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

Pulmonary Embolism Clinical Trial

— HI-PEITHO  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04790370
• Other study ID #: S2479
• Status: Recruiting
• Phase: Phase 4
• Start date: August 2, 2021
• Est. completion date: August 2026

Study information

• Verified date: June 2024
• Source: Boston Scientific Corporation
• Contact: Jackie Lin, M.S.
• Phone: 612-360-8544
• Email: Jackie.Lin[@]bsci.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 544
• Est. completion date: August 2026
• Est. primary completion date: August 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Embolism
• Pulmonary Embolism

Intervention

Drug:
• Anticoagulation with heparin
Low-molecular weight heparin (LMWH) or unfractionated heparin (UFH)

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]

Locations

Country	Name	City	State
Austria	A.o. LKH Univ.-Kliniken Innsbruck	Innsbruck
Austria	Universitätsklinikum St. Pölten	St. Pölten
Austria	Austria Klinik Ottakring Vienna	Vienna
Austria	Allgemeines Krankenhaus AKH	Wien
France	CHU de Besancon	Besançon
France	Hopital Nord de Marseille	Marseille
France	CHU (Nimes Cedex)	Nîmes
France	Hôpital Européen Georges Pompidou (HEGP)	Paris
Germany	Uniklinik Aachen	Aachen
Germany	Klinikum Bielefeld	Bielefeld
Germany	GFO Kliniken Bonn	Bonn
Germany	Klinikum Chemnitz	Chemnitz
Germany	Klinikum Coburg GmbH	Coburg
Germany	Universitaetsklinikum Freiburg	Freiburg
Germany	Klinik Immenstadt	Immenstädt
Germany	Universitaetsklinikum Schleswig-Holstein	Lübeck
Germany	Johannes Gutenberg Universitaet Mainz	Mainz
Germany	Klinikum Rechts der Isar	Munich
Germany	Universitaetsklinikum Tuebingen	Tuebingen
Germany	Universitaetsklinikum Wuerzburg	Würzburg
Ireland	Mater Misericordiae University Hospital	Dublin
Ireland	University Hospital Galway	Galway
Netherlands	Leiden University Medical Center	Leiden
Netherlands	St. Antonius Ziekenhuis	Nieuwegein
Netherlands	Universitair Medisch Centrum	Utrecht
Poland	John Paul II Hospital	Kraków
Poland	Uniwersytecki Szpital Kliniczny w Poznaniu	Poznan
Poland	Medical University of Warsaw	Warsaw
Switzerland	University Hospital Basel	Basel
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne
Switzerland	University Hospital Zurich	Zürich
United Kingdom	University Hospital of Wales	Cardiff
United Kingdom	Guys and St. Thomas NHS Foundation Trust	London
United Kingdom	The Royal Free Hospital	London
United Kingdom	Northwick Park Hospital	Middlesex
United States	University of Michigan Hospitals	Ann Arbor	Michigan
United States	Emory University Hospital	Atlanta	Georgia
United States	Piedmont Hospital	Atlanta	Georgia
United States	Augusta University	Augusta	Georgia
United States	Seton Medical Center	Austin	Texas
United States	University of Maryland School of Medicine	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Cooper Hospital - University Medical Center	Camden	New Jersey
United States	University of Virginia Medical Center	Charlottesville	Virginia
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	Henry Ford Hospital	Detroit	Michigan
United States	St. John Hospital & Medical Center	Detroit	Michigan
United States	Advocate Good Samaritan Hospital	Downers Grove	Illinois
United States	Houston Methodist Sugarland Hospital	Houston	Texas
United States	St. Vincent Heart Center of Indiana	Indianapolis	Indiana
United States	Kettering Health	Kettering	Ohio
United States	Wellmont Holston Valley Medical Center	Kingsport	Tennessee
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	Cedars - Sinai Medical Center	Los Angeles	California
United States	Baptist Health East Louisville	Louisville	Kentucky
United States	Jewish Hospital	Louisville	Kentucky
United States	University of Wisconsin Hospitals	Madison	Wisconsin
United States	Methodist Hospitals	Merrillville	Indiana
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Columbia University Medical Center	New York	New York
United States	Lenox Hill Hospital	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	Christiana Hospital	Newark	Delaware
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	University of Oklahoma Health Science Center	Oklahoma City	Oklahoma
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	The Heart Hospital Baylor Plano	Plano	Texas
United States	Mayo Clinic Foundation	Rochester	Minnesota
United States	St. Francis Hospital	Roslyn	New York
United States	North Mississippi Medical Center	Tupelo	Mississippi
United States	Washington Hospital Center	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
Boston Scientific Corporation	National PERT Consortium, Inc., University Medical Center Mainz

