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Ultrasound-facilitated, Catheter-directed, Thrombolysis in Intermediate-high Risk Pulmonary Embolism (HI-PEITHO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04790370
Recruitment Status : Recruiting
First Posted : March 10, 2021
Last Update Posted : April 15, 2024
Sponsor:
Collaborators:
National PERT Consortium, Inc.
University Medical Center Mainz
Information provided by (Responsible Party):
Boston Scientific Corporation

Study Description
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Brief Summary:

There are many available treatments for pulmonary embolism (PE), but the best treatment for this condition is not known. The HI-PEITHO study will compare two treatment options that are both available on the market for the treatment of PE.

Patients will be randomized 1:1 to receive either blood thinners (anticoagulation) or blood thinners (anticoagulation) in combination with a device called the EkoSonicTM Endovascular device to dissolve blood clots. Patients will be followed for 12 months after randomization and have assessments while in the hospital as well as at 7 days, 30 days, 6 months and 12 months after randomization. The study will try to find out if one of these treatments is better than the other at reducing the risk of death and other serious problems.


Condition or disease Intervention/treatment Phase
Pulmonary Embolism Drug: Anticoagulation with heparin Device: EkoSonicTM Endovascular System Phase 4

Detailed Description:

This study will assess whether ultrasound-facilitated, catheter-directed thrombolysis and standard anticoagulation are associated with a significant reduction in the composite outcome of pulmonary embolism (PE)-related mortality, cardiorespiratory decompensation or collapse, or nonfatal symptomatic and objectively confirmed recurrence of PE compared to anticoagulation alone within seven days of randomization

The HI-PEITHO study has been designed to address the important gaps in clinical evidence by comparing the clinical benefit of the ultrasound-facilitated local delivery of a low dose thrombolytic agent and anticoagulation with those of anticoagulation alone in patients with intermediate-high risk PE at a higher estimated risk of early decompensation based on clinical parameters at presentation.

This study has a focus on improving the safety of thrombolysis and advancing the concept of intermediate-high risk and the PE severity criteria, to better identify patients who may clinically benefit from thrombolysis.

The results of this study will contribute further evidence to the existing data on the treatment and outcomes of acute, intermediate-high risk PE and provide controlled data related to catheter-based interventions.

Data will be entered by the site into an electronic database. The database will include data checks to compare data entered into the database against predefined rules for ranges and consistency with other data fields in the database.

Site monitoring will take place with source data verification to assess the accuracy and completeness of registry data by comparing the data to medical records and study assessments.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 544 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 1:1 randomization
Masking: Single (Outcomes Assessor)
Masking Description: Blinded adjudication of primary composite outcome
Primary Purpose: Treatment
Official Title: A Randomized Trial of Ultrasound-facilitated, Catheter-directed, Thrombolysis Versus Anticoagulation for Acute Intermediate-high Risk Pulmonary Embolism: The Higher-risk Pulmonary Embolism Thrombolysis Study
Actual Study Start Date : August 2, 2021
Estimated Primary Completion Date : August 2025
Estimated Study Completion Date : August 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Anticoagulation
Low-molecular weight heparin (LMWH) or unfractionated heparin (UFH)
 Drug: Anticoagulation with heparin
Low-molecular weight heparin (LMWH) or unfractionated heparin (UFH)
Other Name: heparin, LMWH, UFH, anticoag, antiplatelet
Active Comparator: Anticoagulation and EkoSonicTM Endovascular System
Low-molecular weight heparin (LMWH) or unfractionated heparin (UFH) and EkoSonicTM Endovascular System [ultrasound-facilitated catheter-directed delivery of thrombolytic: 2 mg bolus/catheter + 1 mg/hour/catheter for 7 hours (total of 9 or 18 mg]
 Drug: Anticoagulation with heparin
Low-molecular weight heparin (LMWH) or unfractionated heparin (UFH)
Other Name: heparin, LMWH, UFH, anticoag, antiplatelet

Device: EkoSonicTM Endovascular System
EkoSonicTM Endovascular System [ultrasound-facilitated catheter-directed delivery of thrombolytic: 2 mg bolus/catheter + 1 mg/hour/catheter for 7 hours (total of 9 or 18 mg]
Other Name: EKOS, USCDT, CDT, thrombolysis, fibrinolysis


Outcome Measures
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Primary Outcome Measures :
  1. PE-related mortality [ Time Frame: Within seven days of randomization ]
    death resulting from PE

