Reduced-Dose Thrombolysis in Intermediate-Risk Pulmonary Embolism With High-Risk Features (REDUCTION)
Reduced-Dose Thrombolysis in Intermediate-High Risk Pulmonary Embolism, a Multicenter, Randomized Controlled Trial
Alteplase, a recombinant tissue plasminogen activator (rt-PA), is commonly used for thrombolytic treatment in patients with high-risk acute pulmonary thromboembolism (PTE), whereas the role of thrombolysis in intermediate-risk PTE remains controversial. This multicenter, randomized controlled trial will compare the efficacy and safety of reduced-dose alteplase (25 mg administered intravenously over 2 hours) plus standard anticoagulation with standard anticoagulation alone in patients with intermediate-risk PTE who have high-risk features.
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
In patients with intermediate-risk pulmonary embolism (PE), full-dose systemic thrombolysis has been associated with a reduction in the risk of hemodynamic decompensation but an increased risk of major and intracranial bleeding. Previous studies suggest that reduced-dose thrombolysis may improve right ventricular (RV) function while potentially reducing bleeding complications. However, evidence regarding the efficacy and safety of reduced-dose systemic thrombolysis in patients with intermediate risk PE and additional high-risk clinical features remains limited. This study aims to evaluate the efficacy and safety of reduced-dose thrombolytic therapy in this patient population.
The REDUCTION study is a multicenter, randomized, open-label, controlled trial with blinded endpoint assessment and long-term follow-up.
Eligible patients will be randomly assigned in a 1:1 ratio to receive reduced-dose alteplase combined with standard anticoagulation or standard anticoagulation alone. Randomization will be centrally managed and stratified by participating center.
Patients will receive:
- Reduced-dose alteplase group: Alteplase 25 mg administered by intravenous infusion over 2 hours, followed by standard anticoagulation with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) for at least 5 days.
- Standard anticoagulation group: Standard anticoagulation with LMWH or UFH for at least 5 days without thrombolytic therapy.
The primary objective is to assess the efficacy of reduced-dose alteplase in improving RV function at 48 hours, as measured by the change in the ratio of right ventricular to left ventricular end-diastolic diameters (RVED/LVED) on echocardiography.
The secondary objectives are to evaluate early changes in right ventricular function, clinical deterioration, PE-related mortality, recurrent PE, and bleeding complications. Long-term assessments will evaluate persistent dyspnea, functional status, persistent right ventricular dysfunction, and the occurrence of chronic thromboembolic pulmonary disease (CTEPD) and chronic thromboembolic pulmonary hypertension (CTEPH)
Tipo de estudio
Inscripción (Estimado)
Fase
- Fase 3
Contactos y Ubicaciones
Estudio Contacto
- Nombre: Changming Xiong, Prof.
- Número de teléfono: (+86)010-88396798
- Correo electrónico: xiongcmfw@163.com
Ubicaciones de estudio
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Beijing, Porcelana, 100037
- Chinese Academy of Medical Sciences, Fuwai Hospital
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Contacto:
- Changming Xiong, Prof.
- Número de teléfono: 010-88396798
- Correo electrónico: xiongcmfw@163.com
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Beijing Municipality
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Beijing, Beijing Municipality, Porcelana, 100029
- China-Japan Friendship Hospital
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Contacto:
- Zhenguo Zhai
- Número de teléfono: 010-84205566
- Correo electrónico: zhaizhenguo2011@126.com
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Beijing, Beijing Municipality, Porcelana, 100730
- Peking Union Medical College Hospital
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Contacto:
- Juhong Shi, Prof.
- Número de teléfono: 010-69156114
- Correo electrónico: shijh@pumch.cn
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Beijing, Beijing Municipality, Porcelana, 100029
- Beijing Anzhen Hospital, Capital Medical University
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Contacto:
- Jun Wan, Prof.
- Número de teléfono: 010-64412431
- Correo electrónico: blueswan2013@yahoo.com
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Beijing, Beijing Municipality, Porcelana, 100020
- Beijing ChaoYang Hospital.Capital Medical University
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Contacto:
- Yuanhua Yang, Prof.
