Standard vs. Ultrasound-assisted Catheter Thrombolysis for Submassive Pulmonary Embolism

Not Applicable

Completed

• Conditions: Pulmonary Embolism
• Interventions: Procedure: CDT without ultrasound acceleration; Procedure: CDT with ultrasound acceleration

• Registration Number: NCT02758574
• Lead Sponsor: University of Pittsburgh

Brief Summary

The study will compare standard catheter directed thrombolysis to ultrasound accelerated thrombolysis for the treatment of acute submassive pulmonary embolism (PE). The study population will include patients eligible for catheter directed thrombolysis (CDT) for submassive PE. Subjects will be randomized to, either, standard catheter-directed thrombolysis or ultrasound-accelerated thrombolysis (USAT).

Detailed Description

Acute pulmonary embolism (PE) carries a high morbidity and is the third-leading cause of cardiovascular mortality in the western world. It accounts for 5-10% of in-hospital deaths that for the United States translates to 200,000 deaths per year.1 Recent registries and cohort studies suggest that approximately 10% of all patients with acute PE die during the first 1 to 3 months after diagnosis. Studies that have observed survivors for \>3 months have reported an incidence of chronic thromboembolic pulmonary hypertension (CTEPH) 1-5% within 2-3 years after PE.6-10 It is an incapacitating long-term complication of thromboembolic disease with a negative impact on the patient's quality of life and prognosis.

The management acute PE is mainly guided by the acuity and severity of clinical presentation. Initial systemic anticoagulation (AC) is the standard of care and treatment is escalated based on the clinical presentation and patient characteristics that may stratify them at a higher mortality risk. The goals of therapy are to primarily prevent mortality, and secondarily potentially prevent late onset chronic thromboembolic pulmonary hypertension (CTEPH) and improve quality of life.

Massive PE is defined as PE associated with sustained hemodynamic instability, whereas submassive PE (sPE) is defined as PE without hemodynamic instability but with abnormal right ventricular (RV) function and/or evidence of myocardial necrosis. It is notable that there is ongoing interest to accurately risk stratify sPE to identify the patients who are at increased risk of decompensating and/or dying. Clinical scores, imaging tests and biomarkers are under investigation, yet an ideal prognostic tool is still pending. A novel cardiac biomarker, heart-type fatty acid-binding protein (h-FABP), is emerging as a significant predictor of mortality in patients with submassive PE.

Systemic intravenous thrombolysis is universally recommended by all guideline bodies for massive pulmonary embolism, but remains controversial for submassive PE. In the most recent metaanalysis, the subgroup analysis of 8 submassive PE trials (1993-2014, n=1775) showed that thrombolytic therapy was associated with a mortality reduction (1.39% vs 2.92%) but with an increase in major bleeding (7.74% vs 2.25%). These results were mainly driven by the largest randomized trial (PEITHO, 1006 patients) which compared a single, weight-adapted i.v. bolus of tenecteplase with standard anticoagulation.

The recent development of catheter-directed therapies such as catheter-directed thrombolysis (CDT), ultrasound-accelerated thrombolysis (USAT), and pharmacomechanical or aspiration thrombectomy has introduced more tools for the treatment of acute PE. Proponents of these techniques suggest that they may provide a similar therapeutic benefit as systemic thrombolysis, while decreasing the dose of thrombolytic required and potentially decreasing the risk of adverse bleeding events. Both the American Heart Association and more recently European Society of Cardiology have acknowledged CDT as a viable treatment alternative for high risk acute sPE (echocardiographic RV dysfunction and elevated cardiac biomarkers), if appropriate expertise is available and particularly when the bleeding risk is high.

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. USAT is a modification of this therapy 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.

Several observational non-controlled series have demonstrated the efficacy of catheter-directed techniques in improving clinical and hemodynamic parameters and reducing clot burden while demonstrating a favorable safety profile. The ULTIMA trial was the first randomized controlled trial to include CDIs for sPE comparing standardized fixed-dose of USAT (10mg rtPA per lung over 15 hours) and AC to AC alone. In the USAT group, but not in the heparin group, the mean RV/LV ratio was significantly reduced at 24 hours, but became comparable between the two groups at 90 days. The RV systolic function was significantly improved in the USAT group vs. the heparin group at both 24 hours and 90 days. In both study groups minor bleeding complications were rare and there were no major bleeding complications. The SEATTLE II trial, a single-arm study evaluating the effectiveness of USAT, showed also an RV/LV ratio improvement at 48 hours.