  2. PE recurrence [ Time Frame: Within seven days of randomization ]
    nonfatal symptomatic and objectively confirmed recurrence of PE

  3. Cardiorespiratory decompensation or collapse [ Time Frame: Within seven days of randomization ]

    Cardiorespiratory collapse or decompensation is defined as at least one of the following criteria:

    1. cardiac arrest or need for CPR at any time between randomization and day 7;
    2. signs of shock: new-onset persistent arterial hypotension (systolic blood pressure (SBP) below 90 mmHg or SBP drop by at least 40 mm Hg, over at least 15 minutes and despite an adequate volume status; or need for vasopressors to maintain SBP of at least 90 mmHg), accompanied by end-organ hypoperfusion (altered mental status; oliguria/anuria; or increased serum lactate) at any time between randomization and day 7;
    3. placement on extracorporeal membrane oxygenation (ECMO) at any time between randomization and day 7;
    4. intubation, or initiation of noninvasive mechanical ventilation at any time between randomization and day 7;
    5. National Early Warning Score (NEWS) of 9 or higher, between 24 hours and 7 days after randomization, confirmed on consecutive measurements taken twice, 15 minutes apart.


Other Outcome Measures:
  1. Change in the RV-to-LV diameter ratio as measured by echocardiography [ Time Frame: Between baseline and 48±6 hours ]
  2. PE-related death [ Time Frame: Within 7 days ]
    Death cause by pulmonary embolism (PE)

  3. Cardiorespiratory decompensation [ Time Frame: Within 7 days ]
  4. Placement on ECMO or mechanical ventilation [ Time Frame: Within 7 days ]
  5. GUSTO major (moderate and severe) bleeding [ Time Frame: Within 7 days ]

    Major bleeding will be adjudicated according to the GUSTO criteria:

    1. GUSTO severe or life-threatening bleeding: A bleeding episode that leads to hemodynamic compromise requiring emergency intervention (such as replacement of fluid and/or blood products, inotropic support, or surgical treatment), or is life-threatening or fatal.
    2. GUSTO moderate bleeding (a bleeding episode requiring blood transfusion(s), but which is not deemed life-threatening and does not lead to hemodynamic compromise requiring emergency fluid replacement, inotropic support, or interventional treatment) .

  6. International Society on Thrombosis and Hemostasis (ISTH) major bleeding [ Time Frame: Within 7 days, 30 days, and 6 months ]

    Major bleeding will also be adjudicated according to the ISTH criteria:

    1. Fatal bleeding and/or
    2. Symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome) and/or
    3. Bleeding causing a fall in hemoglobin level of 20 g/L (2 g/dL) or more, or leading to transfusion of two or more units of whole blood or red blood cells.

  7. Ischemic or hemorrhagic stroke [ Time Frame: Within 7 days and 30 days ]
  8. All-cause mortality [ Time Frame: Within 7 days, 30 days, 6 months, and 12 months ]
    Death due to any cause

  9. Serious adverse events [ Time Frame: Within 30 days ]
  10. All-cause mortality, cardiorespiratory collapse or recurrence of PE [ Time Frame: Within 30 days ]

    Death due to any cause,

    Cardiorespiratory collapse or decompensation should fulfill at least one of the following criteria:

    1. cardiac arrest or need for CPR at any time between randomization and day 7;
    2. signs of shock: new-onset persistent arterial hypotension (SBP below 90 mmHg or SBP drop by at least 40 mmHg over at least 15 minutes, and despite an adequate filling status; or need for vasopressors to maintain SBP of at least 90 mmHg), accompanied by end-organ hypoperfusion (altered mental status; oliguria/anuria; or increased serum lactate) at any time between randomization and day 7;
    3. placement on ECMO at any time between randomization and day 7;
    4. intubation, or initiation of non-invasive mechanical ventilation at any time between randomization and day 7;
    5. National Early Warning Score (NEWS) of 9 or higher, between 24 hours and 7 days after randomization, confirmed on consecutive measurements, taken twice.

