Pulmonary Embolism International THrOmbolysis Study-3

Inclusion Criteria: * 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 Exclusion Criteria: * Hemodynamic instability * Active bleeding * History of non-traumatic intracranial bleeding, any time * Acute ischemic stroke or transient ischemic attack (TIA) within the previous 6 months * Known central nervous system neoplasm/metastasis * Neurologic, ophthalmologic, abdominal, cardiac, thoracic, vascular or orthopedic surgery or trauma within 3 previous weeks * 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. * 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. * Any direct oral anticoagulant within 12 hours of inclusion * Uncontrolled hypertension defined by SBP \> 180 mm Hg at the time of inclusion * Known pericarditis or endocarditis * Known significant bleeding risk according to the investigator's judgement * Administration of thrombolytic agents within the previous 4 days * Vena cava filter insertion or pulmonary thrombectomy within the previous 4 days * Current participation in another interventional clinical study * Previous enrolment in this study * 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 previous immune heparin-induced thrombocytopenia * Known severe liver disease (grade ≥ 3) including liver failure, cirrhosis, portal hypertension (esophageal varices) and active hepatitis * Acute symptomatic pancreatitis * Gastrointestinal ulcers or esophageal varices, documented within the past 3 months * Known arterial aneurysm, arterial or venous malformations * Pregnancy or parturition within the previous 30 days or current breastfeeding. * 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 * Any other condition that the investigator feels would place the patient at increased risk upon start of the investigational treatment * Life expectancy of less than 6 months or inability to complete 6-month follow-up. * Patient under legal protection