Pulmonary Embolism Acute
Conditions
Keywords
Acute Pulmonary Embolism, Full dose systemic thrombolysis, Catheter-directed thrombectomy
Brief summary
TORPEDO-NL will be an investigator-initiated, academically sponsored, multicentre, open-label, randomized controlled trial (RCT). Patients with high-risk pulmonary embolism (PE) require immediate reperfusion therapy on top of anticoagulation. The standard reperfusion treatment in these patients is full-dose systemic thrombolysis. This carries a significant risk of major bleeding (10-25%) and intracranial haemorrhage (ICH, 3%). Catheter-directed thrombectomy (CDT) is a promising alternative to systemic thrombolysis with a more direct effect on reducing pulmonary artery clot burden and very likely a better safety profile. Randomized trials evaluating the safety and efficacy of CDT in high-risk patients are currently unavailable. The investigators hypothesize that in high-risk PE patients, CDT is superior to the current standard of systemic thrombolysis in terms of mortality and adverse events, i.e., is associated with a lower composite incidence of all-cause mortality, treatment failure, major bleeding and all-cause stroke. The investigators also hypothesize that CDT will lead to a shorter length of stay (LOS) at the intensive care unit (ICU) and in-hospital, faster recovery, and better long-term quality of life (QoL). Objective: To determine whether CDT in high-risk PE relative to systemic thrombolysis is: * more effective and safer in terms of a reduction of the composite endpoint on all-cause mortality and adverse events defined as treatment failure, major bleeding and all-cause stroke at day 30 (primary outcome) * leads to a better Desirability of Outcome Ranking (DOOR) at day 7 * associated with a lower level of oxygen supplementation at 48 hours * associated with shorter length of stay (LOS) at the intensive care unit (ICU) and in the hospital * associated with better functional recovery as well as better patient-reported outcomes such as QoL at one year * cost-effective after a time horizon of one year
Interventions
DEVICECatheter-directed thrombectomy (CDT)
The intervention consists of immediate thrombectomy (thrombectomy with any approved device) without systemic/locally administered thrombolysis. Thrombectomy is performed via jugular or femoral venous access according to the instructions for use for the particular device. The catheter is advanced over a preplaced guidewire across the right heart into the pulmonary arteries to the location of proximal thrombus. Procedural therapeutic anticoagulation with heparin is administered. After removal of the dilator, the thrombus is extracted by controlled volume aspiration through an aspiration catheter using a syringe or dedicated aspiration system, with multiple aspirations performed as needed. Procedural objectives will be clearly stated prior to the intervention and patient's clinical and hemodynamic status and residual thrombus will guide the investigators to determine when to terminate the procedure. Treatment success is defined as clear evidence of right ventricular recompensation.
Standard reperfusion treatment for high-risk PE patients is thrombolytic therapy, typically consisting of Alteplase, Urokinase, or Tenecteplase, with the idea of accelerated fragmentation of the thrombus by lytic medication given systemically.
Sponsors
Dutch Heart Foundation
ZonMw: The Netherlands Organisation for Health Research and Development
Zorginstituut Nederland: The Health Care Insurance Board
Leiden University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adult patients with confirmed acute PE, i.e. contrast filling defect in a lobar or more proximal pulmonary artery on computed tomography pulmonary angiography (CTPA), and/or obstructive shock with echocardiographic confirmed dilatation of the right ventricle and a congested vena cava inferior, both with/without echocardiographic signs of clot in transit or deep vein thrombosis of the leg. 2. High risk for mortality, i.e. 1. post cardiac arrest (after temporary need for cardiopulmonary resuscitation), OR 2. obstructive shock (systolic blood pressure \<90 mmHg and signs of end-organ hypoperfusion (e.g. elevated lactate levels \>2 mmol/l) or the need for vasopressors (adrenalin or noradrenalin) to maintain an adequate blood pressure), OR 3. persistent hypotension (systolic blood pressure \<90 mmHg or systolic blood pressure drop ≥40 mmHg for at least 15 minutes) not caused by new onset arrhythmia, hypovolemia, or sepsis, OR 4. abnormal RV function on transthoracic echocardiography or CTPA AND elevated cardiac troponin levels AND respiratory failure defined as hypoxemia (SaO2 \<90%) refractory to O2 supplementation by nasal cannula or Venturi mask, requiring full face mask O2 supplementation (100% FiO2), high-flow nasal O2, or (non-)invasive mechanical ventilation. 3. CDT available and technically feasible so as to allow for a randomization-to-needle time of 60 minutes or less.