  11. Symptomatic PE recurrence [ Time Frame: Within 30 days and 6 months ]
  12. Change from baseline in RV dysfunction on echocardiography [ Time Frame: 6 months ]
    Right ventricle to left ventricle end diastolic diameter ratio (RV/LV)

  13. Duration of hospitalization for the index PE event [ Time Frame: Within 30 days ]
    Time from admission to discharge from hospital

  14. Duration of stay at the intensive, intermediate or coronary care unit during hospitalization for the index PE event [ Time Frame: Within 30 days ]
    Time from admission to discharge from ICU, intermediate, or ICC

  15. Functional status as measured by World Health Organization (WHO) functional class [ Time Frame: Up to 7 days, 30 days, 6 and 12 months ]
    The World Health Organization (WHO) Functional Class assessment is a system for assessing the severity of dyspnea in patients with pulmonary hypertension. Subjects will be classified as Class 1-4 at time points throughout their participation in the study.

  16. Functional status as measured by 6-Minute Walk Test (6MWT) [ Time Frame: 30 days, 6 and 12 months ]
    The 6MWT measures the distance a patient can walk on a flat surface in a period of 6 minutes. A 100 meter distance is measured in a hallway and the patient is asked to walk quickly as many laps as they can over the course of the timed test. The total distance is measured. The patient's baseline vitals and symptoms are compared to their condition at the completion of the test.

  17. Functional status as measured by Post-Venous Thromboembolism Functional Status (PVFS) scale [ Time Frame: 30 days, 6 and 12 months ]
    The Post-Venous Thromboembolism (VTE) Functional Status (PVFS) scale focuses on relevant aspects of daily life during follow-up after a venous thromboembolic event. The scale is neither intended to solely focus on VTE-associated functional limitations nor to diagnose post-VTE syndrome. In contrast, the scale has been developed to help users become aware of current functional limitations in patients who have suffered a VTE, whether or not as a result of the specific VTE, and to objectively determine the degree of disability,

  18. Quality of life using PEmb-QOL [ Time Frame: 6 and 12 months ]
    PEmb-QOL is a questionnaire that assesses post-pulmonary embolism quality of life in the context of pulmonary-specific symptoms. The PEmb-QOL questionnaire contains six dimensions based on the contents of the items: frequency of complaints, limitations in activities of daily living, work-related problems, social limitations, intensity of complaints and emotional complaints. Higher scores indicate worse outcome.

  19. Quality of life using SF-36 [ Time Frame: 6 and 12 months ]
    The SF-36 questionnaire is a generic quality of life measure containing eight health domains (physical functioning, physical role, pain, general health, vitality, social function, emotional role functioning, and mental health). The scoring is on a 0-100 scale, with a higher score indicating better health. Scores are combined into two overall summary scores: physical health summary score and mental health summary score.

  20. Quality of life using EQ-5D scale [ Time Frame: 6 and 12 months ]
    The EQ-5D is a patient reported outcome that provides a simple descriptive profile and single index value for health status. The questionnaire consists of 5 questions pertaining to specific health dimensions, including mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and overall health status rating scale.

  21. Diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) [ Time Frame: Within 12 months ]

    CTEPH will be diagnosed by the investigational site according to presence of all of the following criteria:

    1. At least one mismatched segmental perfusion defect demonstrated by ventilation/perfusion scanning after 3 months of adequate therapeutic anticoagulation
    2. Resting mean pulmonary arterial pressure (mPAP) ≥25 mmHg measured by invasive right heart catheterization
    3. Pulmonary capillary wedge pressure ≤15 mmHg.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18-80 years, inclusive
  • Objectively confirmed acute PE, based on computed tomography pulmonary angiography (CTPA) showing a filling defect in at least one main or proximal lobar pulmonary artery

  • Elevated risk of early death/hemodynamic collapse, indicated by at least two of the following new-onset clinical criteria:

    1. ECG-documented tachycardia with heart rate ≥100 beats per minute, not due to hypovolemia, arrhythmia, or sepsis;
    2. SBP ≤ 110 mm Hg for at least 15 minutes;
    3. respiratory rate > 20 x min-1 or oxygen saturation on pulse oximetry (SpO2) < 90% (or partial arterial oxygen pressure < 60 mmHg) at rest while breathing room air;
  • Right-to-left ventricular (RV/LV) diameter ratio ≥ 1.0 on CTPA
  • Serum troponin I or T levels above the upper limit of normal
  • Signed informed consent

Exclusion Criteria:

  • Hemodynamic instability*, i.e. at least one of the following present:

