To determine whether peripheral low dose systemic thrombolysis (PLST) is non-inferior to catheter directed acoustic pulse thrombolysis (ACDT) in improving RV function and reducing pulmonary artery pressures in submassive pulmonary embolism (PE)

Acute pulmonary embolism (PE) is a life-threatening event associated with high morbidity and mortality. With more than 100,000 deaths per year, PE constitutes the third most common cardiovascular cause of death following myocardial infarction and stroke. In non massive PE, anticoagulation is the treatment of choice. Advanced treatment options such as systemic thrombolysis in submassive and massive PE help reduce mortality but unfortunately are associated with bleeding complications such as a 2 to 5% risk of hemorrhagic stroke.This has led to development of pharmaco-mechanical therapies such as catheter directed thrombolysis (CDT).

Current guidelines advocate against the use of full dose systemic thrombolysis for acute submassive PE in all patients unless the bleeding risk is very low. CDT has shown efficiency in reducing right ventricular strain and pulmonary hypertension without increasing bleeding complications in trial populations. Ultrasound assisted CDT (ACDT) is an established treatment modality for acute PE which utilizes high frequency low power ultrasonic waves. It is FDA approved for sub-massive and massive pulmonary embolism. However, ultrasound does not breakdown the thrombus itself but increases the permeability for thrombolytic drugs. The ULTIMA trial showed ACDT was superior to anticoagulation treatment in reducing pulmonary hypertension (PH) and right ventricular dilatation in submassive and massive PE. The trial also reported no intracranial hemorrhage. The exact benefit and mechanism of ACDT in dissolving clots is still not clear. Recently, the PERFECT registry described 100 patients who underwent CDT (64%) and ACDT (46%) for PE, the study showed no difference in reduction of pulmonary artery pressures.

ACDT requires the placement of catheters in the pulmonary arteries in a catheterization laboratory by an interventional cardiologist/radiologist through the internal jugular vein/femoral vein and catheters are kept for 12-24 hrs to infuse recombinant tissue plasminogen activator (r-tpa). While many healthcare systems have developed a pulmonary embolism response team (PERT) to make a prompt therapeutic decision in submassive and massive pulmonary embolism management. However, it is not uncommon for CDT to be delayed (sometimes > 12 hours) after the initial diagnosis due to the availability of the interventional cardiologist. Furthermore, placement of pulmonary catheters in CDT can have the risk, albeit low, of pulmonary vasculature injury.

The investigators hypothesize that low dose thrombolytic therapy can be administered through a peripheral vein. PLST is rapidly administrable and does not require placement in a catheterization laboratory by an interventional cardiologist. In addition, the use of low dose r-tpa reduces risk of major bleeding complications. The investigators aim to see if equivalent low dose r-tpa given peripherally i.e PLST is non-inferior to ACDT for the treatment of submassive PE. Both treatments will be compared in safety, efficacy and overall cardiopulmonary function.

Inclusion Criteria:

1. Age 18 years or older, able to consent
2. Submassive PE evidenced by CT showing saddle pulmonary embolism, central right and/or left main pulmonary artery emboli.
3. Submassive PE confirmed by right ventricular dimension to left ventricular dimension ratio ≥ 1 in apical 4-chamber view echo/CT scan.
4. Signs of RV dysfunction by echocardiogram, or elevated troponin I >0.04, or pro-BNP > 400 on serial measurements.
5. PE symptom duration less than or equal to 14 days -

Exclusion Criteria:

1. Age <18 to age >90 years;

2. PE symptom duration >14 days;

3. Administration of thrombolytic drugs in the last 4 days

4. Contraindications to thrombolytic therapy:

   1. Active bleeding disorder or coagulation disorder;
   2. Platelet count <100 000/mm3
   3. Hematocrit < 30%
   4. INR> 3
   5. Previous history of vitamin K antagonists with international normalized ratio >2.5 on admission
   6. History of intracranial or intraspinal surgery or trauma or intracranial/intraspinal bleeding
   7. Intracranial neoplasm
   8. Arteriovenous malformation, or aneurysm
   9. Gastrointestinal bleeding <3 months
   10. Internal eye surgery or hemorrhagic retinopathy less than three-month duration
   11. Major surgery, cataract surgery, obstetric delivery, cardiopulmonary resuscitation, or invasive procedure less than10 days duration
   12. Allergy, hypersensitivity, or thrombocytopenia caused heparin or tPA

5. Severe contrast allergy to iodinated contrast

6. Large (>10 mm) right atrial or right ventricular thrombus

7. Systolic blood pressure <90 mm Hg

8. Severe hypertension on repeat measurement (systolic >180 mm Hg or diastolic >105 mm Hg)

9. Pregnancy

10. In any other investigational drug or device study

11. Inability to follow instructions or comply with treatment

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Investigators are not planning to share information or participant data with other researchers