Ultrasound-facilitated, Catheter-directed, Thrombolysis in Intermediate-high Risk Pulmonary Embolism

Inclusion Criteria:

• Age 18-80 years, inclusive

• Objectively confirmed acute PE, based on computed tomography pulmonary angiography (CTPA) showing a filling defect in at least one main or proximal lobar pulmonaryartery

• Elevated risk of early death/hemodynamic collapse, indicated by at least two of thefollowing new-onset clinical criteria:

1. ECG-documented tachycardia with heart rate ≥100 beats per minute, not due tohypovolemia, arrhythmia, or sepsis;

2. SBP ≤ 110 mm Hg for at least 15 minutes;

3. respiratory rate > 20 x min-1 or oxygen saturation on pulse oximetry (SpO2) < 90% (or partial arterial oxygen pressure < 60 mmHg) at rest while breathingroom air;

• Right-to-left ventricular (RV/LV) diameter ratio ≥ 1.0 on CTPA

• Serum troponin I or T levels above the upper limit of normal

• Signed informed consent

Exclusion Criteria:

• Hemodynamic instability*, i.e. at least one of the following present:

1. cardiac arrest or need for cardiopulmonary resuscitation;

2. need for ECMO, or ECMO initiated before randomization

3. PE-related shock, defined as: (i) SBP < 90 mmHg, or vasopressors required toachieve SBP ≥ 90 mmHg, despite an adequate volume status; and (ii) end-organhypoperfusion (altered mental status; oliguria/anuria; increased serumlactate);

4. isolated persistent hypotension (SBP < 90 mmHg, or a systolic pressure drop byat least 40 mmHg for at least 15 minutes), not caused by new-onset arrhythmia,hypovolemia, or sepsis * Patients who presented with temporary need for fluidresuscitation and/or low-dose catecholamines may be included, provided thatthey could be stabilized within 2 hours of admission and maintain SBP of ≥ 90mmHg and adequate organ perfusion without catecholamine infusion.

• Need for admission to an intensive care unit for a reason other than the index PEepisode. NB: Patients who test positive for SARS-CoV-2 can be enrolled where theinvestigator believes that the pulmonary embolism is the dominant pathology in thepatient's clinical presentation and qualifying cardiorespiratory parameters.

• Temperature above 39 degrees C / 102.2 degrees F

• Logistical reasons limiting the rapid availability of interventional procedures totreat acute PE (e.g., during the outbreak of an epidemic)

• Index PE symptom duration > 14 days

• Active bleeding

• History of intracranial or intraocular bleeding at any time

• Stroke or transient ischemic attack within the past 6 months, or previous stroke atany time if associated with permanent disability

• Central nervous system neoplasm, or metastatic cancer

• Major neurologic, ophthalmologic, abdominal, cardiac, thoracic, vascular ororthopedic surgery or trauma (including syncope-associated with head strike orskeletal fracture) within the past 3 weeks

• Platelet count < 100 x 109 x L-1

• Patients who have received a once-daily therapeutic dose of LMWH or a therapeuticdose of fondaparinux within 24 hours prior to randomization

• Patients who have received one of the direct oral anticoagulants apixaban orrivaroxaban within 12 hours prior to randomization

• Patients who have received one of the direct oral anticoagulants dabigatran oredoxaban for the index PE episode, as these drugs are not approved for patients whohave not received heparin for at least 5 days

• Administration of a thrombolytic agent or a glycoprotein IIb/IIIa receptorantagonist during the current hospital stay and/or within 30 days, for any reason

• Chronic treatment with antiplatelet agents other than low-dose acetylsalicylic acidor clopidogrel 75 mg once daily (but not both). Dual antiplatelet therapy isexcluded.

• Chronic treatment with a direct oral anticoagulant (apixaban, dabigatran, edoxabanor rivaroxaban)

• Chronic treatment with a vitamin K antagonist, or known coagulopathy includingsevere hepatic dysfunction, with an International Normalized Ratio (INR) > 1.5

• Pregnancy or lactation

• Previous inclusion in the study

• Known hypersensitivity to alteplase, LMWH or UFH, or to any of the excipients

• Life expectancy less than 6 months