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

• ClinicalTrials.gov Identifier: NCT03389971
• Recruitment Status: Active, not recruiting
• First Posted: January 4, 2018
• Last Update Posted: June 4, 2020
• Sponsor: Piedmont Healthcare
• Information provided by (Responsible Party): Piedmont Healthcare

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Submassive Pulmonary Embolism	Procedure: catheter-directed thrombolysis	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: ULTRAsound-assisted Catheter vs. STAndaRd Catheter Thrombolysis for Submassive Pulmonary Embolism
• Actual Study Start Date: December 6, 2017
• Estimated Primary Completion Date: February 1, 2021
• Estimated Study Completion Date: February 1, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. cardiopulmonary and clinical outcomes - echocardiographic [ Time Frame: 12 months post surgery ]
   Determine differences in cardiopulmonary echocardiographic parameters between the two techniques
2. cardiopulmonary and clinical outcomes - hemodynamic [ Time Frame: 12 months post surgery ]
   Determine differences in cardiopulmonary hemodynamic parameters between the two techniques
3. cardiopulmonary and clinical outcomes - respiratory [ Time Frame: 12 months post surgery ]
   Determine differences in cardiopulmonary respiratory parameters between the two techniques
4. cardiopulmonary and clinical outcomes - decompensation [ Time Frame: 12 months post surgery ]
   Determine differences in decompensation clinical outcomes between the two techniques
5. cardiopulmonary and clinical outcomes - mortality [ Time Frame: 12 months post surgery ]
   Determine differences in mortality clinical outcomes between the two techniques
6. cardiopulmonary and clinical outcomes - complications [ Time Frame: 12 months post surgery ]
   Determine differences in clinical complications between the two techniques
7. cardiopulmonary and clinical outcomes - ICU stay [ Time Frame: 12 months post surgery ]
   Determine differences in ICU length of stay between the two techniques
8. 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.
9. 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
10. 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
11. 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. resource utilization [ Time Frame: 12 months post surgery ]
    Perform a resource utilization analysis, what services will be utilized by the patient

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Georgia

Piedmont Healthcare

Atlanta, Georgia, United States, 30309

Sponsors and Collaborators

Piedmont Healthcare

Investigators

• Principal Investigator: Charles Ross, MD; Piedmont Healthcare

More Information

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• Responsible Party: Piedmont Healthcare
• ClinicalTrials.gov Identifier: NCT03389971
• Other Study ID Numbers: UltraStar sPE
• First Posted: January 4, 2018
• Last Update Posted: June 4, 2020
• Last Verified: June 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Pulmonary Embolism; Embolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Lung Diseases; Respiratory Tract Diseases