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Peripheral Systemic Thrombolysis Versus Catheter Directed Thrombolysis for Submassive PE

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ClinicalTrials.gov Identifier: NCT03581877
Recruitment Status : Recruiting
First Posted : July 10, 2018
Last Update Posted : February 11, 2020
Sponsor:
Information provided by (Responsible Party):
Azhar Supariwala MD, FACC, FASE, Northwell Health

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)

Condition or disease Intervention/treatment Phase
Pulmonary Embolism Pulmonary Hypertension Thromboembolism Right Ventricular Dysfunction Drug: Alteplase Device: EKOS Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 158 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: Peripheral Low Dose Systemic Thrombolysis Versus Catheter Directed Acoustic Pulse Thrombolysis for Treatment of Submassive Pulmonary Embolism
Actual Study Start Date : January 28, 2019
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Alteplase

Arm Intervention/treatment
Experimental: Peripheral low dose thrombolysis
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.
Drug: Alteplase
As stated before, low dose r-tpa will be administered through a peripheral vein for PLST.
Other Name: Peripheral low dose systemic thrombolysis (PLST)

Active Comparator: Catheter directed acoustic thrombolysis
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.
Device: EKOS
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.
Other Name: Ultrasound assisted catheter directed thrombolysis (ACDT)




Primary Outcome Measures :
  1. Right ventricle (RV) to Left ventricle (LV) ratio [ Time Frame: 48 hours ]
    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

  2. Pulmonary pressures [ Time Frame: 48 hours ]
    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 :
  1. Mortality [ Time Frame: 30 days ]
    Composite of all-cause mortality and fatal bleeding in-hospital and at 30-day


Other Outcome Measures:
  1. Right ventricle (RV) to Left ventricle (LV) ratio [ Time Frame: 30 days ]
    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

  2. Pulmonary pressures [ Time Frame: 30 days ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 89 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

    -


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03581877


Contacts
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Contact: Azhar Supariwala, MD 631-591-7400 Asupariwala@northwell.edu

Locations
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United States, New York
Southside Northwell Hospital Recruiting
Bay Shore, New York, United States, 11706
Contact: Azhar Supariwala, MD, FACC    631-591-7400    asupariwala@northwell.edu   
Contact: Samy Selim, MD    6315917400    sselim@northwell.edu   
Long Island Jewish Medical Center Recruiting
Queens, New York, United States, 11040
Contact: Avneet Singh, MD    718-470-7330    Asingh1@northwell.edu   
Contact: Seth Koenig, MD    (516) 465-5400    Skoenig@northwell.edu   
Sponsors and Collaborators
Northwell Health
Investigators
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Principal Investigator: Azhar Supariwala, MD Southside Northwell Hospital
Publications:
Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ, Jenkins JS, Kline JA, Michaels AD, Thistlethwaite P, Vedantham S, White RJ, Zierler BK; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; American Heart Association Council on Peripheral Vascular Disease; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011 Apr 26;123(16):1788-830. doi: 10.1161/CIR.0b013e318214914f. Epub 2011 Mar 21. Erratum in: Circulation. 2012 Aug 14;126(7):e104. Circulation. 2012 Mar 20;125(11):e495.

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Responsible Party: Azhar Supariwala MD, FACC, FASE, Director of Structural Imaging Southside Hospital Northwell Health, Northwell Health
ClinicalTrials.gov Identifier: NCT03581877    
Other Study ID Numbers: 18-0805
First Posted: July 10, 2018    Key Record Dates
Last Update Posted: February 11, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Investigators are not planning to share information or participant data with other researchers

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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
Keywords provided by Azhar Supariwala MD, FACC, FASE, Northwell Health:
Alteplase
submassive pulmonary embolism
Thrombolysis
pulmonary catheter
Additional relevant MeSH terms:
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Hypertension, Pulmonary
Pulmonary Embolism
Thromboembolism
Embolism
Ventricular Dysfunction
Ventricular Dysfunction, Right
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Embolism and Thrombosis
Heart Diseases
Tissue Plasminogen Activator
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action