- Número de teléfono: 010-85231777
- Correo electrónico: yyh1031@sina.com
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Guangdong
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Guangzhou, Guangdong, Porcelana, 510120
- Guangdong Provincial Hospital of Chinese Medicine
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Contacto:
- Yinji Xu, Prof.
- Número de teléfono: 020-81887233
- Correo electrónico: xuyinji@163.com
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Guangzhou, Guangdong, Porcelana, 510120
- The First Affiliated Hospital of Guangzhou Medical University / Guangzhou Institute of Respiratory Health (National Clinical Research Center for Respiratory Disease)
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Contacto:
- Nuofu Zhang, Prof.
- Número de teléfono: 020-83062114
- Correo electrónico: nfzhanggird@163.com
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Shenzhen, Guangdong, Porcelana, 518116
- Longgang Central Hospital of Shenzhen
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Contacto:
- Siliang Xu, Prof.
- Número de teléfono: 0755-84806933
- Correo electrónico: 420814562@qq.com
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Hebei
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Zhangjiakou, Hebei, Porcelana, 075000
- The First Affiliated Hospital of Hebei North University
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Contacto:
- Baoli Xiang, Prof.
- Número de teléfono: 0313-8043555
- Correo electrónico: 15530396731@163.com
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Henan
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Xinxiang, Henan, Porcelana, 453400
- HeNan Honliv Hospital
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Contacto:
- Lei Yang, Prof.
- Número de teléfono: 0373-8882288
- Correo electrónico: 61194255@qq.com
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Zhengzhou, Henan, Porcelana, 450052
- The First Affiliated Hospital of Zhengzhou University
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Contacto:
- Zhe Cheng, Prof.
- Número de teléfono: 0371-66913114
- Correo electrónico: chengzhehi@126.com
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Zhengzhou, Henan, Porcelana, 450003
- Henan Provincial People's Hospital
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Contacto:
- Yong Qi, Prof.
- Número de teléfono: 0371-65580014
- Correo electrónico: srmyy123@163.com
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Hubei
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Wuhan, Hubei, Porcelana, 430015
- Wuhan Sixth Hospital (Affiliated Hospital of Jianghan University)
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Contacto:
- Fajiu Li, Prof.
- Número de teléfono: 027-82426502
- Correo electrónico: 80670519@qq.com
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Inner Mongolia
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Baotou, Inner Mongolia, Porcelana, 014010
- Inner Mongolia Baogang Hospital
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Contacto:
- Hongjun Tian, Prof.
- Número de teléfono: 0472-5992811
- Correo electrónico: 1139717960@qq.com
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Tongliao, Inner Mongolia, Porcelana, 028000
- NMG Keerqin District Hosp.
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Contacto:
- Xili Wang, Prof.
- Número de teléfono: 0475-8232510
- Correo electrónico: 861004223@qq.com
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Jiangsu
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Changzhou, Jiangsu, Porcelana, 213003
- The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University
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Contacto:
- Qian Zhang, Prof.
- Número de teléfono: 0519-81099988
- Correo electrónico: kezhang0601@163.com
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Nanjing, Jiangsu, Porcelana, 210006
- Nanjing First Hospital
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Contacto:
- He Xu, Prof.
- Número de teléfono: 025-52271000
- Correo electrónico: hexunj@163.com
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Liaoning
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Shenyang, Liaoning, Porcelana, 110024
- Central Hospital Affiliated to Shenyang Medical College
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Contacto:
- Shuyue Xia, Prof.
- Número de teléfono: 024-85715200
- Correo electrónico: syx262@126.com
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Shenyang, Liaoning, Porcelana, 110003
- General Hospital of Northern Theater Command
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Contacto:
- Liang Shi, Prof.
- Número de teléfono: 024-28886666
- Correo electrónico: 13309889463@163.com
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Ningxia
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Yinchuan, Ningxia, Porcelana, 750004
- Ningxia Medical University General Hospital
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Contacto:
- Juan Chen, Prof.
- Número de teléfono: 0951-6744457
- Correo electrónico: chenjuan7419@163.com
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Shandong
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Jinan, Shandong, Porcelana, 250021
- Shandong Provincial Hospital
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Contacto:
- Ling Zhu, Prof.
