Reduced-Dose Versus Full-Dose Alteplase for High-Risk Pulmonary Embolism

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.

• Reduced-dose alteplase (Drug), also known as Reduced-dose systemic thrombolysis, Low-dose alteplase, tPA: Alteplase 0.6 mg/kg body weight, maximum 50 mg, administered as an intravenous infusion over 15 minutes
• Full-dose alteplase (Drug), also known as Full-dose systemic thrombolysis, Standard-dose alteplase, tPA: 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.

Primary outcomes

• 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 outcomes

• 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.

Other outcomes

• All-cause mortality at 12 months [At 12 months after randomization]: Incidence of death from any cause.
• At 12 months after randomization [At 12 months after randomization]: Incidence of objectively confirmed recurrent pulmonary embolism.
• Persistent dyspnea assessed using the modified Medical Research Council scale [At 3 months and 12 months after randomization]: Persistent dyspnea assessed using the modified Medical Research Council scale.
• Functional status assessed using the Post-VTE Functional Status Scale [At 3 months and 12 months after randomization]: Functional status assessed using the post-VTE functional status (PVFS) scale. Scores range from 0 to 4, where 0 indicates no functional limitations and 4 indicates severe functional limitations. Higher scores indicate worse functional status. Death before the scheduled assessment is recorded as grade D.
• Exercise tolerance assessed using the 6-minute walk test [At 3 months and 12 months after randomization]: Exercise tolerance assessed using the 6-minute walk test, reported as distance walked in meters. A greater distance indicates better exercise tolerance.
• Persistent right ventricular dysfunction assessed by echocardiography [At 3 months and/or 12 months after randomization]: Persistent right ventricular dysfunction according to echocardiography report, when performed as clinically indicated.
• Pulmonary embolism-specific quality of life assessed using the PEmb-QoL questionnaire [At 3 months and 12 months after randomization]: Pulmonary embolism-specific health-related quality of life assessed using the Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire. The PEmb-QoL summary score ranges from 0 to 100, with higher scores indicating worse health-related quality of life.
• Health-related quality of life assessed using EQ-5D-5L [At 3 months and 12 months after randomization]: Health-related quality of life assessed using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) instrument.
• Chronic thromboembolic pulmonary hypertension [At 12 months after randomization]: Incidence of chronic thromboembolic pulmonary hypertension.
• Health care resource utilization [During 12 months after randomization]: Cost of health care resource utilization during the 12-month follow-up period.

Sex: All, ages: 18 Years to any

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.

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• Kristina Svennerholm, Principal investigator, Sahlgrenska University Hospital / University of Gothenburg