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Peripheral Systemic Thrombolysis Versus Catheter Directed Thrombolysis for Submassive PE

Primary Purpose

Pulmonary Embolism, Pulmonary Hypertension, Thromboembolism

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Alteplase
EKOS
Sponsored by
Northwell Health
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Embolism focused on measuring Alteplase, submassive pulmonary embolism, Thrombolysis, pulmonary catheter

Eligibility Criteria

18 Years - 89 Years (Adult, Older Adult)All SexesDoes not accept 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

    -

Sites / Locations

  • Southside Northwell Hospital
  • Long Island Jewish Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Peripheral low dose thrombolysis

Catheter directed acoustic thrombolysis

Arm 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.

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.

Outcomes

Primary Outcome Measures

Right ventricle (RV) to Left ventricle (LV) ratio
Investigators will measure and compare the change between baseline and 48 hours right ventricular diameter to left ventricular diameter (RV:LV ratio) on echocardiogram after PLST or ACDT
Pulmonary pressures
Investigators will measure and compare the change between baseline and 48 hours pulmonary pressures (mm Hg) with echocardiogram following therapy with PLST or ACDT therapy.

Secondary Outcome Measures

Mortality
Composite of all-cause mortality and fatal bleeding in-hospital and at 30-day

Full Information

First Posted
May 7, 2018
Last Updated
March 19, 2023
Sponsor
Northwell Health
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1. Study Identification

Unique Protocol Identification Number
NCT03581877
Brief Title
Peripheral Systemic Thrombolysis Versus Catheter Directed Thrombolysis for Submassive PE
Official Title
Peripheral Low Dose Systemic Thrombolysis Versus Catheter Directed Acoustic Pulse Thrombolysis for Treatment of Submassive Pulmonary Embolism
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Completed
Study Start Date
January 28, 2019 (Actual)
Primary Completion Date
March 19, 2023 (Actual)
Study Completion Date
March 19, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Northwell Health

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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)
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Embolism, Pulmonary Hypertension, Thromboembolism, Right Ventricular Dysfunction
Keywords
Alteplase, submassive pulmonary embolism, Thrombolysis, pulmonary catheter

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
This study will be a prospective randomized interventional study. Patients referred to Southside hospital will be consented to take part in the study. After obtaining written informed consent, investigators will subsequently enroll 158 consecutive patients (aged> 18 years) randomized in a serial 1:1 allocation for either low dose PLST or ACDT for submassive pulmonary embolism.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
31 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Peripheral low dose thrombolysis
Arm Type
Experimental
Arm 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.
Arm Title
Catheter directed acoustic thrombolysis
Arm Type
Active Comparator
Arm 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.
Intervention Type
Drug
Intervention Name(s)
Alteplase
Other Intervention Name(s)
Peripheral low dose systemic thrombolysis (PLST)
Intervention Description
As stated before, low dose r-tpa will be administered through a peripheral vein for PLST.
Intervention Type
Device
Intervention Name(s)
EKOS
Other Intervention Name(s)
Ultrasound assisted catheter directed thrombolysis (ACDT)
Intervention Description
As stated before, the EKos device will be used for ultrasound assisted catheter directed thrombolysis or ACDT, same dose t-tpa will administered through the pulmonary catheter. It will be given at a fixed dose over 24 hours.
Primary Outcome Measure Information:
Title
Right ventricle (RV) to Left ventricle (LV) ratio
Description
Investigators will measure and compare the change between baseline and 48 hours right ventricular diameter to left ventricular diameter (RV:LV ratio) on echocardiogram after PLST or ACDT
Time Frame
48 hours
Title
Pulmonary pressures
Description
Investigators will measure and compare the change between baseline and 48 hours pulmonary pressures (mm Hg) with echocardiogram following therapy with PLST or ACDT therapy.
Time Frame
48 hours
Secondary Outcome Measure Information:
Title
Mortality
Description
Composite of all-cause mortality and fatal bleeding in-hospital and at 30-day
Time Frame
30 days
Other Pre-specified Outcome Measures:
Title
Right ventricle (RV) to Left ventricle (LV) ratio
Description
Investigators will measure and compare the change between baseline and 30 days right ventricular diameter to left ventricular diameter (RV:LV ratio) on echocardiogram after PLST or ACDT
Time Frame
30 days
Title
Pulmonary pressures
Description
Investigators will measure and compare the change between baseline and 30 days pulmonary pressures (mm Hg) with echocardiogram following therapy with PLST or ACDT therapy.
Time Frame
30 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
89 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age 18 years or older, able to consent Submassive PE evidenced by CT showing saddle pulmonary embolism, central right and/or left main pulmonary artery emboli. Submassive PE confirmed by right ventricular dimension to left ventricular dimension ratio ≥ 1 in apical 4-chamber view echo/CT scan. Signs of RV dysfunction by echocardiogram, or elevated troponin I >0.04, or pro-BNP > 400 on serial measurements. PE symptom duration less than or equal to 14 days - Exclusion Criteria: Age <18 to age >90 years; PE symptom duration >14 days; Administration of thrombolytic drugs in the last 4 days Contraindications to thrombolytic therapy: Active bleeding disorder or coagulation disorder; Platelet count <100 000/mm3 Hematocrit < 30% INR> 3 Previous history of vitamin K antagonists with international normalized ratio >2.5 on admission History of intracranial or intraspinal surgery or trauma or intracranial/intraspinal bleeding Intracranial neoplasm Arteriovenous malformation, or aneurysm Gastrointestinal bleeding <3 months Internal eye surgery or hemorrhagic retinopathy less than three-month duration Major surgery, cataract surgery, obstetric delivery, cardiopulmonary resuscitation, or invasive procedure less than10 days duration Allergy, hypersensitivity, or thrombocytopenia caused heparin or tPA Severe contrast allergy to iodinated contrast Large (>10 mm) right atrial or right ventricular thrombus Systolic blood pressure <90 mm Hg Severe hypertension on repeat measurement (systolic >180 mm Hg or diastolic >105 mm Hg) Pregnancy In any other investigational drug or device study Inability to follow instructions or comply with treatment -
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Azhar Supariwala, MD
Organizational Affiliation
Southside Northwell Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Southside Northwell Hospital
City
Bay Shore
State/Province
New York
ZIP/Postal Code
11706
Country
United States
Facility Name
Long Island Jewish Medical Center
City
Queens
State/Province
New York
ZIP/Postal Code
11040
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Investigators are not planning to share information or participant data with other researchers
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Peripheral Systemic Thrombolysis Versus Catheter Directed Thrombolysis for Submassive PE

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