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

Overview

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

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Single (Outcomes Assessor)
  • Study Primary Completion Date: June 5, 2024

Detailed Description

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

Interventions

  • Drug: Alteplase 20 Mg Powder for Solution for Injection Vial
    • Low dose alteplase delivered IV or bu Ultrasound Assisted Thrombolysis device
  • Device: Ultrasound assisted Thrombolysis
    • Ultrasound assisted thrombolysis (USAT)

Arms, Groups and Cohorts

  • Active Comparator: USAT + low dose thrombolysis
    • 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
  • Active Comparator: Low dose thrombolysis
    • Intravenous low dose thrombolysis (20 mg of rtPA, Alteplase) over 6 hours plus UFH or low molecular weight heparin (LMWH).
  • No Intervention: Heparin alone
    • UFH or low molecular weight heparin (LMWH) only (with option for conventional thrombolysis according to local protocols for hemodynamic deterioration)

Clinical Trial Outcome Measures

Primary Measures

  • Reduction in Miller score comparing low dose thrombolysis and heparin alone groups
    • Time Frame: at 48 to 96 hours post randomization
    • 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)
  • Reduction i Miller score comparing low dose thrombolysis by iv and by USATgroups
    • Time Frame: at 48 to 96 hours post randomization
    • 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)

Secondary Measures

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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Rigshospitalet, Denmark
  • Collaborator
    • Herlev and Gentofte Hospital
  • Provider of Information About this Clinical Study
    • Principal Investigator: Jesper Kjaergaard, Sponsor, Primary investigator – Rigshospitalet, Denmark
  • Overall Contact(s)
    • Jesper Kjærgaard, MD PhD DMSc, +45 35450969, jesper.kjaergaard.05@regionh.dk

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