Ultrasound-facilitated, Catheter-directed, Thrombolysis in Intermediate-high Risk Pulmonary Embolism

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Pulmonary Embolism

Intervention / Treatment
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* Drug: Anticoagulation with heparin
* Device: EkoSonicTM Endovascular System


Participation Criteria
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Eligibility Criteria
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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: ECG-documented tachycardia with heart rate ≥100 beats per minute, not due to hypovolemia, arrhythmia, or sepsis; SBP ≤ 110 mm Hg for at least 15 minutes; 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: cardiac arrest or need for cardiopulmonary resuscitation; need for ECMO, or ECMO initiated before randomization 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); 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 1:1 randomization
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Anticoagulation<br>Low-molecular weight heparin (LMWH) or unfractionated heparin (UFH) | Drug: Anticoagulation with heparin<br>* Low-molecular weight heparin (LMWH) or unfractionated heparin (UFH)<br>* Other names: heparin, LMWH, UFH, anticoag, antiplatelet;|
| Active Comparator: Anticoagulation and EkoSonicTM Endovascular System<br>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<br>* Low-molecular weight heparin (LMWH) or unfractionated heparin (UFH)<br>* Other names: heparin, LMWH, UFH, anticoag, antiplatelet;Device: EkoSonicTM Endovascular System<br>* 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]<br>* Other names: EKOS, USCDT, CDT, thrombolysis, fibrinolysis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PE-related mortality | death resulting from PE | Within seven days of randomization | 
| PE recurrence | nonfatal symptomatic and objectively confirmed recurrence of PE | Within seven days of randomization | 
| Cardiorespiratory decompensation or collapse | Cardiorespiratory collapse or decompensation is defined as at least one of the following criteria: cardiac arrest or need for CPR at any time between randomization and day 7; 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; placement on extracorporeal membrane oxygenation (ECMO) at any time between randomization and day 7; intubation, or initiation of noninvasive mechanical ventilation at any time between randomization and day 7; 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. | Within seven days of randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute intermediate-high risk pulmonary embolism, Ultrasound-facilitated, catheter-directed thrombolysis, Thrombolysis