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

Phase 3

Active, not recruiting

• Conditions: Pulmonary Embolism
• Interventions: Drug: Alteplase 20 Mg Powder for Solution for Injection Vial; Device: Ultrasound assisted Thrombolysis

• Registration Number: NCT04088292
• Lead Sponsor: Rigshospitalet, Denmark

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

Study Timeline

• Study Start: 2019-06-06
• Study First Submitted: 2019-09-09
• Study First Submitted QC: 2019-09-11
• Study First Posted: 2019-09-12
• Primary Completion: 2024-06-05
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-14
• Last Update Posted: 2024-11-15
• Study Completion: 2024-11-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 210

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
USAT + low dose thrombolysis	Alteplase 20 Mg Powder for Solution for Injection Vial	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
USAT + low dose thrombolysis	Ultrasound assisted 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
Low dose thrombolysis	Alteplase 20 Mg Powder for Solution for Injection Vial	Intravenous low dose thrombolysis (20 mg of rtPA, Alteplase) over 6 hours plus UFH or low molecular weight heparin (LMWH).

Primary Outcome Measures

Name	Time	Method
Reduction in Miller score comparing low dose thrombolysis and heparin alone groups	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	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 Outcome Measures

Name	Time	Method
Incidence of bleeding complications	Until hospital discharge, on average 1 week	Bleeding complications (major and minor bleeding complication according the TIMI classification)
6 minute walk distance af follow-up	3 months follow-up	6 minute walk distance at 3 months follow-up visit
Health related Quality of Life (PEmb-QoL)	3 months follow-up	Health related Quality of Life at 3 months follow-up using PEmb-QoL (Pulmonary Embolism Quality of Life) ranging from 0 to 100, higher score indicating worse Quality of Life
Health related Quality of Life (EQ-5D-5L)	3 months follow-up	5Q-5D-5L (EuroQoL 5 dimension, 5 level questionnaire, ranging from -0.59 to 1, where 1 is the best possible health state)
Dyspnea index by visual analogue scale	End of study, expected to be 5 years	Dyspnea index (Visual analog scale) after 48-96 h and after 3 months
Length of stay of index admission	End of study, expected to be 5 years	Duration of index admission, including hospital based rehabilitation
Change in oxygen supplement (FiO2)	at 48 to 96 hours post randomization	FiO2 (in %)
Mortality rate	End of study, expected to be 5 years	Mortality in the three groups (log-rank), and hazard ratio in multivariable analysis using the UFH/LMWH as reference
Incidence of Pulmonary Hypertension	3 months follow-up	Incidence of TR gradient \> 40 mmHg at 3 months follow-up echocardiography

Trial Locations

Locations (4)

Copenhagen University Hospital Gentofte; 🇩🇰 Gentofte, Capital Region, Denmark

Copenhagen University Hospital Rigshospitalet; 🇩🇰 Copenhagen, Denmark

Copenhagen University Hospital Bispebjerg Hospital; 🇩🇰 Bispebjerg, Denmark

Copenhagen University Hospital, Herlev Gentofte Hospital; 🇩🇰 Herlev, Denmark