USAT-CDT Trial: Standard vs Ultrasound-assisted Catheter Thrombolysis for Submassive Pulmonary Embolism
Phase: NA
Conditions: Cardiovascular Diseases
Sponsor: Emory University

 
 
 
 
 
 
 
 
Standard vs Ultrasound-assisted Catheter Thrombolysis for 
Submassive Pulmonary 
Embolism 
NCT03086317 
 
Date: February 10, 2017 
IRB number: 00093040 
 

Standard vs Ultrasound-assisted Catheter Thrombolysis for Submassive Pulmonary 
Embolism
Principal Investigators: Wissam Jaber, MD and Michael McDaniel, MD
IRB number: 93040
Draft date:  February 10, 2017
SUMMARY
Background: 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 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, allowing deeper 
penetration of lytics. However, there is limited comparative effectiveness data against standard 
multi-sidehole catheter infusion. More rapid clearance of pulmonary thrombus by USAT compared 
to standard CDT may prove to be clinically and cost effective.  Alternatively, if thrombus clearance 
is similar, the cost of USAT may exceed the cost of CDT (equipment and disposables), without 
offering any potential advantage.
Hypothesis: Ultrasound Accelerated Thrombolysis is superior to Standard Catheter 
Thrombolysis for patients with submassive PE
Objectives/Aims: 1. Determine differences in the percentage of thrombus load reduction (CTA 
Obstruction Index) from baseline to the termination of lysis; 2. Determine differences in 
cardiopulmonary and clinical outcomes; 3. Determine differences in the impact of catheter 
directed intervention on functional capacity (NYHA score and 6-min walk test) and health-related 
quality of life outcomes (SF36, PE QOL, and San Diego Shortness of Breath questionnaires at 3 
and 12 months; 4. Detail the cost differences in hospital resource utilization (i.e., procedure costs, 
adverse event costs, and hospital stay) and discharge costs (nursing care, subsequent outpatient 
care) to inform a Markov state-transition cost-effectiveness model.
Design: Randomized controlled trial.
Statistical Power: The study is powered on the primary endpoint. 40 patients will be needed at 
each group for a power of 0.80.

RESEARCH PLAN 
a. SPECIFIC AIMS
Hypothesis: Ultrasound Accelerated Thrombolysis is superior to Standard Catheter 
Thrombolysis for patients with submassive PE
Aim 1: Determine differences in the percentage of thrombus load reduction from baseline to the 
termination of lysis between the two techniques
Aim 2: Determine differences in cardiopulmonary (echocardiographic, hemodynamic and 
respiratory parameters) and clinical outcomes (decompensation, mortality, complications, 
ICU stay) between the two techniques
Aim 3: Determine differences in the impact of catheter directed interventions on functional 
capacity and health-related quality of life outcomes at 3 and 12 months
Aim 4: Perform a cost effectiveness analysis to compare quality adjust life years and costs of the 
two techniques.
 
b. BACKGROUND AND SIGNIFICANCE
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.1-5 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.2, 
3, 5, 11-14
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.3 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.15, 16
Systemic intravenous thrombolysis is universally recommended by all guideline bodies for 
massive pulmonary embolism, but remains controversial for submassive PE.3-5, 17  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.18
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.2 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.19-24 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.3, 5 
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.2, 19, 23, 25-28 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.21 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.29
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.15, 16, 19, 30 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.28 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.32 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.19, 21 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.33 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.34 
c. INNOVATION
There are no randomized controlled studies that have compared the outcomes of catheter 
directed thrombolysis with and without ultrasound acceleration. 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.
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.28 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.32 Selection bias cannot be underestimated in all these studies.
A controlled randomized study will better determine if ultrasound acceleration adds any 
benefits in the outcomes and costs of catheter directed thrombolysis for patients with acute 
submassive PE.
d. APPROACH
The study will be designed as a randomized controlled trial comparing standard catheter directed 
thrombolysis to ultrasound accelerated thrombolysis for the treatment of acute submassive PE. 
The study will include patients 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).
The treatment with CDT or USAT are standard of care for submassive PE. All the procedures, 
tests and follow up visits are according to current standard of care.
Exclusion criteria: age <18; 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; and inability to comply with study assessments.

