Pulmonary Embolism International THrOmbolysis Study-3

Who can take part

• Age 18 years or older
• Objectively confirmed acute PE with first symptoms occurring 2 weeks or less before randomization. Objective confirmation is based on at least one of the following criteria: (a) at least one segmental ventilation-perfusion mismatch on lung scanning; (b) a spiral computed tomography pulmonary angiography or pulmonary angiography showing a filling defect or an abrupt obstruction of a segmental or more proximal pulmonary artery
• Acute PE confirmed within 24 hours prior to randomization
• Elevated risk of early death, or of hemodynamic collapse, or PE recurrence, indicated by at least one of the following criteria: (a) systolic blood pressure ≤ 110 mm Hg over at least 15 minutes upon enrolment, (b) temporary need for fluid resuscitation and/or treatment with low-dose catecholamines, provided that the patient could be stabilized within 2 hours of admission and maintains SBP of ≥ 90 mmHg and adequate organ perfusion without catecholamine infusion; (c) respiratory rate > 20/min or oxygen saturation on pulse oximetry SpO2 <90% o(or partial arterial oxygen pressure < 60 mm Hg) at rest while breathing room air, (d) documented history of chronic symptomatic heart failure
• Right ventricular dysfunction indicated by RV/LV diameter ratio >1.0 on echocardiography apical four-chamber or subcostal four-chamber view or on Computed Tomography Pulmonary Angiography (transverse plane)
• Serum troponin I or T concentration above the upper limit of local normal using a high-sensitivity assay
• Ability to randomize the patient within 6 hours after the investigator receives the results of the second of the two criteria for RV dysfunction (RV/LV diameter ratio >1.0) and myocardial injury (serum troponin I or T concentration above the upper limit of local normal), whichever comes latest
• Signed informed consent form

Who cannot take part

• Acute ischemic stroke or transient ischemic attack (TIA) within the previous 6 months
• Neurologic, ophthalmologic, abdominal, cardiac, thoracic, vascular or orthopedic surgery or trauma within 3 previous weeks
• Treatment with antiplatelet agents other than (a) acetylsalicylic acid (ASA) ≤ 100 mg once daily or (b) clopidogrel 75 mg once daily or (c) a single loading dose of ASA or clopidogrel. Dual antiplatelet therapy (ASA + clopidogrel) is not allowed
• Administration of thrombolytic agents within the previous 4 days
• Vena cava filter insertion or pulmonary thrombectomy within the previous 4 days
• Previous enrolment in this study
• Known previous immune heparin-induced thrombocytopenia
• Pregnancy or parturition within the previous 30 days or current breastfeeding
• Active bleeding
• History of non-traumatic intracranial bleeding, any time
• Uncontrolled hypertension defined by SBP > 180 mm Hg at the time of inclusion
• Known significant bleeding risk according to the investigator's judgement
• Known hypersensitivity to alteplase, gentamicin (a residue of the Actilyse® manufacturing process present in trace amounts), any of the excipients of Actilyse®, or low-molecular weight heparin (LMWH)
• Known severe liver disease (grade ≥ 3) including liver failure, cirrhosis, portal hypertension (esophageal varices) and active hepatitis
• Any other condition that the investigator feels would place the patient at increased risk upon start of the investigational treatment
• Platelet count < 100 G/L
• INR > 1.4. If INR not available: prothrombin time ratio < 60%. If both INR and prothrombin time ratio are measured, INR is relevant for the assessment of this criterion
• Hemodynamic instability
• Known central nervous system neoplasm/metastasis
• Any direct oral anticoagulant within 12 hours of inclusion
• Known pericarditis or endocarditis
• Current participation in another interventional clinical study
• Acute symptomatic pancreatitis
• Gastrointestinal ulcers or esophageal varices, documented within the past 3 months
• Known arterial aneurysm, arterial or venous malformations
• Women of childbearing potential who do not have a negative pregnancy test at the inclusion visit and do not use one of the following methods of birth control: hormonal contraception or intrauterine device or bilateral tubal occlusion
• Life expectancy of less than 6 months or inability to complete 6-month follow-up
• Patient under legal protection