Clinical trial NCT01482273: Ultrasound-enhanced Thrombolysis Versus Standard Catheter Directed Thrombolysis for Ilio-femoral Deep Vein Thrombosis
Official title: The BERN Ultrasound-enhanced Thrombolysis for Ilio-Femoral Deep Vein Thrombosis versUs Standard Catheter Directed thromboLysis Trial (BERNUTIFUL-Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Venous Thrombosis
Postthrombotic Syndrome
Keywords: catheter-directed thrombolysis
ilio-femoral deep vein thrombosis
Postthrombotic syndrome
Phlebographic scores
Phlebography
Catheters
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
First posted: 2011-11-30
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Patients with deep vein thrombosis (DVT) of the ilio-femoral veins have increased risk for developing post-thrombotic syndrome (PTS) and recurrent venous thromboembolism compared to more distal DVT. There's evidence that the early removal of the obstructing thrombus by catheter directed thrombolysis (CDT) reduces the risk of developing a PTS, and a higher degree of thrombolysis is associated with lower incidence of PTS, better quality of life and lower risk of recurrent venous thromboembolism. A further development is ultrasound-enhanced thrombolysis combining CDT with a sophisticated catheter system that employs high-frequency, low-dose ultrasound. In vitro experiments showed that adding ultrasound to thrombolytic drugs accelerates thrombolysis while Ultrasound exposure alone results in no thrombolysis, however the superiority of ultrasound-enhanced thrombolysis over standard CDT has never been formally assessed in vivo. The hypothesis for this study is that ultrasound-enhanced thrombolysis reaches a higher degree of thrombolysis than standard CDT in patients with symptomatic ilio-femoral DVT.

Detailed description: Background

Deep vein thrombosis (DVT) is a public health problem with an annual incidence of 1 per 1000. Besides the acute risk of potentially fatal pulmonary embolism or phlegmasia cerulea dolens, these patients are at increased risk of recurrent venous thromboembolism, and in the long term 20-40% of them develop a post-thrombotic syndrome (PTS). PTS mainly develops in patients with DVT affecting the ilio-femoral veins, adversely affects the quality of life and causes important health care costs to the society. There's evidence that the early removal of the obstructing thrombus reduces the risk of developing a PTS, and a higher degree of thrombolysis is associated with lower incidence of PTS, better quality of life and lower risk of recurrent venous thromboembolism. Therefore, in addition to standard anticoagulation therapy, the latest international guidelines recommend catheter-directed thrombolysis (CDT) as first-line treatment for patients with ilio-femoral DVT and low bleeding risk. CDT refers to the infusion of thrombolytic drugs directly into the thrombus via a multisidehole catheter which is embedded in the thrombus using imaging guidance. A further development is ultrasound-enhanced thrombolysis combining CDT with a sophisticated catheter system that employs high-frequency, low-dose ultrasound. In vitro experiments showed that adding Ultrasound to thrombolytic drugs accelerates thrombolysis while Ultrasound exposure alone results in no thrombolysis. Although ultrasound-enhanced thrombolysis is now widely used to treat ilio-femoral DVT or high-risk pulmonary embolism, it is currently not known if this technique is superior to standard CDT.

Objective

To determine if the addition of intravascular high-frequency/low-dose ultrasound to standard CDT increases the percentage of clot lysis compared to CDT alone after treatment duration of 15 hours in patients with symptomatic ilio-femoral DVT and low bleeding risk

Methods

Study design: open-label (with blinding of data-analyzing physicians), randomized, controlled, single center clinical trial with a follow-up period of 12 months.

Subjects: total of 20 patients (10 in each study group) of 18-75 years of age with acute, symptomatic, objectively confirmed ilio-femoral DVT and a low bleeding risk.

Intervention: CDT using the EkoSonic Endovascular System with (CDT+US group) or without (CDT-US group) intravascular high-frequency, low-power ultrasound for 15 hours.

Eligibility criteria: Inclusion Criteria:

* Symptomatic proximal DVT involving the iliac and/or common femoral vein, confirmed by Duplex Sonography, Angio-CT, Angio-MRI or Phlebography
* Written informed consent

Exclusion Criteria

* Age less than 18 years or greater than 75 years
* Symptom duration \> 14 days for the DVT episode in the index leg (i.e., non-acute DVT).
* In the index leg: established post-thrombotic syndrome (PTS) or previous symptomatic DVT within the last 2 years.
* Limb-threatening circulatory compromise.
* PE with hemodynamic compromise (i.e., hypotension).
* Inability to tolerate catheter procedure due to severe dyspnea or acute systemic illness.
* Allergy, hypersensitivity, or thrombocytopenia from heparin, r-tPA, or iodinated contrast, except for mild-moderate contrast allergies for which steroid pre-medication can be used.
* Known significant bleeding risk, or known coagulation disorder (including vitamin K antagonists with INR \> 2.0 and platelet count \< 100 000/mm3)
* Severe renal impairment (estimated GFR \< 30 ml/min).
* Active bleeding, recent (\< 3 mo) GI bleeding, severe liver dysfunction, bleeding diathesis.
* Recent (\< 3 mo) internal eye surgery or hemorrhagic retinopathy; recent (\< 10 days) major surgery, cataract surgery, trauma, CPR, obstetrical delivery, or other invasive procedure.
* History of stroke or intracranial/intraspinal bleed, tumor, vascular malformation, aneurysm.
* Severe hypertension on repeated readings (systolic \> 180 mmHg or diastolic \> 105 mmHg).
* Pregnant, lactation or parturition within the previous 30 days (positive pregnancy test, women of childbearing age must be tested or use a medically accepted method of birth control).
* Recently (\< 1 mo) had thrombolysis.
* Life expectancy \< 6 months or chronic non-ambulatory status.
* Participating in any other investigational drug or device study or previous enrollment in this study
* Inability to provide informed consent or to comply with study assessments (e.g. due to cognitive impairment or geographic distance).
* Any other condition that the investigator feels would place the patient at increased risk if the investigational therapy is initiated

Primary outcomes:
measure: Improvement of Total EKOS Thrombus Score, a specifically developed venographic scoring system
timeFrame: After 15 hours of CDT
Secondary outcomes:
measure: Improvement of the "Venous Registry Index" venographic scoring system
timeFrame: After 15 hours of CDT
measure: Early symptom relief assessed by standardized limb circumference measurements and validated visual analogue pain scale
timeFrame: During and after 15 hours of CDT
measure: Treatment related complications
timeFrame: 30 days
measure: Development of PTS assessed by Villalta scale and Quality of life (CIVIQ)
timeFrame: After 12 months
measure: Venous valve patency/insufficiency assessed by duplex sonography
timeFrame: After 12 months
Other outcomes:
Locations:
city: Bern
country: Switzerland
facility: Division of Clinical and Interventional Angiology, Swiss Cardiovascular Center, University Hospital and University of Bern
Study officials:
affiliation: Division of Clinical and Interventional Angiology, Swiss Cardiovascular Center, University Hospital and University of Bern
name: Nils Kucher, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Division of Clinical and Interventional Angiology, Swiss Cardiovascular Center, University Hospital and University of Bern
name: Torsten Willenberg, MD
role: STUDY_DIRECTOR
affiliation: Division of Clinical and Interventional Angiology, Swiss Cardiovascular Center, University Hospital and University of Bern
name: Iris Baumgartner, MD
role: STUDY_DIRECTOR
affiliation: Division of Clinical and Interventional Angiology, Swiss Cardiovascular Center, University Hospital and University of Bern
name: Rolf P Engelberger, MD
role: STUDY_DIRECTOR
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