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

Phase 3Active Not RecruitingNCT04088292

Rigshospitalet, Denmark210 enrolled

Overview

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

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

210

Conditions

Pulmonary Embolism

Interventions

Alteplase 20 Mg Powder for Solution for Injection VialDRUG

Low dose alteplase delivered IV or bu Ultrasound Assisted Thrombolysis device

Ultrasound assisted ThrombolysisDEVICE

Ultrasound assisted thrombolysis (USAT)

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age ≥ 18 years 2. Informed consent for trial participation 3. Intermediate high-risk PE according to ESC criteria 4. Thrombus visible in main, lobar or segmental pulmonary arteries on CT angiography 5. 14 days of symptoms or less Exclusion Criteria: 1. Altered mental state (GCS \< 14) 2. No qualifying CT angiography performed (\> 24 hour since CT angiography) 3. Females of child bearing potential, unless negative HCG test is present 4. Thrombolysis for PE within 14 days of randomization 5. Thrombus passing through patent Foramen Ovale (risk of paradoxical embolism) 6. Ongoing oral anticoagulation therapy (heparins, aspirin, antiplatelet therapy and NOAC allowed) 7. Comorbidity making 6 months survival unlikely 8. Absolute contraindications for thrombolysis 1. Hemorrhagic stroke or stroke of unknown origin at any time 2. Ischemic stroke in the preceding 6 months 3. Central nervous system damage or neoplasms 4. Recent major trauma/surgery/head injury in the preceding 3 weeks 5. Gastrointestinal bleeding within the last month 6. Known bleeding risk

Locations (4)

Copenhagen University Hospital Gentofte

Gentofte Municipality, Capital Region, Denmark

Copenhagen University Hospital Bispebjerg Hospital

Bispebjerg, Denmark

Copenhagen University Hospital Rigshospitalet

Copenhagen, Denmark

Copenhagen University Hospital, Herlev Gentofte Hospital

Herlev, Denmark

Outcomes

Primary Outcomes

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)

Time frame: 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)

Time frame: at 48 to 96 hours post randomization

Secondary Outcomes

Incidence of bleeding complications

Bleeding complications (major and minor bleeding complication according the TIMI classification)

Time frame: Until hospital discharge, on average 1 week

Length of stay of index admission

Duration of index admission, including hospital based rehabilitation

Time frame: End of study, expected to be 5 years

Dyspnea index by visual analogue scale

Dyspnea index (Visual analog scale) after 48-96 h and after 3 months

Time frame: End of study, expected to be 5 years

Change in oxygen supplement (FiO2)

FiO2 (in %)

Time frame: 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

Time frame: End of study, expected to be 5 years

Data from ClinicalTrials.gov

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