Exclusion criteria
1. Catastrophic PE, i.e. ongoing cardiac arrest and/or need for extracorporeal cardiopulmonary resuscitation (ECPR) and/or immediate indication for venoarterial extracorporeal membrane oxygenation (VA-ECMO) as judged by the responsible physician(s) 2. Glascow Coma Scale \<8 following resuscitation for cardiac arrest 3. Alternative diagnosis than acute PE contributing largely to the acute hemodynamic and/or respiratory failure, e.g. sepsis, COPD GOLD 3 or 4, or known heart failure with NYHA Functional Classification of 4, as judged by the treating physician. 4. A known do not admit to the ICU or do not resuscitate directive 5. An absolute contraindication to systemic thrombolysis, i.e. * History of hemorrhagic stroke * Ischemic stroke in past 6 months * Central nervous system neoplasm * Major trauma, major surgery or major head injury in past 3 weeks (note: mild external laceration of the head after, e.g. syncope, does not count as major head injury, especially when a CT scan of the head shows no hematoma) * Active bleeding, life-threatening or into a critically organ/area; OR known severe bleeding diathesis with previous bleeding fulfilling these criteria 6. Reperfusion therapy (systemic thrombolysis, surgical thrombectomy or CDT/other catheter directed therapy), or placement of a non-retrieved inferior vena cava filter for acute pulmonary embolism in the past 3 months 7. Thrombus in transit through a patent foramen ovale. 8. Known chronic thromboembolic pulmonary hypertension (CTEPH), or strong suspicion of CTEPH based on pre-existing clinical findings and combinations of signs of PE chronicity on echocardiography and/or CTPA. 9. Known hypersensitivity to systemic thrombolysis, heparin, or to any of the excipients 10. If, in the Investigator's opinion, or after consultation with the local PERT-team or EC-members, the patient is not appropriate for thrombectomy 11. Chronic use of full-dose oral or parenteral anticoagulation before presentation. 12. Pregnancy 13. Current participation in another study that would interfere with participation in this study 14. Previous enrolment in this study 15. Refusal of deferred consent by the next of kin or by the patient himself to use the data. Deferred consent will not be asked to relatives of patients who die in scene, but are included in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The composite incidence of the binary endpoints of all-cause mortality, treatment failure, major bleeding and all-cause stroke at day 30. | Day 30 | This outcome will be assessed using patient records or information provided by the treating physician. A detailed description of treatment failure is provided in outcome 3 of the secondary outcomes. Major bleeding is defined as Bleeding Academic Research Consortium (BARC)3b and BARC3c bleeding (=intracranial haemorrhage). Ischemic stroke is defined as any stroke (National Institutes of Health Stroke Scale ≥1). Unit of measure: incidence (number and percentage). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower incidence of treatment failure. | Day 7 and day 30 | Treatment failure in the first six hours after randomization is defined as life-threatening hemodynamic or respiratory deterioration. This deterioration is the clinical scenario if, after randomization, the patient develops overt cardiorespiratory instability over at least 15 minutes necessitating CPR, escalation of respiratory support, or ECMO. After these first six hours, treatment failure will also be defined by increasing dosages of cardiorespiratory support (e.g. oxygen, catecholamines), and lack of improvement. Lack of improvement is defined by the presence of at least one of the following criteria: i) an equal or rising SCAI SHOCK stage, ii) an equal or rising Fraction of Inspired Oxygen (FiO2) level to maintain adequate oxygen saturation (i.e. ≥ 92%), or iii) an equal or decreasing P/F ratio. Unit of measure: incidence (number and percentage). |
| To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower incidence of all-cause mortality. | Day 7, day 30 and day 90 | This will be assessed using patient records or information provided by the treating physician. Unit of measure: incidence (number and percentage). |
