Diagnosis Exclusion of Recurrent Deep Vein Thrombosis of the Lower Limbs

Study Overview
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Brief Summary
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The purpose is to assess the safety of a management strategy based on colour doppler ultrasound (CDUS) and D-Dimer test results for the diagnosis exclusion of recurrent deep vein thrombosis (DVT) of the lower limbs. DVT recurrence requires using anticoagulant treatment to prevent thrombosis progression. Given an increased bleeding risk with prolonged treatment, an accurate diagnosis for recurrence is needed. However, the diagnosis of a new thrombosis in a previously involved leg is difficult. Imaging modalities and criteria that are currently used for the diagnosis may be equivocal and unable to discriminate between an old clot and a new one recently developed at the same site. An increase in vein diameter after vein compression by the ultrasound probe was suggested as a diagnostic criterion for a new DVT. This method has many limitations in clinical practice, mainly a lack of availability of a previous measurement and a poor inter-observer agreement. Colour Doppler ultrasound enables to study both the thrombus and the blood flow characteristics that might help to overcome these limitations. CDUS is a well-known method for the diagnosis of vascular diseases and is used in every day clinical practice for the diagnosis of a first DVT and DVT recurrence but CDUS has never been assessed for DVT recurrence in a study. The diagnosis of DVT recurrence may be easily established using the same criteria as for a first DVT episode. Our hypothesis is that CDUS associated with D-Dimer can safely rule out the diagnosis of DVT recurrence while maintaining a good specificity. The strategy consists in performing first a CDUS that helps to classify patients as having (positive CDUS) or not having (negative CDUS) a new thrombosis. In the case of an equivocal CDUS, a D-Dimer test is performed. If the D-dimer is normal, the diagnosis of DVT recurrence is ruled out and the patient is not treated. If the D-dimer is abnormal, the diagnosis cannot be excluded nor confirmed and a second CDUS is performed on D7±2. Meanwhile, patients are not treated by anticoagulants. An unchanged CDUS on D7±2 qualifies patients as free from a new DVT and they are not treated. Conversely a change in CDUS qualifies patients as having a new DVT which requires anticoagulant treatment. All patients have a 3-month follow-up for the assessment of potential venous thromboembolic events.

Detailed Description
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Venous thromboembolism (VTE) recurrence is a common situation after stopping anticoagulant treatment. This recurrence requires extended anticoagulant therapy to prevent thrombosis progression and embolization, but given an increased bleeding risk with prolonged treatment, an accurate diagnosis for VTE recurrence is needed. Unfortunately, there is no reference standard for the diagnosis of deep vein thrombosis (DVT) recurrence and objective and accurate diagnostic methods are lacking. Clinical assessment does not allow discriminating between a previous and a recent thrombosis and there is no clinical prediction rule specific to the suspicion of DVT recurrence. D-dimer assays alone may not be able to safely exclude the diagnosis of DVT recurrence, and they have not been sufficiently validated in combination with clinical probability. The same holds for imaging modalities because normalisation rate after proximal DVT is low and a residual thrombosis may make difficult the diagnosis of a new thrombosis episode at the same site. Phlebography is non-diagnostic in 33% of cases. CT-venography has never been evaluated and MRI direct thrombus imaging (MRDTI) although very promising is still under evaluation. As compression ultrasound (CUS) may be equivocal due to a residual thrombosis, a comparison to baseline measurements of residual vein diameter after full compression at the common femoral and the popliteal vein segments in cross-sectional plane has been suggested with an increase in diameter superior to 2 or 4 mm as a diagnosis criterion. This method has many major limitations related to: 1/the need for a previous measurement almost never available in practice, 2/ the potential for recurrence at a different site than that previously measured, 3/ a poor inter-observer agreement or at least inconsistent inter-observer variability between studies, 4/ small sample sizes in diagnostic accuracy and in diagnostic management studies and 5/ lack of external validation. Due to these limitations, recurrent ipsilateral DVT is mainly diagnosed by CUS when it occurs in a new or a normalised vein segment. Colour Doppler ultrasound (CDUS) enables to study both the thrombus and the blood flow characteristics that might help to overcome the limitations of CUS and diameter measurements. Although CDUS has never been assessed for DVT recurrence in a study, it is used in every day clinical practice and seems very helpful. The diagnosis may be easily established using the same CDUS criteria as for a first DVT episode. Our hypothesis is that CDUS associated with D-Dimer can safely exclude the diagnosis of recurrent DVT while maintaining a good specificity. The strategy consists in performing first a CDUS that helps to classify patients as having (positive CDUS) or not having (negative CDUS) a new thrombosis. In the case of an equivocal (non-diagnostic) CDUS, a D-Dimer test is performed followed by repeat CDUS on D7±2 if D-dimer test result is abnormal. Meanwhile, patients are not treated by anticoagulants. A negative D-dimer test or an unchanged CDUS on D7±2 qualifies patients as free from a new DVT. Conversely a change in CDUS qualifies patients as having a new DVT. Only patients with a new DVT are treated. All patients have a 3-month follow-up for the assessment of venous thromboembolic and bleeding events by an independent adjudication committee.

