ULTRAsound-assisted Catheter vs. STAndaRd Catheter Thrombolysis for Submassive Pulmonary Embolism (UltraStar sPE)

September 23, 2021 updated by: Piedmont Healthcare
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 infusion catheter 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 lysis utilizing a system of local ultrasound to dissociate the fibrin matrix of the thrombus with simultaneous acoustic streaming of the thrombolytic agent, allowing more efficient thrombolysis. However, there is limited comparative effectiveness data against standard multi-side hole catheter infusion. More rapid clearance of pulmonary thrombus by USAT compared to standard CDT may prove to be clinically beneficial and cost effective. Alternatively, if thrombus clearance is similar, the cost of USAT may exceed the cost of CDT (equipment and disposables), without realization any advantage.

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. 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. CTEPH 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%).11 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 with simultaneous acoustic streaming of the infusate, 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. 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. The University of Pittsburgh group's 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. 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)

10

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
    • Georgia
      • Atlanta, Georgia, United States, 30309
        • Piedmont Healthcare

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

Inclusion Criteria:

  • Patients with 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:

  • <18 or >80
  • 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

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 Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: multi-sidehole catheter
Procedure: catheter-directed thrombolysis
catheter-directed thrombolysis with commercially available multi-sidehole catheter or USAT catheter
Experimental: USAT catheter
Procedure: catheter-directed thrombolysis
catheter-directed thrombolysis with commercially available multi-sidehole catheter or USAT catheter

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
thrombus load reduction
Time Frame: 12 months post surgery
Determine differences in the percentage of thrombus load reduction from baseline to the termination of lysis between the two techniques
12 months post surgery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
cardiopulmonary and clinical outcomes - echocardiographic
Time Frame: 12 months post surgery
Determine differences in cardiopulmonary echocardiographic parameters between the two techniques
12 months post surgery
cardiopulmonary and clinical outcomes - hemodynamic
Time Frame: 12 months post surgery
Determine differences in cardiopulmonary hemodynamic parameters between the two techniques
12 months post surgery
cardiopulmonary and clinical outcomes - respiratory
Time Frame: 12 months post surgery
Determine differences in cardiopulmonary respiratory parameters between the two techniques
12 months post surgery
cardiopulmonary and clinical outcomes - decompensation
Time Frame: 12 months post surgery
Determine differences in decompensation clinical outcomes between the two techniques
12 months post surgery
cardiopulmonary and clinical outcomes - mortality
Time Frame: 12 months post surgery
Determine differences in mortality clinical outcomes between the two techniques
12 months post surgery
cardiopulmonary and clinical outcomes - complications
Time Frame: 12 months post surgery
Determine differences in clinical complications between the two techniques
12 months post surgery
cardiopulmonary and clinical outcomes - ICU stay
Time Frame: 12 months post surgery
Determine differences in ICU length of stay between the two techniques
12 months post surgery
San Diego Shortness of Breath questionnaire
Time Frame: 12 months post surgery
Determine differences in the impact of catheter directed interventions on functional capacity and health-related quality of life outcomes at 3 and 12 months using a 0 to 5 scale where zero is nota at all breathless and 5 is maximally breathless or too breathless to do the activity. Total scoring range from 0 to 120.
12 months post surgery
SF36
Time Frame: 12 months post surgery
Determine differences in the impact of catheter directed interventions on functional capacity and health-related quality of life outcomes at 3 and 12 months using the questionnaire noted in the title
12 months post surgery
PE QOL
Time Frame: 12 months post surgery
Determine differences in the impact of catheter directed interventions on functional capacity and health-related quality of life outcomes at 3 and 12 months using the questionnaire noted in the title
12 months post surgery
utilization cost
Time Frame: 12 months post surgery
Perform a cost utilization analysis for the two patient groups to compare differences in medical costs
12 months post surgery
resource utilization
Time Frame: 12 months post surgery
Perform a resource utilization analysis, what services will be utilized by the patient
12 months post surgery

Collaborators and Investigators

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

Sponsor

Piedmont Healthcare

Investigators

  • Principal Investigator: Charles Ross, MD, Piedmont Healthcare

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 (Actual)

December 6, 2017

Primary Completion (Actual)

April 1, 2020

Study Completion (Actual)

April 1, 2020

Study Registration Dates

First Submitted

December 6, 2017

First Submitted That Met QC Criteria

December 27, 2017

First Posted (Actual)

January 4, 2018

Study Record Updates

Last Update Posted (Actual)

September 24, 2021

Last Update Submitted That Met QC Criteria

September 23, 2021

Last Verified

September 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • UltraStar sPE

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

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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