ULTRAsound-assisted Catheter vs. STAndaRd Catheter Thrombolysis for Submassive Pulmonary Embolism

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.

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