    1. cardiac arrest or need for cardiopulmonary resuscitation;
    2. need for ECMO, or ECMO initiated before randomization
    3. PE-related shock, defined as: (i) SBP < 90 mmHg, or vasopressors required to achieve SBP ≥ 90 mmHg, despite an adequate volume status; and (ii) end-organ hypoperfusion (altered mental status; oliguria/anuria; increased serum lactate);
    4. isolated persistent hypotension (SBP < 90 mmHg, or a systolic pressure drop by at least 40 mmHg for at least 15 minutes), not caused by new-onset arrhythmia, hypovolemia, or sepsis * Patients who presented with temporary need for fluid resuscitation and/or low-dose catecholamines may be included, provided that they could be stabilized within 2 hours of admission and maintain SBP of ≥ 90 mmHg and adequate organ perfusion without catecholamine infusion.
  • Need for admission to an intensive care unit for a reason other than the index PE episode. NB: Patients who test positive for SARS-CoV-2 can be enrolled where the investigator believes that the pulmonary embolism is the dominant pathology in the patient's clinical presentation and qualifying cardiorespiratory parameters.
  • Temperature above 39 degrees C / 102.2 degrees F
  • Logistical reasons limiting the rapid availability of interventional procedures to treat acute PE (e.g., during the outbreak of an epidemic)
  • Index PE symptom duration > 14 days
  • Active bleeding
  • History of intracranial or intraocular bleeding at any time
  • Stroke or transient ischemic attack within the past 6 months, or previous stroke at any time if associated with permanent disability
  • Central nervous system neoplasm, or metastatic cancer
  • Major neurologic, ophthalmologic, abdominal, cardiac, thoracic, vascular or orthopedic surgery or trauma (including syncope-associated with head strike or skeletal fracture) within the past 3 weeks
  • Platelet count < 100 x 109 x L-1
  • Patients who have received a once-daily therapeutic dose of LMWH or a therapeutic dose of fondaparinux within 24 hours prior to randomization
  • Patients who have received one of the direct oral anticoagulants apixaban or rivaroxaban within 12 hours prior to randomization
  • Patients who have received one of the direct oral anticoagulants dabigatran or edoxaban for the index PE episode, as these drugs are not approved for patients who have not received heparin for at least 5 days
  • Administration of a thrombolytic agent or a glycoprotein IIb/IIIa receptor antagonist during the current hospital stay and/or within 30 days, for any reason
  • Chronic treatment with antiplatelet agents other than low-dose acetylsalicylic acid or clopidogrel 75 mg once daily (but not both). Dual antiplatelet therapy is excluded.
  • Chronic treatment with a direct oral anticoagulant (apixaban, dabigatran, edoxaban or rivaroxaban)
  • Chronic treatment with a vitamin K antagonist, or known coagulopathy including severe hepatic dysfunction, with an International Normalized Ratio (INR) > 1.5
  • Pregnancy or lactation
  • Previous inclusion in the study
  • Known hypersensitivity to alteplase, LMWH or UFH, or to any of the excipients
  • Life expectancy less than 6 months
Contacts and Locations
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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): NCT04790370


Contacts
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Contact: Jackie Lin, M.S. 612-360-8544 Jackie.Lin@bsci.com
Contact: Chrislee Leyco 763-494-1141 Chrislee.Leyco@bsci.com

Locations
Show Show 64 study locations
Sponsors and Collaborators
Boston Scientific Corporation
National PERT Consortium, Inc.
University Medical Center Mainz
Investigators
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Principal Investigator: Stavros Konstantinides, MD University Medical Center Mainz, Mainz, Germany
Principal Investigator: Kenneth Rosenfield, MD Massachusetts General Hospital, Boston, Massachusetts, USA
More Information
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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.
Cech DJ, Martin ST. Evaluation of function, activity, and participation. Functional Movement Development Across the Life Span (Third Edition), 2012.
Saris-Baglama RN, Dewey CJ, Chisholm GB, et al. QualityMetric health outcomes™ scoring software 4.0. Lincoln, RI: QualityMetric Incorporated, 2010, p. 138.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Boston Scientific Corporation
ClinicalTrials.gov Identifier: NCT04790370    
Other Study ID Numbers: S2479
First Posted: March 10, 2021    Key Record Dates
Last Update Posted: April 15, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Boston Scientific Corporation:
Acute intermediate-high risk pulmonary embolism
Ultrasound-facilitated, catheter-directed thrombolysis
Thrombolysis
Additional relevant MeSH terms:
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Pulmonary Embolism
Embolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
 Heparin
Calcium heparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action