Peripheral Systemic Thrombolysis Versus Catheter Directed Thrombolysis for Submassive PE

Northwell Health

Status and phase: Active, not recruiting; Phase 4

Conditions: Thromboembolism; Pulmonary Embolism; Right Ventricular Dysfunction; Pulmonary Hypertension

Treatments: Drug: Alteplase; Device: EKOS

Study type: Interventional

Funder types: Other

Identifiers

NCT03581877

18-0805

Details and patient eligibility

About

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)

Full description

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.

Enrollment: 31 patients

Sex: All

Ages: 18 to 89 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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31 participants in 2 patient groups

Peripheral low dose thrombolysis

Experimental group

Description:

Peripheral low dose thrombolysis will use a peripheral vein into an arm as in routine intravenous therapy. This is the experimental arm. Alteplate (R-tpa) belong to thrombolytic or fibrnolytic drug class. Routine hospital policies for peripheral venous therapy will be used. A fixed dose of 24 mg of Activase (Atleplase) over 12 hours or 2.0 mg/hr will be administered peripherally. Simultaneously, intravenous unfractionated heparin will be given with a target partial thromboplastin time of 40 to 60 secs.

Treatment:

Drug: Alteplase

Catheter directed acoustic thrombolysis

Active Comparator group

Description:

For ACDT, routine hospital protocols and EKOS(generic) will be used. EKOS is made up of 3 parts which include the drug delivery pulmonary artery catheter, a removable microsonic device, and a reusable Eko-Sonic control unit. Venous access will be obtained by ultrasound guidance in the internal jugular vein or femoral vein. After catheter placement, the right heart pressures will be measured. R-tpa will be directly given into the pulmonary catheter. A fixed dose of 24 mg of tpa over 12 hours or 2.0mg/hr will be given. For unilateral PE, a single catheter will be used with infusion rate of 2 mg//hr and two catheters will be used for bilateral PEs each with 1 mg /hr infusion rate. Intravenous unfractionated heparin will be given with a target partial thromboplastin time of 40 to 60 secs.

Treatment:

Device: EKOS