Standard vs Ultrasound-assisted Catheter Thrombolysis for Submassive Pulmonary Embolism

Study Overview
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Brief Summary
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The study is an investigator-initiated trial comparing two different catheters (standard versus ultrasound assisted) for the treatment of acute high risk pulmonary embolism (blood clots in lung arteries with evidence or heart strain). Patients already planned for the procedure will be randomized to standard catheter-directed thrombolysis (CDT) or to ultrasound-assisted catheter thrombolysis (USAT). Both catheters are currently used routinely in practice for the treatment of pulmonary embolism, but it is not known if USAT is superior to standard CDT, the former being much more expensive and more commonly used. The purpose of the study is to learn about which catheter-directed therapy is more suitable for patients with pulmonary embolism (PE), who are candidates for both standard catheter directed therapy (CDT), and ultrasound-assisted catheter directed therapy (USAT), and to provide information regarding the cost effectiveness of the two different types of treatment. A total of 80 patients are planned to be recruited. All medication administration, procedures or in-hospital tests will be performed as routine clinical practice. The study will compare short term and long term outcomes: resolution of blood clots on CT scan, right ventricular size improvement, quality of life and symptoms at 3 and 12 months, and cost effectiveness.

Detailed Description
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Acute pulmonary embolism (PE) accounts for 5-10% of in-hospital deaths. Systemic anticoagulation (AC) is the standard of care and thrombolysis is recommended for those at a higher mortality risk. Catheter-directed therapies, mainly standard catheter-directed thrombolysis (CDT) and ultrasound-accelerated thrombolysis (USAT), have been introduced as new, more effective, and safer treatment modalities. USAT is a modification of standard catheter thrombolysis, utilizing a system of local ultrasound to dissociate the fibrin matrix of the thrombus, allowing deeper penetration of lytics. However, there is limited data comparing the two treatments. More rapid clearance of pulmonary thrombus by USAT compared to standard CDT may prove to be more effective regarding clinical outcomes and cost (e.g. via reduced length of ICU and hospital stay). Alternatively, if thrombus clearance is similar, the cost of USAT may exceed the cost of CDT (equipment and disposables), without offering any potential advantage. This controlled, randomized study seeks to determine if ultrasound acceleration adds any benefits in the outcomes and costs of catheter-directed thrombolysis for patients with acute submassive PE. The treatment with CDT or USAT are standard of care for submassive PE and participants will be randomized to receive one treatment or the other. Participants will have follow up visits at 3 months and 12 months post procedure. All the procedures, tests, and follow up visits are according to current standard of care.

Official Title
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USAT-CDT Trial: Standard vs Ultrasound-assisted Catheter Thrombolysis for Submassive Pulmonary Embolism

Conditions
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Cardiovascular Diseases

Intervention / Treatment
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* Device: Standard Catheter-Directed Thrombolysis
* Device: Ultrasound-Accelerated Thrombolysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients eligible for catheter directed thrombolysis per the study protocol for submassive pulmonary embolism (PE) CT or echocardiographic RV strain (defined as RV/LV ratio >1) without persisting hypotension <90mmHg or drop of systolic blood pressure by at least 40mm Hg for at least 15 minutes with signs of end-organ hypoperfusion (cold extremities or low urinary output <30 mL/h or mental confusion) without the need of catecholamine support without the need of cardiopulmonary resuscitation Exclusion Criteria: Pregnancy Index PE symptom duration >14 days High bleeding risk (any prior intracranial hemorrhage, known structural intracranial cerebrovascular disease or neoplasm, ischemic stroke within 3 months, suspected aortic dissection, active bleeding or bleeding diathesis, recent spinal or cranial/brain surgery, recent closed-head or facial trauma with bony fracture or brain injury) Participation in any other investigational drug or device study Life expectancy <90 days Inability to comply with study assessments

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized to receive one of two treatments for acute, submassive pulmonary embolism.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Catheter-Directed Thrombolysis<br>Participants randomized to this arm will receive standard catheter-directed thrombolysis, per standard of care, as treatment for acute submassive pulmonary embolism. | Device: Standard Catheter-Directed Thrombolysis<br>* Catheter-directed thrombolysis requires placement of a multi-sidehole infusion catheter within the pulmonary arterial thrombus burden, under angiographic guidance. Thrombolytic medications are slowly infused through the catheter, which is left in place for the duration of the treatment. The treatment will be performed according to current standard of care and all technical considerations will be left to the discretion of the operator performing the procedure. All follow up is according to standard of care.<br>* Other names: CDT;|
| Active Comparator: Ultrasound-Accelerated Thrombolysis<br>Participants randomized to this arm will receive ultrasound-accelerated thrombolysis, per standard of care, as treatment for acute submassive pulmonary embolism. | Device: Ultrasound-Accelerated Thrombolysis<br>* USAT is a modification of standard catheter-directed thrombolysis utilizing a proprietary system of local high frequency, low-power ultrasound to dissociate the fibrin matrix of the thrombus, allowing deeper penetration of lytic medication. The treatment will be performed according to current standard of care and all technical considerations will be left to the discretion of the operator performing the procedure. All follow up is according to standard of care.<br>* Other names: USAT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Thrombus Obstruction | Computed tomography angiography (CTA) will be performed before and after treatment. An independent radiologist will quantify the degree of obstruction from the thrombus by determining the vascular obstruction index. For determining the CT obstruction index, the arterial tree of each lung will be considered to have 10 segmental arteries (three to the upper lobes, two to both the middle lobe and the lingula, and five to the lower lobes). | Baseline to end of lysis treatment (up to 72 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In Hospital Mortality | Mortality during hospitalization will be compared between the two study arms. | Until hospital discharge (an average of 6 days) | 
| 90-day Mortality | Mortality until 90 days post procedure will be compared between the two study arms. | Until 90 days post procedure | 
| Cardiac Decompensation Due to Massive Pulmonary Embolism | Cardiac decompensation, defined as hypotension (<90 millimeters of mercury (mmHg)) and use of catecholamines, will be compared between the two study arms. | Through follow up (12 months) | 
| Major Bleeding | Major bleeding is defined as overt bleeding associated with a hemoglobin level reduction of at least 2.0 grams per deciliter (g/dL), or with transfusion of two or more units of red blood cells, or involvement of a critical site (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome). | Through follow up (12 months) | 
| Minor Bleeding | Clinically overt bleeding not fulfilling the criteria of major bleeding is classified as a minor bleeding complication. | Through follow up (12 months) | 
| Symptomatic Venous Thromboembolism (VTE) | Recurrent venous thromboembolism (VTE) will be diagnosed if symptoms or signs of deep vein thrombosis or acute pulmonary embolism (PE) are confirmed by an imaging test. There will be no routine surveillance for asymptomatic recurrent VTE. | Until 90 days post procedure | 
| Clinical Success of Treatment | Treatment will be considered successful if pulmonary embolism related decompensation is prevented, without the participant experiencing a major adverse event or death. | Until 90 days post procedure | 
| ICU Length of Stay | The number of days participants were admitted to the ICU will be compared between study arms. | Until hospital discharge (an average of 6 days) | 
| Change in Right Ventricular/Left Ventricular (RV/LV) Diameter Ratio | Under normal circumstances, the right ventricle appears smaller than the left ventricle when measured by an echocardiogram (RV/LV ratio<1). An increased RV/LV ratio may be a predictor of poor clinical outcomes following pulmonary embolism. | Baseline, end of lysis treatment, Month 3, Month 12 | 
| Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) | Tricuspid annular plane systolic excursion (TAPSE) is an echocardiographic of measuring right ventricular function. TAPSE measurements can be categorized as normal (1.5-2.0cm), mildly abnormal (1.3-1.5cm), moderately abnormal (1.0-1.2cm) or severely abnormal (<1.0cm). | Baseline, end of lysis treatment, Month 3, Month 12 | 
| Change in Right Ventricular Systolic Pressure (RVSP) | Right ventricular systolic pressure (RVSP) measured by echocardiogram provides an estimate the pressure inside the artery supplying blood to the lungs. Dysfunction in the right ventricle is assessed to predict clinical outcomes following pulmonary embolism. | Baseline, end of lysis treatment, Month 3, Month 12 | 
| Number of Participants Who Had a Decrease in New York Heart Association (NYHA) Functional Classification of Heart Failure From Class 4 to Class 2 | New York Heart Association (NYHA) Functional Classification of heart failure classifies heart failure with a combination of two methods: patient symptoms and objective assessment by a healthcare provider. Patient symptoms are classified as I-IV, where I = no limitation of physical activity and IV = unable to carry on any physical activity without discomfort. An objective assessment by a healthcare provider is classified as A through D where A = objective evidence of cardiovascular disease and D = objective evidence of severe cardiovascular disease. | Month 3, Month 12 | 
| Change in 6-minute Walk Test | The 6-minute walk test (6MWT) measures the distance that can be quickly walked by the study participant in 6 minutes. A 30 meter long walking course is created using cones on a hard, flat surface and the participant will walk the course as many times as they can in 6 minutes while a study team member counts the number of laps completed. Specific test guidelines from the American Thoracic Society will be followed. | Month 3, Month 12 | 
| Change in 36-Item, Short Form (SF-36) Score | The SF-36 is a 36 item survey assessing the quality of life across the 8 domains of physical functioning, limitations due to physical health, limitations due to emotional health, energy, emotional well-being, social functioning, pain, and general health. Each item is scored between 0 and 100 where 0 represents the worst possible quality of life and 100 corresponds with a healthy state of being. The numbers analyzed below represent the average score obtained with 0 being the bottom 25% of the quality of life (score 0-25), 1 is 26-50, 2 is 51-75, and 4 is 76-100. | Month 3, Month 12 | 
| Change in Quality of Life After Pulmonary Embolism (PEmb QoL) Score | Quality of life after pulmonary embolism (PEmb QoL) questionnaire is a 40 item survey asking respondents about their lung symptoms after having a pulmonary embolism. Participants report on 6 dimensions which cover the frequency and intensity of lung symptoms, physical and social limitations due to symptoms, pain, and emotional distress following having a pulmonary embolism. Scoring the responses involves specific instructions to reverse the scores for several dimensions, resulting in a score between 0 and 100 where 0 corresponds with no complaints and 100 is worst possible outcome. | Month 3, Month 12 | 
| Change in Shortness of Breath Questionnaire Score | The University of California San Diego (UCSD) Medical Center Shortness of Breath Questionnaire is a 24 item survey asking respondents how much shortness of breath they experience doing particular activities. Breathlessness is rated on a scale of 0 (not at all breathless) to 5 (maximally breathless or unable to do an activity become of breathlessness). Total scores range from 0 to 120, with higher scores indicating increased shortness of breath. | Month 3, Month 12 | 
| Cost Effectiveness Analysis | A Markov state-transition, cost effectiveness model will be created to simulate patient oriented outcomes assuming a societal perspective with a 12-month time horizon. All point estimates for model parameters will be determined from the prospectively collected data. Quality adjusted life years will be determined for each therapy based on survival, freedom from major adverse events, discharge status, functional status, and quality of life measures. Costs will be calculated for each therapy based on in-hospital resource utilization (i.e., length of stay in the ICU, operating room and procedure costs, and associated adverse event costs) and out-of-hospital costs (outpatient nursing care, loss of work, outpatient testing and follow-up). | Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Medicine, Therapy Evaluation