Submassive Pulmonary Embolism
Conditions
Keywords
Pulmonary embolism, Pulmonary thromboembolism, anticoagulation, thrombolysis, ultrasound accelerated thrombolysis
Brief summary
The ULTIMA study is intended to prove that in patients with pulmonary embolism and a right ventricular end diastolic diameter to left ventricular end diastolic diameter ratio ≥1 (RV/LV ratio) will benefit from treatment with ultrasound accelerated thrombolysis (rt-PA) as compared to unfractionated heparin anticoagulation. Specifically, at 24 hours the RV/LV ratio will be significantly reduced in the treatment arm compared to the control arm.
Interventions
The EkoSonic Endovascular System will be used to deliver \< 20 mg of rt-PA ( Actilyse) directly into the occlusive pulmonary thrombus.
DRUGUnfractionated heparin
Intravenous unfractionated heparin used for anticoagulation treatment
Sponsors
EKOS Corporation
Boston Scientific Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients with acute PE symptoms \< 14 days. * Filling defect by contrast-enhanced chest CT in at least one main or proximal lower lobe pulmonary artery * Right ventricular dysfunction confirmed by echocardiography where the RV/LV end diastolic diameter ratio is ≥ 1.0.
Exclusion criteria
* Age less than 18 years or greater than 80 years * Index PE symptom duration \> 14 days * Insufficient echocardiographic image quality in the apical or subcostal four-chamber view that prohibits the measurement of the right and left ventricular end-diastolic dimensions * Known significant bleeding risk * Administration of thrombolytic agents, e.g., tissue plasminogen activator, streptokinase, or urokinase, within the previous 4 days * Active bleeding * Known bleeding diathesis * Known coagulation disorder, platelet count \< 100 000/mm3, or previous use of vitamin K antagonists with INR \> 2.5 * History of any intracranial or intraspinal surgery or trauma or intracranial/intraspinal bleed * Intracranial neoplasm, arteriovenous malformation, or aneurysm * Recent (\< 3 months) GI bleeding. * Recent (\< 3 months) internal eye surgery or hemorrhagic retinopathy; recent (\< 10 days) major surgery, cataract surgery, trauma, CPR, obstetrical delivery, or other invasive procedure. * Allergy, hypersensitivity, or thrombocytopenia from heparin, rt-PA, or iodinated contrast, except for mild-moderate contrast allergies for which steroid pre-medication can be used. * Estimated glomerular filtration rate (eGFR) \< 50 ml/min as calculated by the Cockroft formula. * Hemodynamic collapse at presentation defined as: need for cardiopulmonary resuscitation; or systolic blood pressure \< 90 mm Hg for at least 15 min, or drop of systolic blood pressure by at least 40 mm Hg for at least 15 min with signs of end organ hypoperfusion (cold extremities or low urinary output \< 30 mL/h or mental confusion); or need for catecholamine administration to maintain adequate organ perfusion and a systolic blood pressure of \> 90 mm Hg. * Severe hypertension on repeated readings (systolic \> 180 mmHg or diastolic \> 105 mmHg). * Pregnant, lactation or parturition within the previous 30 days (positive pregnancy test, women of childbearing age must be tested). * Participating in any other investigational drug or device study. * Life expectancy \< 90 days. * Inability to comply with study assessments (e.g. due to geographic distance). * Previous enrollment in this study * Any other condition that the investigator feels would place the patient at increased risk if the investigational therapy is initiated. * Known right-to-left shunt, for example from large patent foramen ovale or atrial septal defect * Large (\>10 mm) right atrial or right ventricular thrombus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reduction of RV/LV Ratio | 24 hours | Change in the end-diastolic RV/LV ratio from baseline to 24 hours by echocardiography. |
| Major Bleeding and Intracranial Bleeding at 30 Days. | 30 days | Bleeding will be classified as major if it is associated with a fall in the hemoglobin level of at least 2.0 g/dl, transfusion of ≥ 2 units of red blood cells, or involvement of a critical site (e.g., intracranial, intraspinal). To aid in evaluating the relationship of bleeding events to rt-PA administration, they will also be categorized by whether they occurred within 3 days after the initiation of thrombolytic therapy. |
Countries
Germany, Switzerland
Participant flow
Recruitment details
Multi-center, Phase III study at 8 tertiary care hospitals in Germany and Switzerland
Pre-assignment details
Acute symptomatic PE confirmed by contrast-enhanced computed tomography (CT) with embolus located in at least 1 main or proximal lower lobe pulmonary artery RV to left ventricular dimension (RV/LV) ratio ≥1 obtained from the echocardiographic apical 4-chamber view
Participants by arm
| Arm | Count |
|---|---|
| UFH (Alone) Patients in this arm received the standard of care: intravenous unfractionated heparin used as anticoagulation treatment. | 29 |
| UFH + EkoSonic Procedure Patients in this arm received anticoagulation (intravenous unfractionated heparin) plus the EkoSonic Endovascular System was used to deliver a low dose of \<20mg rt-PA (Actilyse) directly into the occlusive pulmonary thrombus. | 30 |
| Total | 59 |
Baseline characteristics
| Characteristic | UFH (Alone) | UFH + EkoSonic Procedure | Total |
|---|---|---|---|
| Age, Continuous | 62.0 years STANDARD_DEVIATION 13.4 | 64.1 years STANDARD_DEVIATION 15.2 | 63.1 years STANDARD_DEVIATION 14.3 |
| Sex: Female, Male Female | 12 Participants | 19 Participants | 31 Participants |
| Sex: Female, Male Male | 17 Participants | 11 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 29 | 0 / 30 |
| serious Total, serious adverse events | 4 / 29 | 3 / 30 |
Outcome results
Primary
Major Bleeding and Intracranial Bleeding at 30 Days.
Bleeding will be classified as major if it is associated with a fall in the hemoglobin level of at least 2.0 g/dl, transfusion of ≥ 2 units of red blood cells, or involvement of a critical site (e.g., intracranial, intraspinal). To aid in evaluating the relationship of bleeding events to rt-PA administration, they will also be categorized by whether they occurred within 3 days after the initiation of thrombolytic therapy.
Time frame: 30 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Unfractionated Heparin (UFH) Alone | Major Bleeding and Intracranial Bleeding at 30 Days. | 0 participants |
| Unfractionated Heprin + EkoSonic Procedure | Major Bleeding and Intracranial Bleeding at 30 Days. | 0 participants |
Primary
Reduction of RV/LV Ratio
Change in the end-diastolic RV/LV ratio from baseline to 24 hours by echocardiography.
Time frame: 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Unfractionated Heparin (UFH) Alone | Reduction of RV/LV Ratio | 0.03 Ratio | Standard Deviation 0.16 |
| Unfractionated Heprin + EkoSonic Procedure | Reduction of RV/LV Ratio | 0.30 Ratio | Standard Deviation 0.2 |