Countries where clinical trial is conducted

United States,  Austria,  France,  Germany,  Ireland,  Netherlands,  Poland,  Switzerland,  United Kingdom, 

References & Publications (27)

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Marti C, John G, Konstantinides S, Combescure C, Sanchez O, Lankeit M, Meyer G, Perrier A. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J. 2015 Mar 7;36(10):605-14. doi: 10.1093/eurheartj/ehu218. Epub 2014 Jun 10. — View Citation

Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47. doi: 10.1161/CIRCULATIONAHA.110.009449. No abstract available. — View Citation

Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, Bluhmki E, Bouvaist H, Brenner B, Couturaud F, Dellas C, Empen K, Franca A, Galie N, Geibel A, Goldhaber SZ, Jimenez D, Kozak M, Kupatt C, Kucher N, Lang IM, Lankeit M, Meneveau N, Pacouret G, Palazzini M, Petris A, Pruszczyk P, Rugolotto M, Salvi A, Schellong S, Sebbane M, Sobkowicz B, Stefanovic BS, Thiele H, Torbicki A, Verschuren F, Konstantinides SV; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. doi: 10.1056/NEJMoa1302097. — View Citation

Piazza G, Hohlfelder B, Jaff MR, Ouriel K, Engelhardt TC, Sterling KM, Jones NJ, Gurley JC, Bhatheja R, Kennedy RJ, Goswami N, Natarajan K, Rundback J, Sadiq IR, Liu SK, Bhalla N, Raja ML, Weinstock BS, Cynamon J, Elmasri FF, Garcia MJ, Kumar M, Ayerdi J, Soukas P, Kuo W, Liu PY, Goldhaber SZ; SEATTLE II Investigators. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC Cardiovasc Interv. 2015 Aug 24;8(10):1382-1392. doi: 10.1016/j.jcin.2015.04.020. — View Citation

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* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in the RV-to-LV diameter ratio as measured by echocardiography		Between baseline and 48±6 hours
Other	PE-related death	Death cause by pulmonary embolism (PE)	Within 7 days
Other	Cardiorespiratory decompensation		Within 7 days
Other	Placement on ECMO or mechanical ventilation		Within 7 days
Other	GUSTO major (moderate and severe) bleeding	Major bleeding will be adjudicated according to the GUSTO criteria: 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.; 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) .	Within 7 days
Other	International Society on Thrombosis and Hemostasis (ISTH) major bleeding	Major bleeding will also be adjudicated according to the ISTH criteria: Fatal bleeding and/or; Symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome) and/or; 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.	Within 7 days, 30 days, and 6 months
Other	Ischemic or hemorrhagic stroke		Within 7 days and 30 days
Other	All-cause mortality	Death due to any cause	Within 7 days, 30 days, 6 months, and 12 months
Other	Serious adverse events		Within 30 days
Other	All-cause mortality, cardiorespiratory collapse or recurrence of PE	Death due to any cause,; Cardiorespiratory collapse or decompensation should fulfill 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 (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; placement on ECMO at any time between randomization and day 7; intubation, or initiation of non-invasive 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.	Within 30 days
Other	Symptomatic PE recurrence		Within 30 days and 6 months
Other	Change from baseline in RV dysfunction on echocardiography	Right ventricle to left ventricle end diastolic diameter ratio (RV/LV)	6 months
Other	Duration of hospitalization for the index PE event	Time from admission to discharge from hospital	Within 30 days
Other	Duration of stay at the intensive, intermediate or coronary care unit during hospitalization for the index PE event	Time from admission to discharge from ICU, intermediate, or ICC	Within 30 days
Other	Functional status as measured by World Health Organization (WHO) functional class	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.	Up to 7 days, 30 days, 6 and 12 months
Other	Functional status as measured by 6-Minute Walk Test (6MWT)	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.	30 days, 6 and 12 months
Other	Functional status as measured by Post-Venous Thromboembolism Functional Status (PVFS) scale	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,	30 days, 6 and 12 months
Other	Quality of life using PEmb-QOL	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.	6 and 12 months
Other	Quality of life using SF-36	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.	6 and 12 months
Other	Quality of life using EQ-5D scale	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.	6 and 12 months
Other	Diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH)	CTEPH will be diagnosed by the investigational site according to presence of all of the following criteria: At least one mismatched segmental perfusion defect demonstrated by ventilation/perfusion scanning after 3 months of adequate therapeutic anticoagulation; Resting mean pulmonary arterial pressure (mPAP) =25 mmHg measured by invasive right heart catheterization; Pulmonary capillary wedge pressure =15 mmHg.	Within 12 months
Primary	PE-related mortality	death resulting from PE	Within seven days of randomization
Primary	PE recurrence	nonfatal symptomatic and objectively confirmed recurrence of PE	Within seven days of randomization
Primary	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