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    Clinical Trial Results:
    Low dose catheter directed thrombolysis for acute intermediary-high risk pulmonary embolism.

    Summary
    EudraCT number
    		 2018-003564-31
    Trial protocol
    		 DK  
    Global end of trial date
    21 Jan 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jan 2026
    First version publication date
    22 Jan 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    190580-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03854266
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul Jensens Boulevard 99, Aarhus N, Denmark, 8200
    Public contact
    Asger Andersen, Aarhus University Hospital, 45 26363226, asger.andersen@clin.au.dk
    Scientific contact
    Asger Andersen, Aarhus University Hospital, 45 26363226, asger.andersen@clin.au.dk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Jan 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jan 2025
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jan 2025
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate if low dose catheter directed fibrinolysis for 2 h is superior to unfractioned heparin with regards to unloading the right ventricle in acute intermediate-high risk pulmonary embolism.
    Protection of trial subjects
    The study adhered to Danish laws of ethics and management of personal data. The study was approved by “Datatilsynet”, the Regional Ethics Committee and Lægemiddelstyrelsen. The study adhered to the standards of good clinical practice and was monitored by the local GCP unit. The study has payed the outmost respect to the included patients mental and physical health and their personal integrity. The patients included in the trial was exposed to an extra CTA which exposes the patient to 4-8 msievert which approximates the background radiation a person receives over 3 years and increases the risk of a fatal cancer from 25% to 25.045%. Patients randomized to CDT received an additional 1-2 msievert from the fluoroscopy. The patients included in this study had an estimated 30 day mortality of 15% and solid preliminary data suggest the treatment to be effective and safe. Therefore it is the investigators opinion that the benefits of doing this study outweighed the risks. The treatment is considered safe and previous studies suggest that this approach may be better than conventional therapy. All patients will be monitored closely during the study period and in the catheterization laboratorium when treated with low dose heparin. The invasive procedure will be performed by a trained invasive cardiologist whose expertise is to catheterize the pulmonary circulation. Using the low dose short period regime suggested in this protocol there have not been reported any bleedings in clinical studies.
    Background therapy
    		 Standard unfractionated heparin infusion.
    Evidence for comparator
    		 The treatment of low and intermediate-low risk pulmonary embolism patients is anticoagulation and for high-risk patients treatment it is reperfusion. These treatment strategies are well documented, but in patients with intermediate-high risk the choice of treatment is more tricky. Anticoagulation does not introduce a quick relief of the struggling right ventricle and despite being effective at reducing thrombus burden, the risk of major bleedings outweighs the benefit of systemic thrombolysis. The optimal treatment should quickly reduce thrombus mass without increasing bleeding risk. Based on this principle, local catheter based trombolysis (CDT) could be ideal. In combination with low frequency ultrasound, CDT unloads the right ventricle more efficiently than anticoagulation and without increasing bleeding risk. And it has been reported to be as effective to use a low dose of the fibrinolytic agent for a shorter period of time making the approach more applicable in the clinical setting. The ultrasound assisted CDT is however more complicated to use and more expensive than conventional CDT and it is highly speculative if ultrasound have any additive effect to CDT alone . But, there are no data from randomized trials that have investigated the effect of CDT in PE. This wasthe first randomized trial to investigate if low dose CDT is superior to anticoagulation in PE.
    Actual start date of recruitment
    01 Apr 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    26
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between August 2020 and October 2024, 60 patients with acute intermediate-high risk PE were randomized to receive UFH plus CDT (n = 30) or UFH alone (n = 30).

    Pre-assignment
    Screening details
    		 Patients presenting with acute PE at one of the hospitals in the two Danish regions were eligible if they were older than 17 years and younger than 81 years, had symptom onset within 14 days before diagnosis, and had acute intermediate-high risk PE according to the European Society of Cardiology (ESC) guidelines.

