Augmented Ultrasound-Facilitated, Catheter-Directed Fibrinolysis for PE

Brigham and Women's Hospital60 enrolled

Overview

SONIC-PE is a multicenter, prospective, single-arm study of 10 patients with bilateral PE treated with ultrasound-facilitated, catheter-directed lower-dose fibrinolysis (total dose 8 mg tPA given as 2 mg/hour/catheter over 2 hours) followed by 50 patients (total dose 6 mg tPA given as 3 mg/hour/catheter given over 1 hour) with the EKOS+™ system to determine its impact on the change in RV-to-LV diameter, refined Modified Miller Score, and distal pulmonary vascular blood volume as well as to assess International Society on Thrombosis and Haemostasis (ISTH) major bleeding.

Patients with intermediate-high risk pulmonary embolism (PE) comprise a population at increased risk for clinical deterioration despite initially stable hemodynamics. The pathophysiology of hemodynamic deterioration in intermediate-high risk PE includes an abrupt increase in pulmonary vascular resistance, due to proximal as well as distal pulmonary artery occlusion, pulmonary hypertension, right ventricular (RV) pressure overload, and, ultimately, RV failure. While full-dose systemic fibrinolysis for PE has demonstrated efficacy for prevention of early morbidity and mortality, its net clinical benefit is attenuated by the risk of major bleeding, in particular intracranial hemorrhage. Catheter-directed therapies have been demonstrated to facilitate RV recovery while reducing the risk of major bleeding through use of lower-dose fibrinolysis or avoiding it altogether. Specifically, lower-dose regimens for ultrasound-facilitated, catheter-directed fibrinolysis result in sustained recovery of echocardiographically-determined RV function, reduction in Modified Miller Score (large-vessel pulmonary angiographic obstruction), functional status, and quality of life over the year following ultrasound-facilitated, catheter-directed fibrinolysis. Recently, an upgrade to the output of the ultrasonic core catheter of the EKOS™ Endovascular System (EKOS+™) has demonstrated the ability to enhance fibrinolysis within a lower fibrinolytic dose range in preliminary studies (Boston Scientific Corporation, Maple Grove, MN). Compared with current EkoSonic™ system, a 50% increase in ultrasound power (measured in watts) with EKOS+™ resulted in a 130% increase in in vitro clot lysis compared with conventional catheter-directed fibrinolysis using the same dose of fibrinolytic drug. SONIC-PE is multicenter, prospective single-arm study of 10 patients with bilateral PE treated with ultrasound-facilitated, catheter-directed lower-dose fibrinolysis (total dose 8 mg tPA given as 2 mg/hour/catheter over 2 hours) followed by 50 patients (total dose 6 mg tPA given as 3 mg/hour/catheter given over 1 hour) with the EKOS+™ system to determine its impact on the change in RV-to-LV diameter, refined Modified Miller Score, and distal pulmonary vascular blood volume as well as assess International Society on Thrombosis and Haemostasis (ISTH) major bleeding. The study will have an adaptive design component with transition to 8 mg tPA/2 hours if there is an excess of bleeding or observed lack of efficacy, as determined by an Independent Study Safety Monitor.

Interventions

Ultrasound-facilitated, catheter-directed lower-dose fibrinolysisDEVICE

Ultrasound-facilitated, catheter-directed lower-dose fibrinolysis (treated with a total dose 8 mg tPA given as 2 mg/hour/catheter over 2 hours for first 10 patients followed by 50 patients treated with total dose 6 mg tPA given as 3 mg/hour/catheter given over 1 hour) with the EKOS+™ system

Tissue Plasminogen ActivatorDRUG

total dose 8 mg tPA given as 2 mg/hour/catheter over 2 hours for first 10 patients followed by 50 patients treated with total dose 6 mg tPA given as 3 mg/hour/catheter given over 1 hour

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. patients at least 18 years of age, 2. symptomatic PE defined as symptoms for \<14 days with normal systolic blood pressure (\>90 mmHg), RV-to-LV diameter ratio ≥0.9 on initial chest CT, bilateral filling defects located in at least 1 main or proximal lobar pulmonary artery, and cardiac troponin greater than the upper limit of normal (cTnI, cTnT, hsTnI, or hsTnT), AND 3. in whom ultrasound-facilitated, catheter-directed lower-dose fibrinolysis has been selected for treatment on a clinical basis. Exclusion Criteria: 1. stroke or transient ischemic attack, head trauma, other active intracranial or intraspinal disease (including malignancy) within 1 year 2. recent active bleeding from a major organ within 1 month 3. major surgery within 7 days of screening 4. contraindication to therapeutic anticoagulation 5. systolic blood pressure \<90 mm Hg, systolic blood pressure drop by at least 40 mmHg over at least 15 minutes, shock, use of vasopressors, need for CPR, or need for ECMO 6. need for mechanical ventilation, including non-invasive positive pressure ventilation 7. hematocrit \<30%, platelet count \<100,000/μl 8. international normalized ratio \>3 9. serum creatinine \> 2 mg/dL 10. liver cirrhosis 11. known hypersensitivity to tPA, heparin, or any excipients 12. perceived high risk for fatal or catastrophic bleeding 13. prescription of dual antiplatelet therapy (DAPT) at time of screening 14. Patients treated with any other advanced therapy, such as surgical embolectomy, catheter-based mechanical embolectomy, or fibrinolytic therapy, within the prior 30 days 15. pregnancy or lactation

Outcomes

Primary Outcomes

Change in RV-to-LV diameter ratio as measured by chest CT from baseline to 48 ± 6 hours

Change in RV-to-LV ratio will be determined by a dedicated core imaging laboratory, blinded to clinical data and timing of the CT studies

Time frame: 48 ± 6 hours

Frequency of ISTH major bleeding at 72 hours

Adjudicated independently using ISTH criteria

Time frame: 72 hours

Secondary Outcomes

Change in chest CT-measured blood volume in the distal pulmonary vasculature from baseline to 48 ± 6 hours

Baseline and 48 ± 6 hours CT scans will be analyzed offline using 3D volumetric analysis

Time frame: 48 ± 6 hours

Change in refined Modified Miller Score as measured by chest CT from baseline to 48 ± 6 hours as measured by chest CT from baseline to 48 ± 6 hours

Determined by a dedicated core imaging laboratory, blinded to clinical data and timing of the CT studies. Scores range from 0-40 with 0 meaning no obstruction.

Time frame: 48 ± 6 hours

Augmented Ultrasound-Facilitated, Catheter-Directed Fibrinolysis for PE

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes