Reduced-Dose Versus Full-Dose Alteplase for High-Risk Pulmonary Embolism (REDSTEM)

Reduced-Dose Versus Full-Dose Systemic Thrombolysis for High-Risk Pulmonary Embolism: A Multicentre, Randomised, Open-Label, Blinded-Endpoint Trial

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Pulmonary Embolism Acute
• Intervention / Treatment: Drug: Reduced-dose alteplase; Drug: Full-dose alteplase

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.

• Study Type: Interventional
• Enrollment (Estimated): 400
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Svennerholm; Phone Number: +46313421000; Email: kristina.svennerholm@vgregion.se
• Study Contact Backup: Name: Annika Odenstedt, Coordinator; Phone Number: +46313421000

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Rigshospitalet
    • Contact: Jesper Kjaergaard, MD, PhD
• Norway
  • Bergen, Norway, 5021
    • Haukeland University Hospital
    • Contact: Lasse Melvear Gii, MD, PhD
  • Drammen, Norway, 3004
    • Drammen Hospital
    • Contact: Jonas Pivoriunas, MD, PhD
  • Grålum, Norway, 1714
    • Ostfold Hisptal
    • Contact: Hans Joakim Myklebust-Hansen, MD
  • Lörenskog, Norway, 1478
    • Akershus University Hospital
    • Contact: Hamza Nahoui, MD
  • Oslo, Norway, 0450
    • Oslo University Hospital, Ullevål
    • Contact: Mari Asphjell Björnaas, MD, PhD
  • Stavanger, Norway, 4021
    • Stavanger University Hospital
    • Contact: Trond Johan Cooper, MD
• Sweden
  • Falun, Sweden
    • Falun Hospital
    • Contact: Jessica Silfverberg, MD
  • Gothenburg, Sweden
    • Sahlgrenska University Hospital/Östra
    • Contact: Katarina Glise Sandblad, MD, PhD
  • Jönköping, Sweden
    • Ryhov County Hospital
    • Contact: Antheia Kissopoulou, MD, PhD
  • Lund, Sweden
    • Skåne University Hospital, Lund
    • Contact: Marcus Ohlsson, MD
  • Malmö, Sweden
    • Skåne University Hospital, Malmö
    • Contact: Marcus Ohlsson, MD, PhD
  • Mölndal, Sweden
    • Sahlgrenska University Hospital/Mölndal
    • Contact: Louise Martinell, MD, PhD
  • Norrtälje, Sweden
    • Norrtälje Hospital
    • Contact: Sune Forsberg, MD, PhD
  • Skövde, Sweden
    • Skaraborgs Hospital Skövde
    • Contact: Freyr Einarsson, MD
    • Contact: Erik Ullemark, MD
  • Stockholm, Sweden
    • Danderyd Hospital
    • Contact: Nina Olausson, MD, PhD
  • Stockholm, Sweden
    • Karolinska University Hospital, Solna
    • Contact: Therese Djärv, MD, PhD
  • Stockholm, Sweden
    • Karolinska University Hospital, Huddinge
    • Contact: Therese Djärv, MD, PhD
  • Stockholm, Sweden
    • Capio S:t Göran's Hospital
    • Contact: Rickard Markgren, MD, PhD
  • Stockholm, Sweden
    • Södersjukhuset, Stockholm South General Hospital
    • Contact: Jacob Hollenberg, MD, PhD
  • Umeå, Sweden
    • University Hospital of Umeå
    • Contact: Johanna Pennlert, MD, PhD
  • Uppsala, Sweden
    • Uppsala university hospital
    • Contact: Sofia Vikman, MD, PhD
  • Västra Götaland County
    • Gothenburg, Västra Götaland County, Sweden, 413 45
      • Sahlgrenska University Hospital
      • Contact: Kristina Svennerholm, MD, PhD; Email: kristina.svennerholm@vgregion.se
      • Contact: Katarina Glise Sandblad, MD, PhD; Email: katarina.glise.sandblad@vgregion.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Reduced-Dose Alteplase; Participants randomized to reduced-dose systemic thrombolysis will receive alteplase 0.6 mg/kg body weight, up to a maximum dose of 50 mg, administered intravenously over 15 minutes.	Drug: Reduced-dose alteplase; Alteplase 0.6 mg/kg body weight, maximum 50 mg, administered as an intravenous infusion over 15 minutes; Other Names: Reduced-dose systemic thrombolysis, Low-dose alteplase, tPA
Active Comparator: Full-Dose Alteplase; Participants randomized to standard full-dose systemic thrombolysis will receive alteplase 1.5 mg/kg body weight, up to a maximum dose of 100 mg, administered as a 10 mg intravenous bolus over 1 to 2 minutes followed by a 90 mg intravenous infusion over 2 hours.	Drug: Full-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.; Other Names: Full-dose systemic thrombolysis, Standard-dose alteplase, tPA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of composite efficacy endpoint	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.	Within 7 days after randomization