- Número de teléfono: 0531-87938911
- Correo electrónico: zhuling7103@163.com
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Linyi, Shandong, Porcelana, 276000
- Linyi People's Hospital
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Contacto:
- Le Kang, Prof.
- Número de teléfono: 0539-8616398
- Correo electrónico: 593119267@qq.com
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Shanghai Municipality
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Shanghai, Shanghai Municipality, Porcelana, 200120
- Shanghai East Hospital, School of Medicine, Tongji University
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Contacto:
- Yingqun Ji, Prof.
- Número de teléfono: 021-38804518
- Correo electrónico: jiyingqun@163.com
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Sichuan
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Chengdu, Sichuan, Porcelana, 610041
- West China Hospital, Sichuan University
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Contacto:
- Maojun Wang, Prof.
- Número de teléfono: 028-85422114
- Correo electrónico: wmmyun@hotmail.com
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Tianjin Municipality
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Tianjin, Tianjin Municipality, Porcelana, 300052
- Tianjin Medical University General Hospital
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Contacto:
- Lixia Dong, Prof.
- Número de teléfono: 022-96580
- Correo electrónico: 18355193818@163.COM
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Tianjin, Tianjin Municipality, Porcelana, 300222
- Tianjin Chest Hospital
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Contacto:
- Songtao Gu
- Número de teléfono: 022-88185111
- Correo electrónico: gusongtaodoctor@126.com
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
Inclusion Criteria:
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Age 18 to 75 years
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Objectively confirmed acute pulmonary thromboembolism (PTE) with symptom onset within 14 days, based on at least one of the following:
- Ventilation/perfusion lung scan showing at least one segmental or larger mismatched perfusion defect;
- Computed tomography pulmonary angiography (CTPA) or pulmonary angiography showing a filling defect or abrupt obstruction in a segmental or more proximal pulmonary artery.
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Intermediate-high-risk PTE, with both of the following:
- Right ventricular dysfunction (RVD) on echocardiography or CTPA. Echocardiographic RVD is defined by at least one of the following:(1) right ventricular dilation with RV/LV end-diastolic diameter ratio >1.0; (2) reduced right ventricular free-wall motion; (3) increased tricuspid regurgitation velocity;(4) tricuspid annular plane systolic excursion <16 mm; (5) tricuspid annular systolic velocity (S') <9.5 cm/s. CTPA evidence of RVD is defined as right ventricular dilation with RV/LV end-diastolic diameter ratio >1.0.
- Cardiac injury or heart failure biomarker above the local upper limit of normal, including cardiac troponin, BNP, or NT-proBNP.
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Elevated risk of early death/hemodynamic collapse, indicated by at least one of the following high-risk features: Systolic blood pressure ≤110 mmHg, Heart rate ≥100 beats/min, Oxygen saturation (SpO₂) <90% (respiratory rate >20 breaths/min or arterial partial pressure of oxygen [PaO₂] <60 mmHg).
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Signed informed consent
Exclusion Criteria:
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High-risk PTE with hemodynamic instability, including cardiac arrest, obstructive shock, or persistent hypotension defined as systolic blood pressure <90 mmHg or a decrease of ≥40 mmHg from baseline lasting at least 15 minutes, after excluding hypotension caused by new-onset arrhythmia, hypovolemia, or sepsis.
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Intermediate-low-risk PTE, defined as hemodynamically stable PE with only one of the following findings: right ventricular dysfunction on imaging or elevated cardiac biomarkers.
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Low-risk PTE, defined as hemodynamically stable PTE without right ventricular dysfunction and without elevated cardiac injury or heart failure biomarkers.