    Period 1
    Period 1 title
    Overall study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Data analyst [1]
    Blinding implementation details
    Analyst of CT data was blinded to the study arm

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Unfractionated Heparin alone
    Arm description
    		 Standard treatment is unfractionated heparin infusion alone. Treatment is initiated at the time of study inclusion. Initial dose is 80 IE/kg bolus followed by 18 IE/kg as continuous infusion with dose adjustment every 6 h and once daily when APTT is 1.5-2.3 times control value. Dose adjustment is guided by APTT according to ESC guidelines
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Catheter Directed Thormbolysis + Unfractionated Heparin
    Arm description
    		 Patients randomized to CDT were transferred to the cardiac catheterization laboratory and treated within 48 hours of PE diagnosis. The procedure was performed by experienced interventional cardiologists under continuous hemodynamic and electrocardiographic monitoring. Two Uni*Fuse side-hole infusion catheter (AngioDynamics, USA) (one for each lung) were placed for all patients. Recombinant tissue plasminogen activator (r-tPA) was infused at a dose of 4 mg per catheter over 2 hours (2 mg/h, diluted in saline at an infusion rate of 35 mL/h). Patients also recieved UFH similar to controls.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Actilyse
    Investigational medicinal product code
    PR1
    Other name
    Alteplase
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    A continuous infusion of Actilyse 2 mg/h mixed in saline for an infusion rate of 35 ml/h in two catheters administered to the pulmonary circulation for a total time of 2 h. Total dosage of 8 mg.

    Investigational medicinal product name
    Actilyse
    Investigational medicinal product code
    PR1
    Other name
    Alteplase
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravascular use
    Dosage and administration details
    A continuous infusion of Actilyse 2 mg/h mixed in saline for an infusion rate of 35 ml/h in two catheters administered to the pulmonary circulation for a total time of 2 h. Total dosage of 8 mg.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The person analyzing the CT scans at baseline and 24 hour follow up was blinded to the treatment arm. The investigators and patients were not blinded.
    Number of subjects in period 1
    		Unfractionated Heparin alone Catheter Directed Thormbolysis + Unfractionated Heparin
    Started
    30
    30
    Completed
    29
    29
    Not completed
    1
    1
         Adverse event, serious fatal
    1
    -
         Screening failure. Right atrial mass. Excluded.
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Unfractionated Heparin alone
    Reporting group description
    		 Standard treatment is unfractionated heparin infusion alone. Treatment is initiated at the time of study inclusion. Initial dose is 80 IE/kg bolus followed by 18 IE/kg as continuous infusion with dose adjustment every 6 h and once daily when APTT is 1.5-2.3 times control value. Dose adjustment is guided by APTT according to ESC guidelines

    Reporting group title
    Catheter Directed Thormbolysis + Unfractionated Heparin
    Reporting group description
    		 Patients randomized to CDT were transferred to the cardiac catheterization laboratory and treated within 48 hours of PE diagnosis. The procedure was performed by experienced interventional cardiologists under continuous hemodynamic and electrocardiographic monitoring. Two Uni*Fuse side-hole infusion catheter (AngioDynamics, USA) (one for each lung) were placed for all patients. Recombinant tissue plasminogen activator (r-tPA) was infused at a dose of 4 mg per catheter over 2 hours (2 mg/h, diluted in saline at an infusion rate of 35 mL/h). Patients also recieved UFH similar to controls.

    Reporting group values
    		 Unfractionated Heparin alone Catheter Directed Thormbolysis + Unfractionated Heparin Total
    Number of subjects
    		 30 30 60
    Age categorical
    Age categorial
    Units: Subjects
        Adults (18-64 years)
    		 17 9 26
        From 65-84 years
    		 13 21 34
    Age continuous
    Age Continuous
    Units: years
        median (standard deviation)
    		 64 ( 16 ) 61 ( 15 ) -
    Gender categorical
    Units: Subjects
        Female
    		 11 12 23
        Male
    		 19 18 37

    End points

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    End points reporting groups
    Reporting group title
    Unfractionated Heparin alone
    Reporting group description
    		 Standard treatment is unfractionated heparin infusion alone. Treatment is initiated at the time of study inclusion. Initial dose is 80 IE/kg bolus followed by 18 IE/kg as continuous infusion with dose adjustment every 6 h and once daily when APTT is 1.5-2.3 times control value. Dose adjustment is guided by APTT according to ESC guidelines

