LV at 48 hours Safety Endpoints Major bleeding within 12 months PE recurrence within 12 months Mortality within 12 months https://clinicaltrials.gov/ct2/show/NCT02396758 Recruiting though March 2017 Estimated N = 100 PE – pulmonary embolism CTA – computed tomography angiography RV:LV – right to left ventricle ratio TBD – to be determined Randomization 2 hrs 4mg vs. 8mg 4 hrs 4mg vs. 8mg 6hrs 6mg vs. 12mg 12mg vs. 24mg TBD TBD vs. TBD

26. ©2015 MFMER | slide-26 The primary outcome finding in ULTIMA and SEATTLE II, a statistically significant __________, supports the use of UACDT over heparin alone in the treatment of PE. A.Reduction in RV:LV B.Reduction in hemodynamic collapse C.Improvement in quality of life D.Reduction in mortality aPTT – activated partial thromboplastin time UACDT – ultrasound-assisted catheter-directed thrombolysis Assessment Question Clinical Evidence

27. ©2015 MFMER | slide-27 The primary outcome finding in ULTIMA and SEATTLE II, a statistically significant __________, supports the use of UACDT over heparin alone in the treatment of PE. A.Reduction in RV:LV B.Reduction in hemodynamic collapse C.Improvement in quality of life D.Reduction in mortality aPTT – activated partial thromboplastin time UACDT – ultrasound-assisted catheter-directed thrombolysis Assessment Question Clinical Evidence

28. ©2015 MFMER | slide-28 Pharmacotherapy Considerations Describe important pharmacotherapy considerations for patients receiving UACDT UACDT – Ultrasound-assisted catheter-directed thrombolysis Jaff MR, McMurtry S, et al. Circulation. 2011;123:1788-1830. Konstantinides S, Torbicki A, et al. Eur Heart J. 2014;35(43):3033-3069.

29. ©2015 MFMER | slide-29 UACDT – Ultrasound-assisted catheter-directed thrombolysis Real World Application Pharmacotherapy McCabe JM. Am J Cardiol. 2015;115(6):821-824. Cardiac cath lab Measurements Placement Pre-UACDT Alteplase 0.75-2 mg/hr/strand Bolus 2 ± 1.4 mg Infusion 1.5 (1-1.5) mg/hr Total dose 24.6 ± 9 mg Total infusion time 15.9 ± 3 hrs Heparin Goal aPTT 40-60 Peak aPTT 42.5 (38.5-55.6) During UACDT Heparin Goal aPTT 60-80 Long-term Anticoagulant Post-UACDT 53% warfarin 19% enoxaparin 13% rivaroxaban 6% dalteparin N = 53

30. ©2015 MFMER | slide-30 UACDT – Ultrasound-assisted catheter-directed thrombolysis PAP – pulmonary artery pressure RV:LV – right ventricle to left ventricle McCabe JM. Am J Cardiol. 2015;115(6):821-824. P < 0.001 P = 0.03 Real World Application Efficacy N = 53

31. ©2015 MFMER | slide-31 UACDT – Ultrasound-assisted catheter-directed thrombolysis Real World Application Safety Persistent access site bleeding Spontaneous retroperitoneal bleed Asymptomatic intraventricular hemorrhage s/p ventriculoperitoneal shunt placement Rectus sheath hematoma s/p cesarean section McCabe JM. Am J Cardiol. 2015;115(6):821-824. Length of stay: 4 (3-5.5) days N = 53

32. ©2015 MFMER | slide-32 Based on published literature, what is the goal aPTT for heparin administration during UACDT? A.No goal – not concurrently administered B.No goal – no titration, fixed rate C.Goal aPTT 40 – 80 D.Goal aPTT 60 – 80 aPTT – activated partial thromboplastin time UACDT – ultrasound-assisted catheter-directed thrombolysis Assessment Question Pharmacotherapy Considerations

33. ©2015 MFMER | slide-33 Based on published literature, what is the goal aPTT for heparin administration during UACDT? A.No goal – not concurrently administered B.No goal – no titration, fixed rate C.Goal aPTT 40 – 80 D.Goal aPTT 60 – 80 aPTT – activated partial thromboplastin time UACDT – ultrasound-assisted catheter-directed thrombolysis Assessment Question Pharmacotherapy Considerations

34. ©2015 MFMER | slide-34 Summary Submassive PE and Massive PE Systemic thrombolysis vs. UACDT Bleeding risk Mobilization to cardiac cath lab PE – pulmonary embolism UACDT – Ultrasound-assisted catheter-directed thrombolysis

35. ©2015 MFMER | slide-35 Summary Mechanisms of UACDT for PE Ultrasonic fibrin separation Acoustic streaming active drug delivery Plasminogen-activated thrombolysis Evidence supporting UACDT for PE ULTIMA, SEATTLE II Reduction in RV:LV OPTALYSE PE Pharmacotherapy considerations During UACDT Alteplase 0.75–2 mg/hr/strand over 12–24 hr + heparin aPTT 40–80 Following UACDT Heparin aPTT 60–80 + transition to long-term anticoagulant UACDT – Ultrasound-assisted catheter-directed thrombolysis PE – pulmonary embolism PAP – pulmonary artery pressures RV:LV – right ventricular to left ventricular ratio aPTT – activated partial thromboplastin time

36. ©2015 MFMER | slide-36 Less Lytic Ultrasound-assisted catheter-directed thrombolysis in the treatment of pulmonary embolism Brianne M. Ritchie, PharmD MBA BCPS Pharmacy Grand Rounds July 12, 2016 Questions & Discussion

37. ©2015 MFMER | slide-37 References Agnelli G. Acute pulmonary embolism. N Engl J Med. 2010;363:266-274. Beckman MG. Venous thromboembolism: a public health concern. Am J Prev Med. 2010;38(4S):S495-501. Engelberger RP. Ultrasound-assisted thrombolysis for acute pulmonary embolism: a systematic review. Eur Heart J. 2014;35:758-764. Goldhaber SZ. Venous thromboembolism: epidemiology and magnitude of the problem. Best Pract Res Clin Haematol. 2012;25(3):235-242. Goldhaber SZ. Pulmonary embolism and deep vein thrombosis. Lancet. 2012;379:1835-1846. Jaff MR. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension. Circulation. 2011;123:1788-1830. Konstantinides S. Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-3069. Kucher N. Randomized, controlled trial of ultrasound-assisted, catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129:479-486. McCabe JM. Usefulness and safety of ultrasound-assisted catheter-directed thrombolysis for submassive pulmonary embolism. Am J Cardiol. 2015;115(6):821-824. Meyer G. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370:1402- 1411. Office of the Surgeon General. The Surgeon General’s call to action to prevent deep vein thrombosis and pulmonary embolism. Publications and Reports of the Surgeon General. 2008. Piazza G. Prospective, single-arm, multicenter trial of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis for acute massive and submassive pulmonary embolism. J Am Coll Cardiol Intv. 2015;8(10):1382- 1392. Tapson VF. Acute pulmonary embolism. N Engl J Med. 2008;358:1037-1052.