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Any contraindication to systemic thrombolysis, including:
- Known hypersensitivity to alteplase, gentamicin, heparin, low-molecular-weight heparin, or any component of the study treatment;
- Active bleeding or high risk of bleeding;
- Known or suspected intracranial hemorrhage;
- Suspected subarachnoid hemorrhage or aneurysmal subarachnoid hemorrhage;
- Significant bleeding disorder within the previous 6 months;
- Known bleeding diathesis;
- Acute ischemic stroke or transient ischemic attack within the previous 6 months;
- Ophthalmic surgery within the previous 3 months, or abdominal, cardiac, thoracic, vascular, or orthopedic surgery or trauma within the previous 3 months;
- History of central nervous system disease or trauma, including tumor, aneurysm, head trauma, intracranial surgery, or spinal surgery;
- Platelet count <100 × 10^9/L;
- International normalized ratio (INR) >1.3;
- Current effective oral anticoagulant treatment;
- Traumatic cardiopulmonary resuscitation;
- Infective endocarditis or pericarditis;
- Acute pancreatitis;
- Noncompressible vascular puncture;
- Severe uncontrolled hypertension, with systolic blood pressure >180 mmHg and/or diastolic blood pressure >110 mmHg;
- Any other condition considered by the investigator to confer a high bleeding risk;
- Severe liver disease, including liver failure, cirrhosis, portal hypertension, esophageal varices, or active hepatitis;
- Gastrointestinal ulcer, esophageal varices, arterial aneurysm, or arteriovenous malformation within the previous 3 months;
- Tumor with bleeding tendency;
- Pregnancy or within 1 week postpartum;
- Diabetes with hemorrhagic retinopathy;
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Body weight ≤40 kg.
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Thrombolytic treatment within 30 days before randomization for the current episode of acute PE, including systemic or catheter-directed thrombolysis.
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Catheter-directed mechanical thrombectomy or surgical pulmonary embolectomy before randomization for the current episode of acute PE.
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Use of any direct oral anticoagulant within 30 days before randomization.
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Current dual antiplatelet therapy.
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Current participation in another interventional clinical trial.
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Women of childbearing potential who are unwilling to use effective contraception or abstinence during the study.
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Any other disease or condition that, in the investigator's judgment, would increase treatment risk.
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Life expectancy <3 months or inability to complete 3-month follow-up.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Único
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
|---|---|
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Comparador activo: Reduced-Dose Alteplase and Standard Anticoagulation
Low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) and reduced-dose alteplase [25 mg continuous intravenous infusion for 2 hours] |
Alteplase 25 mg will be administered by continuous intravenous infusion over 2 hours Standard anticoagulation will consist of LMWH or UFH administered according to current guideline recommendations for at least 5 days |
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Comparador activo: Standard Anticoagulation
Low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) |
Standard anticoagulation will consist of LMWH or UFH administered according to current guideline recommendations for at least 5 days |
¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Periodo de tiempo |
|---|---|
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Change in the ratio of right ventricular end-diastolic diameter to left ventricular end-diastolic diameter (RVED/LVED) as measured by echocardiography
Periodo de tiempo: Between baseline and 48 hours
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Between baseline and 48 hours
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Change in the ratio of right ventricular end-diastolic diameter to left ventricular end-diastolic diameter (RVED/LVED) as measured by echocardiography
Periodo de tiempo: Between baseline and 7 days
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Between baseline and 7 days
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Clinical Deterioration
Periodo de tiempo: 7 days
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7 days
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PE-Related Death
Periodo de tiempo: 7 days
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Death caused by pulmonary embolism (PE) |
7 days
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All cause Death
Periodo de tiempo: 7 days
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7 days
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Recurrent PE
Periodo de tiempo: 7 days
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7 days
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Persistent Dyspnea
Periodo de tiempo: 6 months
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Persistent Dyspnea Assessed by the Medical Research Council (MRC) Dyspnea Scale |
6 months
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Functional outcome
Periodo de tiempo: 6 months
