Pulmonary Embolism Acute
Conditions
Keywords
Systemic thrombolysis, Efficacy, Safety, Reduced-dose, Alteplase
Brief summary
High-risk pulmonary embolism is a life-threatening condition requiring immediate reperfusion therapy. Full-dose systemic thrombolysis is recommended as first-line treatment, but its use is limited by the risk of major bleeding, including intracranial hemorrhage. Reduced-dose systemic thrombolysis may reduce bleeding while maintaining clinical efficacy, but this strategy has not been adequately evaluated in patients with high-risk pulmonary embolism. REDSTEM is an international, multicenter, randomized, adaptive, open-label, blinded-endpoint phase 4 trial comparing reduced-dose alteplase with standard full-dose alteplase in adults with acute high-risk pulmonary embolism. The trial will assess whether reduced-dose alteplase preserves early clinical efficacy while reducing severe clinically significant bleeding. Participants will be followed for up to 12 months.
Detailed description
Systemic thrombolysis is recommended as first-line reperfusion therapy for high-risk pulmonary embolism. However, bleeding complications limit its use in clinical practice and contribute to undertreatment of eligible patients. Existing evidence from small randomized trials, observational studies, and meta-analyses suggests that lower-dose thrombolysis may improve safety while maintaining efficacy, but previous studies have included mixed-risk pulmonary embolism populations and only a limited number of patients with high-risk pulmonary embolism. REDSTEM was designed to evaluate whether a reduced-dose alteplase strategy can provide a more favorable balance between efficacy and safety compared with standard full-dose alteplase in patients with high-risk pulmonary embolism. The study uses randomized treatment allocation, blinded endpoint adjudication, independent safety monitoring, and an adaptive design allowing sample-size re-estimation if required. The trial includes early clinical assessments during the acute phase and follow-up through 12 months to evaluate clinical outcomes, safety, functional recovery, quality of life, and health care resource utilization.
Interventions
DRUGReduced-dose alteplase
Alteplase 0.6 mg/kg body weight, maximum 50 mg, administered as an intravenous infusion over 15 minutes
DRUGFull-dose alteplase
Alteplase 1.5 mg/kg body weight, maximum 100 mg, administered as a 10 mg intravenous bolus over 1 to 2 minutes followed by 90 mg as an intravenous infusion over 2 hours.
Sponsors
Sahlgrenska University Hospital
Göteborg University
Leiden University Medical Center
Assistance Publique - Hôpitaux de Paris
Rigshospitalet, Denmark
University Hospital, Akershus
University of Zurich
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
The trial is open-label because alteplase dose and administration regimen differ between treatment groups and immediate clinical management requires knowledge of treatment allocation. The primary endpoint and key secondary endpoint will be adjudicated by an independent central Critical Events Committee blinded to treatment allocation. The trial statistician responsible for the final analyses will remain blinded until database lock and completion of all prespecified analyses
Intervention model description
Participants will be randomized in a 1:1 ratio to reduced-dose alteplase or standard full-dose alteplase.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participant aged 18 years or older. 2. Acute pulmonary embolism verified by computed tomography pulmonary angiography or pulmonary angiography. In hemodynamically unstable participants unable to undergo immediate imaging, presumed pulmonary embolism may be diagnosed based on bedside echocardiographic findings consistent with acute right ventricular pressure overload and high clinical suspicion of pulmonary embolism, provided that alternative causes of hemodynamic instability have been reasonably excluded. In such cases, the treating clinician must have independently decided to initiate thrombolytic therapy irrespective of study participation, and confirmatory imaging demonstrating pulmonary embolism must be performed as soon as clinically feasible. 3. High risk for early death, defined by at least one of the following: 1. High-risk pulmonary embolism according to European Society of Cardiology criteria: * Cardiac arrest with return of spontaneous circulation; * Obstructive shock, defined as systolic blood pressure \<90 mmHg or use of vasopressors to maintain systolic blood pressure ≥90 mmHg despite adequate filling status, together with end-organ hypoperfusion such as elevated serum lactate \>2 mmol/L, altered mental status, or cold clammy skin; * Persistent hypotension, defined as systolic blood pressure \<90 mmHg or a drop in systolic blood pressure ≥40 mmHg for longer than 15 minutes, not caused by new-onset arrhythmia, hypovolemia, or sepsis. 2. Abnormal right ventricular function on echocardiography or computed tomography pulmonary angiography, defined as right ventricular/left ventricular ratio ≥1.0, and elevated cardiac troponin above the local upper reference limit, and acute respiratory failure not primarily caused by underlying lung disease, defined as requiring facemask oxygen supplementation ≥12 L/min, high-flow nasal oxygen, or non-invasive ventilation with FiO2 ≥60% to reach oxygen saturation ≥94%. 4. Female participants of childbearing potential must have a negative urine or serum pregnancy test.
Exclusion criteria
1. Catastrophic pulmonary embolism, defined as ongoing cardiac arrest and/or need for extracorporeal cardiopulmonary resuscitation and/or immediate VA-ECMO as judged by the treating physicians. 2. Known hypersensitivity to alteplase or any of its excipients. 3. Contraindication to systemic thrombolysis with one or more of the following: * History of hemorrhagic stroke; * Ischemic stroke within the previous 6 months; * Central nervous system neoplasm; * Major trauma, major surgery, or major head injury within the previous 3 weeks; * Active life-threatening bleeding, bleeding into a critical organ or area, or known severe bleeding diathesis; * Chronic use of full-dose oral or parenteral anticoagulation before presentation. 4. The participant has already received reperfusion treatment for the index pulmonary embolism before randomization, including systemic thrombolysis, surgical embolectomy, or catheter-directed intervention. 5. Pregnancy. 6. Current participation in another study that would interfere with participation in this trial. 7. Any other condition that would put the participant at unacceptable risk from the trial interventions as judged by the treating clinician. 8. In countries where required by national regulations: lack of affiliation to a social security system or equivalent health insurance coverage.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of composite efficacy endpoint | Within 7 days after randomization | Incidence of a composite endpoint comprising all-cause mortality within 7 days, cardiopulmonary resuscitation and/or veno-arterial extracorporeal membrane oxygenation within 7 days, recurrent pulmonary embolism within 7 days, clinical deterioration within 24 hours, and lack of clinical improvement at 6 hours. |
| Key secondary endpoint - Incidence of severe clinically significant bleeding | Within 7 days after randomization | Incidence of severe clinically significant bleeding, defined as major bleeding according to International Society on Thrombosis and Haemostasis criteria or bleeding requiring urgent medical intervention. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-cause mortality | At 7 days and 30 days after randomization | Incidence of death from any cause. |
| Pulmonary embolism-related mortality | At 7 days and 30 days after randomization | Incidence of pulmonary embolism-related death. |
| Cardiopulmonary resuscitation and/or VA-ECMO | Within 7 days after randomization | Incidence of cardiopulmonary resuscitation and/or veno-arterial extracorporeal membrane oxygenation. |
| Incidence of clinical deterioration | Within 24 hours after randomization | Incidence of life-threatening hemodynamic or respiratory decline requiring cardiopulmonary resuscitation, endotracheal intubation, or VA-ECMO, or an increase in SCAI SHOCK stage after investigational medicinal product administration. |
| Lack of clinical improvement assessed by SCAI SHOCK stage and oxygen requirement | At 6 hours after randomization | Incidence of unchanged SCAI SHOCK stage or unchanged or rising fraction of inspired oxygen required to maintain oxygen saturation of at least 94%. |
| Time to clinical stabilization based on predefined hemodynamic and respiratory criteria | From randomization until clinical stabilization, assessed up to 7 days after randomization | Time from randomization to the time point at which predefined hemodynamic or respiratory stabilization criteria have been continuously fulfilled for at least 30 minutes |
| Incidence of recurrent pulmonary embolism | At 7 days and 30 days after randomization | Incidence of objectively confirmed recurrent pulmonary embolism. |
| Initiation of invasive or non-invasive mechanical ventilation | Within 7 days after randomization | Incidence of initiation of invasive or non-invasive mechanical ventilation. |
| Win ratio for efficacy | Within 7 days after randomization | Win ratio based on all-cause mortality, cardiopulmonary resuscitation and/or VA-ECMO, clinical deterioration, lack of clinical improvement, recurrent pulmonary embolism, and time to clinical stabilization. |
| Net clinical benefit | Within 7 days after randomization | Composite net clinical benefit including severe clinically significant bleeding, all-cause mortality, cardiopulmonary resuscitation and/or VA-ECMO, recurrent pulmonary embolism, clinical deterioration, and lack of clinical improvement. |
| Rescue treatment | Before clinical stabilization, up to 7 days after randomization | Need for rescue treatment, defined as additional alteplase, catheter-directed intervention, surgical embolectomy, or VA-ECMO before stabilization. |
| ICU or high-dependency unit length of stay in days | Within 30 days after randomization | Length of stay in intensive care unit and/or high-dependency unit. |
| Hospital length of stay | Within 30 days after randomization | Length of hospital stay. |
| Major bleeding | At 48 hours, 7 days, and 30 days after randomization | Incidence of major bleeding according to International Society on Thrombosis and Haemostasis criteria. |
| Bleeding requiring urgent medical intervention | At 48 hours, 7 days, and 30 days after randomization | Incidence of severe bleeding requiring urgent medical intervention. |
| Intracerebral bleeding | Within 7 days after randomization | Incidence of intracerebral bleeding. |
Countries
Denmark, Norway, Sweden
Contacts
CONTACTKristina Svennerholm, MD PhD
CONTACTAnnika Odenstedt, Coordinator
PRINCIPAL_INVESTIGATORKristina Svennerholm
Sahlgrenska University Hospital / University of Gothenburg
Outcome results
None listed