At baseline all patients need to have
1.
Chest CT angiogram with contrast diagnostic of PE
2.
Baseline transthoracic echocardiogram
3.
Baseline cardiac biomarkers 
a.
Cardiac troponin (cTn) 
b.
Brain Natriuretic Peptide (BNP) and/or N-terminal pro-BNP (NT-proBNP)
All patients will be treated initially with unfractionated heparin by using a standardized dosing 
protocol. Immediately after consent, vital signs will be recorded, a pulse oximetry reading will be 
obtained with the patient breathing room air for 2 min.
All eligible patients will undergo catheter-directed thrombolysis randomized to either a standard 
commercially available multi-sidehole catheter or a USAT catheter. 
Technical considerations (access, intraoperative tPA bolus, tPA dripping dose etc) will be left to 
the discretion and preference of the operator. Invasive pressure tracings will be obtained from the 
drug delivery catheters when positioned in the pulmonary arteries (main, right or left). The 
maximum tPA dosing should not exceed 24mg.
Termination of lysis will be left to the discretion of the operator. As a general recommendation 
lysis should be terminated once clinical (e.g. O2 requirements), hemodynamic (e.g. pulse rate or 
blood pressure) and/or echocardiographic parameters (e.g. RV dilatation) improve or if a 
complication occurs. Lysis catheters and sheaths can be removed at the bedside. Before removal, 
invasive pressure tracings will be recorded from the drug delivery catheter.
A transthoracic echocardiogram should be obtained just before or within 24 hours after the 
termination of lysis.
Within 48h after the termination of lysis patients will get a chest CTA examination.
Patients will be followed up at 3 months and 12 months.
Primary Endpoint: PE thrombus load reduction (CT obstruction index) from baseline to the 
termination of lysis.
The pre and post lysis CTA will be compared by 2 blinded independent radiologists. 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). The vascular obstruction scores will be determined 
as previously described by Qanadli et al. and Mastora et al.35,36
Secondary Endpoints:
1.
Clinical outcomes comparison
a.
In hospital and 90-day mortality
b.
Decompensation to massive PE (hypotension <90mmHg and use of 
catecholamines)
c.
Major and minor bleeding. Major bleeding is defined as overt bleeding associated 
with a fall in the hemoglobin level of at least 2.0 g/dL or with transfusion of ≥2 U of 
red blood cells or involvement of a critical site (intracranial, intraspi-nal, intraocular, 
retroperitoneal, intra-articular or pericardial, or intra-muscular with compartment 

syndrome). Clinically overt bleeding not fulfilling the criteria of major bleeding is 
classified as a minor bleeding complication.
d.
Recurrent venous thromboembolism (VTE) during 90-day follow-up. There will be 
no routine surveillance for asymptomatic recurrent VTE. Recurrent VTE will be 
diagnosed if suspected symptoms or signs of deep vein thrombosis or acute PE 
are objectively confirmed by an imaging test (new filling defect by pulmonary 
angiography or contrast-enhanced chest CT, new high-probability perfusion defect 
revealed by lung scan, or positive compression ultrasound study for deep vein 
thrombosis). 
e.
Major adverse events up to 90 days after randomization.
f.
Clinical success: PE related decompensation prevention without a 90-day major 
adverse event or death.
g.
ICU length of stay
2.
Echocardiographic parameters comparison
a.
RV/LV, TAPSE (Tricuspid annular plane systolic excursion) and RVSP (Right 
Ventricular Systolic Pressure) improvement from baseline to the termination of 
lysis
b.
RV/LV, TAPSE and RVSP at 90 days
c.
RV/LV, TAPSE and RVSP at 12 months
The echocardiograms will be interpreted by 2 blinded independent cardiologists.
3.
Functional status and quality of life
At the 3 and 12-month follow-up visit, patients will complete a written survey to assess the 
NYHA score and answer other questions about functional status. Patients will then 
perform a 6-minute walk test according to published guidelines.37,38Transthoracic 
echocardiography will be also performed as described earlier.
Quality of life will be assessed at 3 and 12 months using SF36, PE QOL, and San Diego 
Shortness of Breath questionnaires.  
4.
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, 
as described above. 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). 

Schedule of Events
 
Baseline
Screening
Randomization
US assisted or 
standard 
catheter 
thrombolysis
Lysis 
Procedure
Prior to Lysis 
Termination 
or within 24h 
post lysis
Within 
48hrs 
post lysis
3month 
f-up
+/-14 
days  
12month 
f-up
+/- 30 
days
 
 
 
 
 
 
 
 
 
Informed Consent
 
X
 
 
 
 
 
 
Chest CTA
X
 
 
 
 
X
 
 
Transthoracic  
Echocardiogram
X
 
 
 
X
 
X
X
Cardiac troponin 
(cTn)
X
 
 
 
 
 
 
 
Brain Natriuretic 
Peptide (BNP)
X
 
 
 
 
 
 
 
N-terminal pro-
BNP(NT-proBNP)
X
 
 
 
 
 
 
 
IV Unfractionated 
Heparin 
 
X
 
 
 
 
 
 
Vital Signs
 
X
 
 
 
 
 
 
2min Pulse Ox
 
X
 
 
 
 
 
 
Ultrasound 
Catheter Placement 
 
 
X
X
 
 
 
 
Standard Catheter 
placement
 
 
X
X
 
 
 
 
Invasive Pressure 
Tracings from drug 
delivery catheter
 
 
 
X(a)
X(b)
 
 
 
Functional Status 
NYHA
 
 
 
 
 
 
X
X
Quality of Life 
Questionnaires
 
 
 
 
 
 
X
X
Six Minute Walk 
Test
 
 
 
 
 
 
X
X
(a) Before lytics administered
(b) After lytics administered

Statistical Analysis: 
The study is powered on the primary endpoint that is thrombus load reduction (obstruction index). 
We propose to compare standard CDT and USAT at post-treatment with analysis of covariance, 
controlling for differences remaining after randomization. Population parameters for the 
obstruction score have not been published, so we consulted several relevant studies reporting on 
thrombus reduction scores in order to predict sample size.19,31,34,39 We assumed that CDT with 
ultrasound enhancement (USAT group) should be ≥50% more effective than without ultrasound 
enhancement (control group) and calculated an expected relative mean thrombus reduction of 
43% in the CDT control group.40.41 We estimated a sample size of 40 per group to detect the 
differences with a power of 0.80.
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