Low Dose Thrombolysis, Ultrasound Assisted Thrombolysis or Heparin for Intermediate High Risk Pulmonary Embolism

Study Overview
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Brief Summary
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Open label clinical randomized trial comparing three strategies for managing acute intermediate-high risk pulmonary embolism

Detailed Description
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Trial acronym: STRATIFY Background: Intermediate-high risk pulmonary embolism (PE) is associated with a significant risk of death or hemodynamic deterioration. The optimal treatment strategy should balance efficacy in reducing thrombus burden and hemodynamic compromise with risk of complications, in particular bleeding. Previous studies have investigated conventional high-dose, short term thrombolysis by (rtPA), finding a reduction in risk hemodynamic deterioration, but no reduction in mortality and a substantial increase in significant bleeding complications. Catheter based techniques and low dose thrombolysis may offer lower risk of complication with reasonable efficacy. Such studies have not been performed in RCTs with a reasonable sample size, and no study have compared low dose intravenous thrombolysis and catheter based techniques. The current trial addresses this paucity of data by randomizing patients to one of three treatment modalities: Intervention: 1:1:1 randomization, stratified for site to UltraSound Assisted Thrombolysis (USAT) with low dose thrombolysis (20 mg of rtPA, Alteplase) over 6 hours plus unfractionated heparin (UFH) or low molecular weight heparin (LMWH) within 12 hours of randomization Intravenous low dose thrombolysis (20 mg of rtPA, Alteplase) over 6 hours plus UFH or low molecular weight heparin (LMWH). UFH or low molecular weight heparin (LMWH) only (with option for conventional thrombolysis according to local protocols for hemodynamic deterioration) Design: Regional collaborative, randomized trial with 1:1:1 allocation of 210 patients with acute intermediate-high risk PE with no absolute contraindications to thrombolysis

Official Title
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Low Dose Thrombolysis, Ultrasound Assisted Thrombolysis or Heparin for Intermediate High Risk Pulmonary Embolism

Conditions
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Pulmonary Embolism

Intervention / Treatment
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* Drug: Alteplase 20 Mg Powder for Solution for Injection Vial
* Device: Ultrasound assisted Thrombolysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Informed consent for trial participation Intermediate high-risk PE according to ESC criteria Thrombus visible in main, lobar or segmental pulmonary arteries on CT angiography 14 days of symptoms or less Exclusion Criteria: Altered mental state (GCS < 14) No qualifying CT angiography performed (> 24 hour since CT angiography) Females of child bearing potential, unless negative HCG test is present Thrombolysis for PE within 14 days of randomization Thrombus passing through patent Foramen Ovale (risk of paradoxical embolism) Ongoing oral anticoagulation therapy (heparins, aspirin, antiplatelet therapy and NOAC allowed) Comorbidity making 6 months survival unlikely Absolute contraindications for thrombolysis Hemorrhagic stroke or stroke of unknown origin at any time Ischemic stroke in the preceding 6 months Central nervous system damage or neoplasms Recent major trauma/surgery/head injury in the preceding 3 weeks Gastrointestinal bleeding within the last month Known bleeding risk

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized clinical trial with 1:1:1 allocation to treatment strata
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: USAT + low dose thrombolysis<br>UltraSound Assisted Thrombolysis (USAT) with low dose thrombolysis (20 mg of rtPA, Alteplase) over 6 hours plus unfractionated heparin (UFH) or low molecular weight heparin (LMWH) within 12 hours of randomization | Drug: Alteplase 20 Mg Powder for Solution for Injection Vial<br>* Low dose alteplase delivered IV or bu Ultrasound Assisted Thrombolysis device<br>Device: Ultrasound assisted Thrombolysis<br>* Ultrasound assisted thrombolysis (USAT)<br>|
| Active Comparator: Low dose thrombolysis<br>Intravenous low dose thrombolysis (20 mg of rtPA, Alteplase) over 6 hours plus UFH or low molecular weight heparin (LMWH). | Drug: Alteplase 20 Mg Powder for Solution for Injection Vial<br>* Low dose alteplase delivered IV or bu Ultrasound Assisted Thrombolysis device<br>|
| No Intervention: Heparin alone<br>UFH or low molecular weight heparin (LMWH) only (with option for conventional thrombolysis according to local protocols for hemodynamic deterioration) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in Miller score comparing low dose thrombolysis and heparin alone groups | Reduction in Miller Score and on follow-up (48-96 h) CT pulmonary Angiography comparing low-dose rtPA (±USAT) to UFH/LMWH group (p<0.01, N=210) | at 48 to 96 hours post randomization | 
| Reduction i Miller score comparing low dose thrombolysis by iv and by USATgroups | reduction in Miller Score and on follow-up (48-96 h) CT pulmonary Angiography comparing low-dose rtPA by USAT to iv, p<0.04, N=140) | at 48 to 96 hours post randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of bleeding complications | Bleeding complications (major and minor bleeding complication according the TIMI classification) | Until hospital discharge, on average 1 week | 
| Length of stay of index admission | Duration of index admission, including hospital based rehabilitation | End of study, expected to be 2 years | 
| Dyspnea index by visual analogue scale | Dyspnea index (Visual analog scale) after 48-96 h and after 3 months | End of study, expected to be 2 years | 
| Change in oxygen supplement (FiO2) | FiO2 (in %) | at 48 to 96 hours post randomization | 
| Mortality rate | Mortality in the three groups (log-rank), and hazard ratio in multivariable analysis using the UFH/LMWH as reference | End of study, expected to be 2 years | 
| Reduction in D-dimer values | Reduction in D-dimer from baseline to 48-96h post randomization | at 48 to 96 hours post randomization | 
| Incidence of Pulmonary Hypertension | Incidence of TR gradient > 40 mmHg at 3 months follow-up echocardiography | 3 months follow-up | 
| Reduction in troponin levels | Relative reduction in TnI/T from baseline to 48-96 h post intervention | at 48 to 96 hours post randomization | 
| Reduction in NT-pro-BNP levels | Reduction in NT-pro-BNP at 48-96 hours and 3 months | 3 months follow-up |