Peripheral Systemic Thrombolysis Versus Catheter Directed Thrombolysis for Submassive 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