Clinical trial NCT03868956: Diagnosis Exclusion of Recurrent Deep Vein Thrombosis of the Lower Limbs
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Deep Vein Thrombosis
Keywords: Deep vein thrombosis
Recurrence
Diagnostic strategy
Colour doppler ultrasound
D-dimer
Lead sponsor: Centre Hospitalier Intercommunal de Toulon La Seyne sur Mer
Sponsor class: OTHER
Collaborators: name: Centre Hospitalier Universitaire de Saint Etienne
name: Investigation network on venous thrombo-embolism
First posted: 2019-03-11
Enrollment: 466
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Adjudicated symptomatic venous thromboembolic events
timeFrame: 3 months
Secondary outcomes:
measure: Prevalence of deep vein thrombosis recurrence
timeFrame: Up to 3 months
measure: Proportion of patients tested negative
timeFrame: A day if the diagnostic strategy is conclusive (either positive or negative) at day 0, or 7 days if it is inconclusive
measure: Proportion of complete patients
timeFrame: 3 months
measure: Bleeding complication occurrence
timeFrame: 3 months
measure: Correlation of possible strategy failure in not anticoagulated patients and patient characteristics
timeFrame: 3 months
measure: Prevalence of isolated superficial vein thrombosis
timeFrame: 3 months
Other outcomes:
Locations:
city: Vichy
country: France
facility: Centre Hospitalier de Vichy
state: Allier
city: Nice
country: France
facility: Centre Hospitalier Universitaire de Nice
state: Alpes-Maritimes
city: Carcassonne
country: France
facility: Centre Hospitalier de Carcassonne
state: Aude
city: Carcassonne
country: France
facility: Centre d'angiologie
state: Aude
city: Marseille
country: France
facility: APHM La Timone
state: Bouches Du Rhône
city: Aubagne
country: France
facility: Cabinet libéral Pung
state: Bouches-du-Rhône
city: Istres
country: France
facility: Cabinet libéral Dias
state: Bouches-du-Rhône
city: Marseille
country: France
facility: Cabinet libéral Sidoli
state: Bouches-du-Rhône
city: Marseille
country: France
facility: Cabinet libéral El Haddad
state: Bouches-du-Rhône
city: Ajaccio
country: France
facility: Cabinet libéral De Mari
state: Corse Du Sud
city: Ajaccio
country: France
facility: Cabinet libéral Secondi
state: Corse Du Sud
city: Dijon
country: France
facility: Centre Hospitalier Universitaire Bocage
state: Cote d'Or
city: Dijon
country: France
facility: Centre Hospitalier Universitaire François Mitterrand
state: Côte d'Or
city: Brest
country: France
facility: Centre hospitalier Universitaire Cavale Blanche
state: Finistère
city: Nîmes
country: France
facility: Centre Hospitalier Universitaire de Nîmes
state: Gard
city: Auch
country: France
facility: Centre Hospitalier d'Auch
state: Gers
city: Auch
country: France
facility: Cabinet libéral Cazaux
state: Gers
city: Bordeaux
country: France
facility: Hôpital Saint André
state: Gironde
city: Langon
country: France
facility: Centre de medicine vasculaire interventionnel
state: Gironde
city: Bastia
country: France
facility: Cabinet libéral Casanova
state: Haute Corse
city: Bastia
country: France
facility: Cabinet libéral Bonavita
state: Haute-Corse
city: Balma
country: France
facility: Cabinet libéral Bourrinet
state: Haute-Garonne
city: Toulouse
country: France
facility: Centre Hospitalier Universitaire Rangueil
state: Haute-Garonne
city: Toulouse
country: France
facility: Clinique Rive Gauche
state: Haute-Garonne
city: Lourdes
country: France
facility: Cabinet libéral Wagner
state: Hautes-Pyrénées
city: Tarbes
country: France
facility: Cabinet libéral Esteve
state: Hautes-Pyrénées
city: Montpellier
country: France
facility: Centre Hospitalier Universitaire de Montpellier
state: Hérault
city: Paris
country: France
facility: Centre d'explorations vasculaires
state: Ile-de-France
city: Rennes
country: France
facility: Centre Hospitalier Universitaire de Rennes
state: Ille-et-Vilaine
city: Grenoble
country: France
facility: Centre Hospitalier Universitaire de Grenoble
state: Isère
city: Saint-Étienne
country: France
facility: Centre Hospitalier Universitaire Nord
state: Loire
city: Angers
country: France
facility: Centre Hospitalier Universitaire d'Angers
state: Maine-et-Loire
city: Nancy
country: France
facility: Centre Hospitalier Universitaire de Nancy
state: Meurthe Et Moselle
city: Arras
country: France
facility: Espace Artois Santé
state: Pas-de-Calais
city: Clermont-Ferrand
country: France
facility: Centre Hospitalier Universitaire de Clermont-Ferrand
state: Puy-de-Dôme
city: Lyon
country: France
facility: Hôpital Edouard Herriot
state: Rhône
city: Amiens
country: France
facility: Centre Hospitalier Universitaire d'Amiens
state: Somme
city: Ollioules
country: France
facility: Cabinet libéral Besancon - polyclinique des Fleurs
state: Var
city: Ollioules
country: France
facility: Clinique des Fleurs
state: Var
city: Sanary-sur-Mer
country: France
facility: Cabinet libéral Richard
state: Var
city: Six-Fours-les-Plages
country: France
facility: Cabinet libéral Ben Sedrine
state: Var
city: Six-Fours-les-Plages
country: France
facility: Cabinet libéral Riviere
state: Var
city: Six-Fours-les-Plages
country: France
facility: Cabinet libéral Zimmermann
state: Var
city: Toulon
country: France
facility: Centre Hospitalier Intercommunal Toulon La Seyne sur Mer
state: Var
city: Paris
country: France
facility: Hôpital Saint Joseph
Study officials:
affiliation: Centre Hospitalier Intercommunal Toulon La Seyne sur Mer
name: Antoine Elias, MD
role: STUDY_DIRECTOR
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