Official Title
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Safety of a Management Strategy Based on Colour Doppler ULTrasound and D-Dimer Testing for the Diagnosis Exclusion of RECurrent Deep Vein Thrombosis of the Lower Limbs. The ULTREC Project

Conditions
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Deep Vein Thrombosis

Intervention / Treatment
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* Diagnostic Test: Colour doppler ultrasound with or without D-dimer test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years Known history of objectively documented deep vein thrombosis of the lower limb (with or without pulmonary embolism) Out-patients referred for clinically suspected acute recurrent ipsilateral DVT of the lower limb i.e. the occurrence of new symptoms and signs of DVT or the increase of symptoms and signs in patients with post-thrombotic syndrome Patients covered by social security or equivalent regimen Signed and dated informed consent Exclusion Criteria: Known current pregnancy Any condition, which, in the opinion of the investigator may prevent him from performing the colour doppler ultrasound test (plaster cast, inaccessible vein segment after abdominal or pelvic surgery, or other causes that may lead to a technically inadequate CDUS) Delay from onset of symptoms to inclusion of more than 10 days Therapeutic anticoagulation for more than 48 hours in the two days prior to consent or a need for long term anticoagulation Prophylactic anticoagulation for more than 48 hours in the two days prior to consent Clinical symptoms of pulmonary embolism Life expectancy less than 3 months Patient unable to adhere to protocol or follow-up visits and contacts Participants under legal guardianship or incapacitation Patient already enrolled in a deep vein thrombosis (DVT) diagnostic research

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Diagnostic strategy<br>Colour doppler ultrasound (CDUS) with or without D-dimer test to rule-in or rule-out deep vein thrombosis recurrence | Diagnostic Test: Colour doppler ultrasound with or without D-dimer test<br>* Positive CDUS: anticoagulant treatment Negative CDUS: no anticoagulant treatment Non diagnostic CDUS : reference to routine D-dimer test Negative test : no anticoagulant treatment Positive test : second CDUS 7 days (±2) after first one No change in CDUS : no anticoagulant treatment Change in CDUS : anticoagulant treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjudicated symptomatic venous thromboembolic events | Rate of adjudicated symptomatic venous thromboembolic (VTE) events among patients not treated by anticoagulants according to the diagnostic strategy The criteria for recurrent VTE include: objectively confirmed pulmonary embolism (PE) by either CT pulmonary angiography or ventilation-perfusion scan, death due to PE, and recurrent DVT of the leg Death, cause of death, VTE comprising isolated proximal or distal DVT and PE (with or without DVT), will be adjudicated by an independent clinical event committee blinded to the classification of the diagnostic strategy. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of deep vein thrombosis recurrence | Proportion of patients with a new DVT among all patients included based on the results of the diagnostic tests used in the strategy and on the occurrence of VTE events during follow-up in patients untreated | Up to 3 months | 
| Proportion of patients tested negative | Proportion of patients tested negative by the strategy for DVT recurrence among all patients included | A day if the diagnostic strategy is conclusive (either positive or negative) at day 0, or 7 days if it is inconclusive | 
| Proportion of complete patients | Proportion of patients who completed the strategy | 3 months | 
| Bleeding complication occurrence | The occurrence of bleeding complications will be assessed among all patients included during a 3-month follow-up period. The severity of these complications will be adjudicated by the independent clinical event committee according to the International Society on Thrombosis and Haemostasis classification criteria. | 3 months | 
| Correlation of possible strategy failure in not anticoagulated patients and patient characteristics | Identification of clinical and ultrasound factors which could explain failure of the strategy in non anticoagulated patients | 3 months | 
| Prevalence of isolated superficial vein thrombosis | Proportion of patients with isolated superficial vein thrombosis during a 3-month follow-up among all patients included | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Deep vein thrombosis, Recurrence, Diagnostic strategy, Colour doppler ultrasound, D-dimer