Limited data exists for comparing different catheter-directed therapies for acute PE. The majority of recent series for catheter-directed interventions utilize USAT exclusively; however there is limited comparative effectiveness data comparing this modality to standard multi-sidehole catheter infusion. Preliminary, non-controlled data are conflicting. One series by Lin and colleagues of 33 high-risk PE patients suggested benefit for USAT for angiographic clearance of thrombus burden with more bleeding events in the CDT group.31 Kuo and colleagues noted no difference in outcomes and treatment specifics between USAT and CDT in the recently published early results of a multicenter prospective registry. Our retrospective analysis of 63 patients suggests that there may be no difference between the two treatment modalities, demonstrating similar rates of outcomes such as survival, hemodynamic stabilization, and echocardiographic parameters in both groups with similar procedure length and lytic dose in the time-adjusted cohorts. Selection bias cannot be underestimated in all these studies.

The expected benefit of USAT has been dependent on the device's ability to increase penetration of lytic into thrombus using high frequency, low power ultrasound, due to its reversible effects on fibrin dissociation. This benefit has been shown to result in faster thrombus clearance in selected vascular beds in some studies, such as the recently published DUET study comparing USAT and CDT in arterial occlusions. More rapid clearance of pulmonary thrombus by USAT compared to standard CDT may prove to be clinically and cost effective (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 (proprietary equipment and disposables), without offering any potential advantage. Evidence from the venous circulation, coming from the recent BERNUTIFUL trial demonstrated no difference in time to thrombus clearance in lower extremity deep venous thrombosis.

Study Timeline

• Study First Submitted: 2016-03-22
• Study First Submitted QC: 2016-04-27
• Study Start: 2016-05
• Study First Posted: 2016-05-02
• Primary Completion: 2021-08
• Study Completion: 2021-08
• Status Verified: 2021-09
• Last Update Submitted: 2021-09-03
• Last Update Posted: 2021-09-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 77

Inclusion Criteria

• Subject is eligible for catheter directed thrombolysis per the study protocol for submassive 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) and without the need of catecholamine support or cardiopulmonary resuscitation).

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Exclusion Criteria

• pregnancy;
• index PE symptom duration >14 days;
• high bleeding rsk (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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CDT without ultrasound acceleration	CDT without ultrasound acceleration	Standard Catheter-Directed Thrombolysis: Utilization of a standard infusion catheter, placed at the site of pulmonary thrombus. The catheter will be used for the delivery of thrombolytic medications to treat/dissolve pulmonary embolus
CDT ultrasound accelerated	CDT with ultrasound acceleration	Ultrasound Accelerated Catheter-Directed Thrombolysis: Utilization of an infusion catheter that incorporates an ultrasound emitting wire both placed at the site of pulmonary thrombus. The catheter will be used for the delivery of thrombolytic medications with the ultrasound emitting wire activated to treat/dissolve pulmonary embolus

Primary Outcome Measures

Name	Time	Method
PE thrombus load reduction (CT obstruction index) from baseline to the termination of lysis	48 hours

Secondary Outcome Measures

Name	Time	Method
Stroke	30 days	Any ischemic or hemorrhagic stroke
Quality of life Questionnaire San Diego Shortness of Breath (score)	12 months
Major Bleeding	30 days	Any major bleeding event defined as hemorrhagic stroke, need to transfuse or need to intervene
Mortality	90 days
Echocardiographic Right Ventricular/Left Ventricular Diameter (ratio)	12 months
Cost effectiveness analysis	12 months	Quality Adjusted Life Years - Costs based on in-hospital resource utilization and out-of hospital care and follow-up.
Functional status (6 min walk test)	12 months	6 min walk test (meters)
Echocardiographic Tricuspid Annular Plane Systolic Excursion (cm)	12 months
Quality of life Questionnaire SF36 (score)	12 months
Quality of life Questionnaire PE QOL (score)	12 months

Trial Locations

Locations (4)

UPMC Mercy; 🇺🇸 Pittsburgh, Pennsylvania, United States

UPMC Passavant; 🇺🇸 Pittsburgh, Pennsylvania, United States

UPMC Presbyterian; 🇺🇸 Pittsburgh, Pennsylvania, United States

UPMC Shadyside; 🇺🇸 Pittsburgh, Pennsylvania, United States