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Functional status will be assessed using the Post-Venous Thromboembolism Functional Status (PVFS) Scale, which measures limitations in usual activities and daily functioning after venous thromboembolism. The scale ranges from grade 0 (no functional limitations) to grade 4 (severe functional limitations requiring assistance with activities of daily living). Higher grades indicate greater functional impairment. Grade D indicates death before the scheduled assessment. |
6 months
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Persistent Right Ventricular Dysfunction
Periodo de tiempo: 6 months
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Persistent right ventricular dysfunction is defined as an intermediate or high probability of pulmonary hypertension on echocardiography according to the European Society of Cardiology (ESC) criteria. |
6 months
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Chronic thromboembolic pulmonary disease (CTEPD) and/or Chronic thromboembolic pulmonary hypertension (CTEPH)
Periodo de tiempo: 12 months
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12 months
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Major bleeding
Periodo de tiempo: 30 days
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Major bleeding will be defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria as fatal bleeding, symptomatic bleeding in a critical area or organ, a decrease in hemoglobin of ≥2 g/dL, or transfusion of ≥2 units of whole blood or red blood cells. The number of participants experiencing major bleeding will be recorded |
30 days
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Clinically relevant non-major bleeding
Periodo de tiempo: 30 days
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Clinically relevant non-major bleeding will be defined according to ISTH criteria as bleeding that does not meet the criteria for major bleeding but requires medical intervention, leads to hospitalization or an increased level of care, or prompts a face-to-face evaluation by a healthcare professional. The number of participants experiencing clinically relevant non-major bleeding will be recorded. |
30 days
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Minor bleeding
Periodo de tiempo: 30 days
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Minor bleeding will be defined as any overt bleeding event that does not meet the criteria for major bleeding or clinically relevant non-major bleeding and does not require medical attention. The number of participants experiencing minor bleeding will be recorded. |
30 days
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Colaboradores e Investigadores
Patrocinador
Investigadores
- Investigador principal: Changming Xiong, Prof., Chinese Academy of Medical Sciences, Fuwai Hospital
- Investigador principal: Zhenguo Zhai, Prof., China-Japan Friendship Hospital
Publicaciones y enlaces útiles
Publicaciones Generales
- Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M; "MOPETT" Investigators. Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). Am J Cardiol. 2013 Jan 15;111(2):273-7. doi: 10.1016/j.amjcard.2012.09.027. Epub 2012 Oct 24.
- Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, Bluhmki E, Bouvaist H, Brenner B, Couturaud F, Dellas C, Empen K, Franca A, Galie N, Geibel A, Goldhaber SZ, Jimenez D, Kozak M, Kupatt C, Kucher N, Lang IM, Lankeit M, Meneveau N, Pacouret G, Palazzini M, Petris A, Pruszczyk P, Rugolotto M, Salvi A, Schellong S, Sebbane M, Sobkowicz B, Stefanovic BS, Thiele H, Torbicki A, Verschuren F, Konstantinides SV; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. doi: 10.1056/NEJMoa1302097.
- 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.
- 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.
- Liu L, Li C, Shi L, Ma D, Zhang Z, Bao H, Li C, Li L, Wang M, Ma Z, Zhang J. Efficacy and safety of low-dose thrombolysis in acute intermediate-high risk pulmonary thromboembolism complicated by PaO2/FiO2 < 300. Front Med (Lausanne). 2026 Jul 9;13:1849541. doi: 10.3389/fmed.2026.1849541. eCollection 2026.
- Yilmaz ES, Uzun O. Low-dose thrombolysis for submassive pulmonary embolism. J Investig Med. 2021 Dec;69(8):1439-1446. doi: 10.1136/jim-2021-001816. Epub 2021 Jun 7.
- Zhang LY, Gao BA, Jin Z, Xiang GM, Gong Z, Zhang TT, Lu HF, Wang YQ, Gong Y, Lu C, Huang WL. Clinical efficacy of low dose recombinant tissue-type plasminogen activator for the treatment of acute intermediate-risk pulmonary embolism. Saudi Med J. 2018 Nov;39(11):1090-1095. doi: 10.15537/smj.2018.11.22717.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Estimado)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Enfermedades Vasculares
- Enfermedades cardiovasculares
- Enfermedades de las vías respiratorias
- Enfermedades pulmonares
- Embolia y Trombosis
- Embolia
- Embolia pulmonar
- Aminoácidos, péptidos y proteínas
- Proteínas
- Factores biológicos
- Hidrolasas
- Enzimas
- Enzimas y coenzimas
- Proteínas de la sangre
- Endopeptidasas
- Hidrolasas peptídicas
- Serina endopeptidasas
- Serina proteasas
- Activadores de plasminógeno
- Factores de coagulación de sangre
- Activador del plasminógeno tisular
Otros números de identificación del estudio
- 2026ZD0556203-02
- 2026ZD0556203 (Otro número de subvención/financiamiento: Noncommunicable Chronic Diseases-National Science and Technology Major Project)
Plan de datos de participantes individuales (IPD)
¿Planea compartir datos de participantes individuales (IPD)?
Información sobre medicamentos y dispositivos, documentos del estudio
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