Evaluation of Percutaneous Embolectomy, Ultrasound-Assisted Low-Dose Thrombolysis with Alteplase, and Heparin in Intermediate-High Risk Pulmonary Embolism

The primary objective of the STRATIFY II trial is to evaluate the **efficacy** of three distinct therapeutic strategies in reducing thrombus burden in patients with acute intermediate high-risk **pulmonary embolism**. The approaches under investigation include percutaneous embolectomy using the Flow Triever® system, ultrasound-assisted thrombolysis (USAT) with the EKOS® system and low-dose alteplase, and heparin with the option for full-dose thrombolysis. This study is clinically relevant as it aims to determine the most effective treatment modality for managing thrombus burden in this patient population, potentially improving clinical outcomes and reducing the risk of complications associated with pulmonary embolism.

The clinical trial focuses on patients diagnosed with **pulmonary embolism**, specifically those classified as having intermediate high-risk according to ESC criteria. The study population includes both male and female participants aged 18 years and older. Participants must have a thrombus visible in the main, lobar, or segmental pulmonary arteries on CT angiography and have experienced symptoms for 14 days or less. The trial does not include vulnerable populations. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria ensure that the study population is representative of individuals with acute intermediate high-risk pulmonary embolism, allowing for a comprehensive assessment of the trial's objectives.

The clinical trial is designed to evaluate the efficacy of three different therapeutic approaches for patients with **pulmonary embolism**. The study employs a randomized, controlled, and double-blind methodology to ensure the reliability and validity of the results. Participants will be randomly assigned to one of three treatment arms: percutaneous embolectomy, ultrasound-assisted low-dose thrombolysis using the EKOS® system with **alteplase**, or standard heparin therapy with the option for full-dose thrombolysis. The trial is categorized as a low-intervention study due to the use of authorized medicinal products and is expected to run until December 31, 2031, with recruitment starting on September 2, 2024.

Participants will undergo a series of study visits, beginning with an inclusion visit to confirm eligibility based on criteria such as age (≥18 years), presence of intermediate high-risk pulmonary embolism, and thrombus visibility on CT angiography. Follow-up visits will be scheduled to monitor the primary endpoint, which is the reduction in the modified Miller score, and secondary endpoints, including bleeding complications, duration of hospital admission, and quality of life assessments. The end-of-study visit will conclude the participant's involvement, which is anticipated to last approximately three months, depending on individual response and adherence to the protocol.

Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or non-compliance with study procedures. The trial aims to provide comprehensive data on the comparative effectiveness of the treatment modalities, with a focus on improving patient outcomes in the management of pulmonary embolism.

The clinical trial involves the use of **Actilyse**, a pharmaceutical product containing the active substance **alteplase**. Actilyse is formulated as a powder and solvent for solution for injection and infusion. The product is administered via infusion, with a maximum daily dose of 10 mg and a total dose not exceeding 10 mg. The treatment period is limited to one day. Alteplase, a protein-based substance, is utilized for its thrombolytic properties, aiding in the dissolution of blood clots. The product is manufactured by Boehringer Ingelheim International GmbH and is not a pediatric formulation.

In addition to the experimental medication, the trial incorporates the use of the **EKOS® system**, a device that employs ultrasound technology to enhance the efficacy of thrombolysis. This system unwinds and thins fibrin strands, increasing drug receptor site exposure and facilitating deeper drug penetration into the clot. The EKOS® system is used in conjunction with low-dose alteplase administration. The trial also includes the option of using **heparin**, a standard anticoagulant therapy, with the potential for full-dose thrombolysis if necessary. Participant compliance with the dosing schedule and administration is monitored throughout the trial to ensure adherence to the protocol.

The efficacy of the STRATIFY II clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on the reduction in the modified Miller score, which evaluates thrombus involvement and segmental flow. This score will be compared between groups treated with percutaneous embolectomy and ultrasound-assisted thrombolysis (USAT) versus those receiving heparin or low molecular weight heparin (LMWH). Specifically, the trial will compare the combined percutaneous treatment groups (embolectomy and USAT) to the heparin/LMWH group, as well as a direct comparison between percutaneous embolectomy and USAT.

Secondary endpoints include a range of clinical outcomes such as bleeding complications classified by the TIMI classification, duration of the index hospital admission, and dyspnea index measured using a visual analogue scale at 48-96 hours and after 3 months. Additional secondary endpoints involve the rate of further interventions for pulmonary embolism during admission, mortality rates across the three treatment arms, and the incidence of tricuspid regurgitation gradient greater than 40 mmHg at 3 months follow-up echocardiography. Functional outcomes such as the six-minute walking distance and quality of life, assessed by the PEmbQoL scale at 3 months follow-up, will also be evaluated. These efficacy parameters will be collected and analyzed at specified time points to determine the comparative effectiveness of the treatment strategies in patients with acute intermediate high-risk **pulmonary embolism**.