Pulmonary Embolism International THrOmbolysis Study-3

A Reduced Dose of Thrombolytic Treatment for Patients With Intermediate High-risk Acute Pulmonary Embolism: a Randomized Controled Trial

In this study, we will assess the efficacy and safety of a reduced dose of thrombolytic therapy given in addition to low-molecular-weight heparin in patients with intermediate-high-risk acute pulmonary embolism. Half of participants will receive thrombolytic treatment, while the other half will receive a placebo.

In patients with intermediate-risk pulmonary embolism, full-dose thrombolytic treatment was associated with a reduction in the combined risk of hemodynamic instability or death but was also associated with an increased risk of major and intracranial bleeding. Previous studies suggest that reduced dose of thrombolytic treatment may be as effective as the full dosage, but with a decreased risk of life-threatening bleeding. In this study, we will assess the efficacy and safety of a reduced dosage of thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism.

The study is a randomized, placebo-controlled, double blind, multicenter, multinational trial with long-term follow-up.

Patients fulfilling the inclusion criteria and without any of the exclusion criteria will be randomized within 6 hours after the investigator had confirmed the diagnosis.

Patients will receive:

• Alteplase (if randomized in the experimental group) or placebo (if randomized in the reference group) given within 30 minutes of randomization as a 15 min intravenous infusion at a dosage of 0.6 mg/kg with a total dose not exceeding 50 mg.
• Parenteral anticoagulation with low molecular weight heparin, unfractionnated heparin or fondaparinux

Primary objective is to assess the efficacy of reduced dose thrombolytic therapy in patients with acute intermediate-high-risk pulmonary embolism at day 30.

Secondary objectives are:

1. To assess the safety of reduced dose thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism at day 30
2. To assess the net clinical benefit of reduced dose thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism at day 30
3. To assess the effect of reduced dose thrombolytic therapy on overall mortality of patients with intermediate-high-risk acute pulmonary embolism at day 30
4. To assess the effect of reduced dose thrombolytic therapy on long-term mortality, functional impairment, residual right ventricular dysfunction and chronic thromboembolic pulmonary hypertension at 6 months and 2 years
5. To assess the effect of reduced-dose thrombolytic therapy on utilization of health care resources at day 30 and day 180

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