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 beforerandomization. Objective confirmation is based on at least one of the followingcriteria: (a) at least one segmental ventilation-perfusion mismatch on lungscanning; (b) a spiral computed tomography pulmonary angiography or pulmonaryangiography showing a filling defect or an abrupt obstruction of a segmental or moreproximal 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 fluidresuscitation and/or treatment with low-dose catecholamines, provided that thepatient could be stabilized within 2 hours of admission and maintains SBP of ≥ 90mmHg and adequate organ perfusion without catecholamine infusion; (c) respiratoryrate > 20/min or oxygen saturation on pulse oximetry SpO2 <90% o(or partial arterialoxygen pressure < 60 mm Hg) at rest while breathing room air, (d) documented historyof chronic symptomatic heart failure

• Right ventricular dysfunction indicated by RV/LV diameter ratio >1.0 onechocardiography apical four-chamber or subcostal four-chamber view or on ComputedTomography Pulmonary Angiography (transverse plane)

• Serum troponin I or T concentration above the upper limit of local normal using ahigh-sensitivity assay

• Ability to randomize the patient within 6 hours after the investigator receives theresults 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 upperlimit 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 6months

• Known central nervous system neoplasm/metastasis

• Neurologic, ophthalmologic, abdominal, cardiac, thoracic, vascular or orthopedicsurgery 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 andprothrombin time ratio are measured, INR is relevant for the assessment of thiscriterion.

• Treatment with antiplatelet agents other than (a) acetylsalicylic acid (ASA) ≤ 100mg once daily or (b) clopidogrel 75 mg once daily or (c) a single loading dose ofASA 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, portalhypertension (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 theinclusion 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 increasedrisk 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