Standard vs. Ultrasound-assisted Catheter Thrombolysis for Submassive Pulmonary Embolism (SUNSET sPE)

September 3, 2021 updated by: Efthymios Avgerinos, MD, University of Pittsburgh

Comparison of Standard Catheter Directed Thrombolysis vs. Ultrasound Assisted Thrombolysis for Patients With Acute Submassive Pulmonary Embolism

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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

77

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15219
        • UPMC Mercy
      • Pittsburgh, Pennsylvania, United States, 15213
        • UPMC Presbyterian
      • Pittsburgh, Pennsylvania, United States, 15232
        • UPMC Shadyside
      • Pittsburgh, Pennsylvania, United States, 15237
        • UPMC Passavant

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Criteria: 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).

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: 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
Procedure: CDT without ultrasound acceleration
A pulmonary arteriogram will be performed. Upon confirmation of the pulmonary embolus a standard infusion catheter will be placed within the clot. The catheter will be used for infusion of thrombolytics to treat/dissolve the pulmonary embolus.
Other Names:
  • Standard CDT
EXPERIMENTAL: CDT ultrasound accelerated
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
Procedure: CDT with ultrasound acceleration
A pulmonary arteriogram will be performed. Upon confirmation of the pulmonary embolus an infusion catheter that incorporates an ultrasound emitting wire will be placed within the clot. The catheter will be used for infusion of thrombolytics to treat/dissolve the pulmonary embolus. The wire will be connected to an ultrasound generating device.
Other Names:
  • Ultrasound assisted CDT

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
PE thrombus load reduction (CT obstruction index) from baseline to the termination of lysis
Time Frame: 48 hours
48 hours

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Pittsburgh

Investigators

  • Principal Investigator: Efthymios Avgerinos, M.D., University of Pittsburgh

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2016

Primary Completion (ACTUAL)

August 1, 2021

Study Completion (ACTUAL)

August 1, 2021

Study Registration Dates

First Submitted

March 22, 2016

First Submitted That Met QC Criteria

April 27, 2016

First Posted (ESTIMATE)

May 2, 2016

Study Record Updates

Last Update Posted (ACTUAL)

September 5, 2021

Last Update Submitted That Met QC Criteria

September 3, 2021

Last Verified

September 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PRO15090058

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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