Key secondary endpoint - Incidence of severe clinically significant bleeding	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.	Within 7 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality	Incidence of death from any cause.	At 7 days and 30 days after randomization
Pulmonary embolism-related mortality	Incidence of pulmonary embolism-related death.	At 7 days and 30 days after randomization
Cardiopulmonary resuscitation and/or VA-ECMO	Incidence of cardiopulmonary resuscitation and/or veno-arterial extracorporeal membrane oxygenation.	Within 7 days after randomization
Incidence of clinical deterioration	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.	Within 24 hours after randomization
Lack of clinical improvement assessed by SCAI SHOCK stage and oxygen requirement	Incidence of unchanged SCAI SHOCK stage or unchanged or rising fraction of inspired oxygen required to maintain oxygen saturation of at least 94%.	At 6 hours after randomization
Time to clinical stabilization based on predefined hemodynamic and respiratory criteria	Time from randomization to the time point at which predefined hemodynamic or respiratory stabilization criteria have been continuously fulfilled for at least 30 minutes	From randomization until clinical stabilization, assessed up to 7 days after randomization
Incidence of recurrent pulmonary embolism	Incidence of objectively confirmed recurrent pulmonary embolism.	At 7 days and 30 days after randomization
Initiation of invasive or non-invasive mechanical ventilation	Incidence of initiation of invasive or non-invasive mechanical ventilation.	Within 7 days after randomization
Win ratio for efficacy	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.	Within 7 days after randomization
Net clinical benefit	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.	Within 7 days after randomization
Rescue treatment	Need for rescue treatment, defined as additional alteplase, catheter-directed intervention, surgical embolectomy, or VA-ECMO before stabilization.	Before clinical stabilization, up to 7 days after randomization
ICU or high-dependency unit length of stay in days	Length of stay in intensive care unit and/or high-dependency unit.	Within 30 days after randomization
Hospital length of stay	Length of hospital stay.	Within 30 days after randomization
Major bleeding	Incidence of major bleeding according to International Society on Thrombosis and Haemostasis criteria.	At 48 hours, 7 days, and 30 days after randomization
Bleeding requiring urgent medical intervention	Incidence of severe bleeding requiring urgent medical intervention.	At 48 hours, 7 days, and 30 days after randomization
Intracerebral bleeding	Incidence of intracerebral bleeding.	Within 7 days after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality at 12 months	Incidence of death from any cause.	At 12 months after randomization
At 12 months after randomization	Incidence of objectively confirmed recurrent pulmonary embolism.	At 12 months after randomization
Persistent dyspnea assessed using the modified Medical Research Council scale	Persistent dyspnea assessed using the modified Medical Research Council scale.	At 3 months and 12 months after randomization
Functional status assessed using the Post-VTE Functional Status Scale	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.	At 3 months and 12 months after randomization
Exercise tolerance assessed using the 6-minute walk test	Exercise tolerance assessed using the 6-minute walk test, reported as distance walked in meters. A greater distance indicates better exercise tolerance.	At 3 months and 12 months after randomization
Persistent right ventricular dysfunction assessed by echocardiography	Persistent right ventricular dysfunction according to echocardiography report, when performed as clinically indicated.	At 3 months and/or 12 months after randomization
Pulmonary embolism-specific quality of life assessed using the PEmb-QoL questionnaire	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.	At 3 months and 12 months after randomization
Health-related quality of life assessed using EQ-5D-5L	Health-related quality of life assessed using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) instrument.	At 3 months and 12 months after randomization
Chronic thromboembolic pulmonary hypertension	Incidence of chronic thromboembolic pulmonary hypertension.	At 12 months after randomization
Health care resource utilization	Cost of health care resource utilization during the 12-month follow-up period.	During 12 months after randomization