| To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower incidence of all-cause stroke. | Day 7 and day 30 | Ischemic stroke is defined as any stroke (National Institutes of Health Stroke Scale ≥1).This will be assessed using patient records or information provided by the treating physician. Unit of measure: incidence (number and percentage). |
| To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower composite incidence of the binary endpoints of the primary outcome at day 7. | Day 7 | This will be assessed using patient records or information provided by the treating physician. A detailed description of treatment failure is provided in outcome 3 of the secondary outcomes. Major bleeding is defined as Bleeding Academic Research Consortium (BARC)3b and BARC3c bleeding (=intracranial haemorrhage). Ischemic stroke is defined as any stroke (National Institutes of Health Stroke Scale ≥1). Unit of measure: incidence (number and percentage). |
| To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a better Desirability of Outcome Ranking (DOOR). | Day 7 | The DOOR concept evaluates treatment benefits and harms using efficacy, safety, and functional outcomes. Patients are classified into an ordinal global outcome based on overall desirability. The probability of a more favorable result with one treatment is assessed by comparing pairwise results, ranked by the number of days requiring organ support. Organ support includes respiratory (high-flow nasal cannula or (non-)invasive mechanical ventilation) or cardiovascular (vasopressors or inotropes). DOOR outcomes, ranked from most to least desirable: 1. Survival with no severe functional limitations, no treatment failure, and no adverse events; 2. Survival with severe functional limitations, no adverse events or treatment failure; 3. Survival with BARC3b bleeding; 4. Survival with BARC3c bleeding or stroke; 5. Survival with treatment failure; 6. Death. Functional limitations are defined by the PVFS scale (grade 4 = severe limitations). |
| To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a better survival. | Day 7 and day 30 | This will be assessed using patient records or information provided by the treating physician. Unit of measure: incidence (number and percentage). |
| To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower incidence of ISTH major and non-major clinically relevant bleeding. | Day 7 and day 30 | This will be assessed using patient records or information provided by the treating physician. Unit of measure: incidence (number and percentage). |
| To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower level of oxygen supplementation. | 48 hours | This will be assessed using patient records or information provided by the treating physician. Unit of measure: LO2/min |
| To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with shorter length of stay (days) at the ICU (Intensive Care Unit) and in hospital. | Up to 1 year | This will be assessed using patient records or information provided by the treating physician. Unit of measure: time in days. |
| To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with better patient-relevant outcomes such as Quality of life (QoL), functional recovery and symptom burden. | Day 7 and after 3, 6, 9 and 12 months | This will be assessed using a selection of the questionnaires mentioned in the ICHOM Set of Patient-Centered Outcome Measures for Venous Thromboembolism. The exact questionnaires used can be found in Table 2 of the study protocol. |
| Cost-effectiveness analysis after a time horizon of one year and budget impact analysis | 1 Year | This will be assessed using questionnaires, the exact questionnaires used can be found in Table 2 of the study protocol. A more detailed description of how cost-effectiveness and budget impact will be assessed is provided in section 10.2 of the study protocol. |
| To evaluate, after randomization, whether CDT in high-risk PE patients relative to systemic thrombolysis is associated with a lower incidence of BARC3b and BARC3c bleeding. | Day 7 and day 30 | Major bleeding is defined as Bleeding Academic Research Consortium (BARC)3b and BARC3c bleeding (=intracranial haemorrhage). This will be assessed using patient records or information provided by the treating physician. Unit of measure: incidence (number and percentage). |
Countries
Netherlands
Contacts
Primary ContactW. J.E. Stenger, MD
Backup ContactF. A. Klok, Prof. MD. PhD.
Outcome results
None listed