    Reporting group title
    Catheter Directed Thormbolysis + Unfractionated Heparin
    Reporting group description
    		 Patients randomized to CDT were transferred to the cardiac catheterization laboratory and treated within 48 hours of PE diagnosis. The procedure was performed by experienced interventional cardiologists under continuous hemodynamic and electrocardiographic monitoring. Two Uni*Fuse side-hole infusion catheter (AngioDynamics, USA) (one for each lung) were placed for all patients. Recombinant tissue plasminogen activator (r-tPA) was infused at a dose of 4 mg per catheter over 2 hours (2 mg/h, diluted in saline at an infusion rate of 35 mL/h). Patients also recieved UFH similar to controls.

    Primary: Right ventricular to left ventricular diameter ratio

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    End point title
    		 Right ventricular to left ventricular diameter ratio
    End point description
    End point type
    Primary
    End point timeframe
    Change from baseline to 24 hours follow up compared between the two arms.
    End point values
    		 Unfractionated Heparin alone Catheter Directed Thormbolysis + Unfractionated Heparin
    Number of subjects analysed
    29
    29
    Units: ratio
        arithmetic mean (standard deviation)
    -0.17 ( 0.33 )
    0.02 ( 0.25 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    Catheter Directed Thormbolysis + Unfractionated Heparin v Unfractionated Heparin alone
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: CT obstruction score

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    End point title
    		 CT obstruction score
    End point description
    End point type
    Secondary
    End point timeframe
    Change in obstruction score from baseline to 24 hours follow up.
    End point values
    		 Unfractionated Heparin alone Catheter Directed Thormbolysis + Unfractionated Heparin
    Number of subjects analysed
    29
    29
    Units: score
        arithmetic mean (standard error)
    -2.76 ( 0.07 )
    -0.58 ( 0.65 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    Catheter Directed Thormbolysis + Unfractionated Heparin v Unfractionated Heparin alone
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.26
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Mortality

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    End point title
    		 Mortality
    End point description
    End point type
    Secondary
    End point timeframe
    30 day mortality
    End point values
    		 Unfractionated Heparin alone Catheter Directed Thormbolysis + Unfractionated Heparin
    Number of subjects analysed
    30
    29
    Units: 1
    1
    0
    No statistical analyses for this end point

    Secondary: Major bleedings

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    End point title
    		 Major bleedings
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours
    End point values
    		 Unfractionated Heparin alone Catheter Directed Thormbolysis + Unfractionated Heparin
    Number of subjects analysed
    30
    30
    Units: 1
    0
    0
    No statistical analyses for this end point

    Secondary: Minor bleeding

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    End point title
    		 Minor bleeding
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours
    End point values
    		 Unfractionated Heparin alone Catheter Directed Thormbolysis + Unfractionated Heparin
    Number of subjects analysed
    30
    30
    Units: 1
    3
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    3 months
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    0
    Reporting groups
    Reporting group title
    UFH alone
    Reporting group description
    		 -

    Reporting group title
    UFH + CDT
    Reporting group description
    		 -

    Serious adverse events
    		 UFH alone UFH + CDT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Cardiac disorders
    Death
    Additional description: Cardiogenic shock due to pulmonary embolism leading to cardiac arrest. Attempts to resuscitate not succesfull.
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiogenic shock
    Additional description: During CDT the patient had hemodynamic decompensation. Resolved by Actilyse bolus 8mg.
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 UFH alone UFH + CDT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 30 (3.33%)
    Cardiac disorders
    Chest discomfort
    Additional description: Chest discomfort following CDT. All exams normal. Resolved with no interventions.
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
    Additional description: Rash following treatment with Eliquis. Changed to Xarelto. Resolved.
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Mar 2020
    Due to the COVID pandemic, the study was temporarily suspended for inclusion fra March 17 2020 to August 20 2020.
    20 Aug 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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