Collaborators and Investigators

• Sponsor: Sahlgrenska University Hospital
• Collaborators: Assistance Publique - Hôpitaux de Paris; University of Zurich; Göteborg University; Rigshospitalet, Denmark; University Hospital, Akershus; Leiden University Medical Center
• Investigators: Principal Investigator: Svennerholm, Sahlgrenska University Hospital / University of Gothenburg

Publications and helpful links

General Publications

• Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.
• Wang C, Zhai Z, Yang Y, Wu Q, Cheng Z, Liang L, Dai H, Huang K, Lu W, Zhang Z, Cheng X, Shen YH; China Venous Thromboembolism (VTE) Study Group. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest. 2010 Feb;137(2):254-62. doi: 10.1378/chest.09-0765. Epub 2009 Sep 9.
• Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, Huisman MV, Humbert M, Jennings CS, Jimenez D, Kucher N, Lang IM, Lankeit M, Lorusso R, Mazzolai L, Meneveau N, Ni Ainle F, Prandoni P, Pruszczyk P, Righini M, Torbicki A, Van Belle E, Zamorano JL; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020 Jan 21;41(4):543-603. doi: 10.1093/eurheartj/ehz405. No abstract available.
• Sanchez O, Charles-Nelson A, Ageno W, Barco S, Binder H, Chatellier G, Duerschmied D, Empen K, Ferreira M, Girard P, Huisman MV, Jimenez D, Katsahian S, Kozak M, Lankeit M, Meneveau N, Pruszczyk P, Petris A, Righini M, Rosenkranz S, Schellong S, Stefanovic B, Verhamme P, de Wit K, Vicaut E, Zirlik A, Konstantinides SV, Meyer G; PEITHO-3 Investigators. Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial. Thromb Haemost. 2022 May;122(5):857-866. doi: 10.1055/a-1653-4699. Epub 2021 Oct 31.
• Stevens SM, Woller SC, Kreuziger LB, Bounameaux H, Doerschug K, Geersing GJ, Huisman MV, Kearon C, King CS, Knighton AJ, Lake E, Murin S, Vintch JRE, Wells PS, Moores LK. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest. 2021 Dec;160(6):e545-e608. doi: 10.1016/j.chest.2021.07.055. Epub 2021 Aug 2.
• Silver MJ, Giri J, Duffy A, Jaber WA, Khandhar S, Ouriel K, Toma C, Tu T, Horowitz JM. Incidence of Mortality and Complications in High-Risk Pulmonary Embolism: A Systematic Review and Meta-Analysis. J Soc Cardiovasc Angiogr Interv. 2023 Jan 27;2(1):100548. doi: 10.1016/j.jscai.2022.100548. eCollection 2023 Jan-Feb.
• Keller K, Hobohm L, Ebner M, Kresoja KP, Munzel T, Konstantinides SV, Lankeit M. Trends in thrombolytic treatment and outcomes of acute pulmonary embolism in Germany. Eur Heart J. 2020 Jan 21;41(4):522-529. doi: 10.1093/eurheartj/ehz236.
• Goldhaber SZ, Agnelli G, Levine MN. Reduced dose bolus alteplase vs conventional alteplase infusion for pulmonary embolism thrombolysis. An international multicenter randomized trial. The Bolus Alteplase Pulmonary Embolism Group. Chest. 1994 Sep;106(3):718-24. doi: 10.1378/chest.106.3.718.
• Melamed R, Tierney DM, Xia R, Brown CS, Mara KC, Lillyblad M, Sidebottom A, Wiley BM, Khapov I, Gajic O. Safety and Efficacy of Reduced-Dose Versus Full-Dose Alteplase for Acute Pulmonary Embolism: A Multicenter Observational Comparative Effectiveness Study. Crit Care Med. 2024 May 1;52(5):729-742. doi: 10.1097/CCM.0000000000006162. Epub 2024 Jan 3.
• Stadlbauer A, Verbelen T, Binzenhofer L, Goslar T, Supady A, Spieth PM, Noc M, Verstraete A, Hoffmann S, Schomaker M, Hopler J, Kraft M, Tautz E, Hoyer D, Tongers J, Haertel F, El-Essawi A, Salem M, Rangel RH, Hullermann C, Kriz M, Schrage B, Moises J, Sabate M, Pappalardo F, Crusius L, Mangner N, Adler C, Tichelbacker T, Skurk C, Jung C, Kufner S, Graf T, Scherer C, Villegas Sierra L, Billig H, Majunke N, Speidl WS, Zilberszac R, Chiscano-Camon L, Uribarri A, Riera J, Roncon-Albuquerque R Jr, Terauda E, Erglis A, Tavazzi G, Zeymer U, Knorr M, Kilo J, Mobius-Winkler S, Schwinger RHG, Frank D, Borst O, Haberle H, De Roeck F, Vrints C, Schmid C, Nickenig G, Hagl C, Massberg S, Schafer A, Westermann D, Zimmer S, Combes A, Camboni D, Thiele H, Lusebrink E; High-risk P. E. Investigator Group. Management of high-risk acute pulmonary embolism: an emulated target trial analysis. Intensive Care Med. 2025 Mar;51(3):490-505. doi: 10.1007/s00134-025-07805-4. Epub 2025 Feb 25.

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2026
• Primary Completion (Estimated): January 31, 2030
• Study Completion (Estimated): January 31, 2031

Study Registration Dates

• First Submitted: September 2, 2026
• First Submitted That Met QC Criteria: September 10, 2026
• First Posted (Actual): September 14, 2026

Study Record Updates

• Last Update Posted (Actual): September 14, 2026
• Last Update Submitted That Met QC Criteria: September 10, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: Safety; Efficacy; Alteplase; Systemic thrombolysis; Reduced-dose
• Additional Relevant MeSH Terms: Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Hydrolases; Enzymes; Enzymes and Coenzymes; Blood Proteins; Endopeptidases; Peptide Hydrolases; Serine Endopeptidases; Serine Proteases; Plasminogen Activators; Blood Coagulation Factors; Tissue Plasminogen Activator
• Other Study ID Numbers: REDSTEM; 2024-515904-37-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data underlying the published results may be shared upon reasonable request after publication. Access will require approval by the sponsor and principal investigator, a scientifically sound proposal, scientific collaboration with the trial investigators, compliance with applicable ethical, regulatory, data protection, and consent requirements, and a signed data sharing agreement.
• IPD Sharing Time Frame: After publication of the trial results.
• IPD Sharing Access Criteria: Reasonable request, subject to approval by the sponsor and principal investigator and applicable legal, ethical, and data protection requirements.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No