Clinical trial NCT04088292: Low Dose Thrombolysis, Ultrasound Assisted Thrombolysis or Heparin for Intermediate High Risk Pulmonary Embolism
Official title: Low Dose Thrombolysis, Ultrasound Assisted Thrombolysis or Heparin for Intermediate High Risk Pulmonary Embolism
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Pulmonary Embolism
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Herlev and Gentofte Hospital
name: University Hospital Bispebjerg and Frederiksberg
name: Hillerod Hospital, Denmark
name: Copenhagen University Hospital, Hvidovre
First posted: 2019-09-12
Enrollment: 210
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized clinical trial with 1:1:1 allocation to treatment strata
Primary purpose: TREATMENT

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

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

Eligibility criteria: 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

Primary outcomes:
measure: Reduction in Miller score comparing low dose thrombolysis and heparin alone groups
timeFrame: at 48 to 96 hours post randomization
measure: Reduction i Miller score comparing low dose thrombolysis by iv and by USATgroups
timeFrame: at 48 to 96 hours post randomization
Secondary outcomes:
measure: Incidence of bleeding complications
timeFrame: Until hospital discharge, on average 1 week
measure: Length of stay of index admission
timeFrame: End of study, expected to be 5 years
measure: Dyspnea index by visual analogue scale
timeFrame: End of study, expected to be 5 years
measure: Change in oxygen supplement (FiO2)
timeFrame: at 48 to 96 hours post randomization
measure: Mortality rate
timeFrame: End of study, expected to be 5 years
measure: Incidence of Pulmonary Hypertension
timeFrame: 3 months follow-up
measure: 6 minute walk distance af follow-up
timeFrame: 3 months follow-up
measure: Health related Quality of Life (PEmb-QoL)
timeFrame: 3 months follow-up
measure: Health related Quality of Life (EQ-5D-5L)
timeFrame: 3 months follow-up
Other outcomes:
Locations:
city: Gentofte
country: Denmark
facility: Copenhagen University Hospital Gentofte
state: Capital Region
city: Bispebjerg
country: Denmark
facility: Copenhagen University Hospital Bispebjerg Hospital
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital Rigshospitalet
city: Herlev
country: Denmark
facility: Copenhagen University Hospital, Herlev Gentofte Hospital
Study officials:
References: