Diagnosis Exclusion of Recurrent Deep Vein Thrombosis of the Lower Limbs

Deep Vein Thrombosis Clinical Trial

— ULTREC  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03868956
• Other study ID #: 2018-CHITS-04
• Secondary ID: 2019-A00136-51
• Status: Completed
• Phase: N/A
• Start date: January 17, 2020
• Est. completion date: January 30, 2023

Study information

• Verified date: March 2024
• Source: Centre Hospitalier Intercommunal de Toulon La Seyne sur Mer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 466
• Est. completion date: January 30, 2023
• Est. primary completion date: January 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Deep Vein Thrombosis
• Thrombosis
• Venous Thrombosis

Intervention

Diagnostic Test:
• Colour doppler ultrasound with or without D-dimer test
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

Locations

Country	Name	City	State
France	Cabinet libéral De Mari	Ajaccio	Corse Du Sud
France	Cabinet libéral Secondi	Ajaccio	Corse Du Sud
France	Centre Hospitalier Universitaire d'Amiens	Amiens	Somme
France	Centre Hospitalier Universitaire d'Angers	Angers	Maine-et-Loire
France	Espace Artois Santé	Arras	Pas-de-Calais
France	Cabinet libéral Pung	Aubagne	Bouches-du-Rhône
France	Cabinet libéral Cazaux	Auch	Gers
France	Centre Hospitalier d'Auch	Auch	Gers
France	Cabinet libéral Bourrinet	Balma	Haute-Garonne
France	Cabinet libéral Bonavita	Bastia	Haute-Corse
France	Cabinet libéral Casanova	Bastia	Haute Corse
France	Hôpital Saint André	Bordeaux	Gironde
France	Centre hospitalier Universitaire Cavale Blanche	Brest	Finistère
France	Centre d'angiologie	Carcassonne	Aude
France	Centre Hospitalier de Carcassonne	Carcassonne	Aude
France	Centre Hospitalier Universitaire de Clermont-Ferrand	Clermont-Ferrand	Puy-de-Dôme
France	Centre Hospitalier Universitaire Bocage	Dijon	Cote d'Or
France	Centre Hospitalier Universitaire François Mitterrand	Dijon	Côte d'Or
France	Centre Hospitalier Universitaire de Grenoble	Grenoble	Isère
France	Cabinet libéral Dias	Istres	Bouches-du-Rhône
France	Centre de medicine vasculaire interventionnel	Langon	Gironde
France	Cabinet libéral Wagner	Lourdes	Hautes-Pyrénées
France	Hôpital Edouard Herriot	Lyon	Rhône
France	APHM La Timone	Marseille	Bouches Du Rhône
France	Cabinet libéral El Haddad	Marseille	Bouches-du-Rhône
France	Cabinet libéral Sidoli	Marseille	Bouches-du-Rhône
France	Centre Hospitalier Universitaire de Montpellier	Montpellier	Hérault
France	Centre Hospitalier Universitaire de Nancy	Nancy	Meurthe Et Moselle
France	Centre Hospitalier Universitaire de Nice	Nice	Alpes-Maritimes
France	Centre Hospitalier Universitaire de Nîmes	Nîmes	Gard
France	Cabinet libéral Besancon - polyclinique des Fleurs	Ollioules	Var
France	Clinique des Fleurs	Ollioules	Var
France	Centre d'explorations vasculaires	Paris	Ile-de-France
France	Hôpital Saint Joseph	Paris
France	Centre Hospitalier Universitaire de Rennes	Rennes	Ille-et-Vilaine
France	Centre Hospitalier Universitaire Nord	Saint-Étienne	Loire
France	Cabinet libéral Richard	Sanary-sur-Mer	Var
France	Cabinet libéral Ben Sedrine	Six-Fours-les-Plages	Var
France	Cabinet libéral Riviere	Six-Fours-les-Plages	Var
France	Cabinet libéral Zimmermann	Six-Fours-les-Plages	Var
France	Cabinet libéral Esteve	Tarbes	Hautes-Pyrénées
France	Centre Hospitalier Intercommunal Toulon La Seyne sur Mer	Toulon	Var
France	Centre Hospitalier Universitaire Rangueil	Toulouse	Haute-Garonne
France	Clinique Rive Gauche	Toulouse	Haute-Garonne
France	Centre Hospitalier de Vichy	Vichy	Allier

Sponsors (3)

Lead Sponsor	Collaborator
Centre Hospitalier Intercommunal de Toulon La Seyne sur Mer	Centre Hospitalier Universitaire de Saint Etienne, Investigation network on venous thrombo-embolism

Country where clinical trial is conducted

France, 

References & Publications (24)

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Heijboer H, Jongbloets LM, Buller HR, Lensing AW, ten Cate JW. Clinical utility of real-time compression ultrasonography for diagnostic management of patients with recurrent venous thrombosis. Acta Radiol. 1992 Jul;33(4):297-300. — View Citation

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Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores L. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-352. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7. Erratum In: Chest. 2016 Oct;150(4):988. — View Citation

Le Gal G, Kovacs MJ, Carrier M, Do K, Kahn SR, Wells PS, Anderson DA, Chagnon I, Solymoss S, Crowther M, Righini M, Perrier A, White RH, Vickars L, Rodger M. Validation of a diagnostic approach to exclude recurrent venous thromboembolism. J Thromb Haemost. 2009 May;7(5):752-9. doi: 10.1111/j.1538-7836.2009.03324.x. Epub 2009 Feb 18. — View Citation

Le Gal G, Righini M, Roy PM, Sanchez O, Aujesky D, Perrier A, Bounameaux H. Value of D-dimer testing for the exclusion of pulmonary embolism in patients with previous venous thromboembolism. Arch Intern Med. 2006 Jan 23;166(2):176-80. doi: 10.1001/archinte.166.2.176. — View Citation

Linkins LA, Stretton R, Probyn L, Kearon C. Interobserver agreement on ultrasound measurements of residual vein diameter, thrombus echogenicity and Doppler venous flow in patients with previous venous thrombosis. Thromb Res. 2006;117(3):241-7. doi: 10.1016/j.thromres.2005.02.011. Epub 2005 Mar 21. — View Citation

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Prandoni P, Tormene D, Dalla Valle F, Concolato A, Pesavento R. D-dimer as an adjunct to compression ultrasonography in patients with suspected recurrent deep vein thrombosis. J Thromb Haemost. 2007 May;5(5):1076-7. doi: 10.1111/j.1538-7836.2007.02455.x. Epub 2007 Mar 15. No abstract available. — View Citation

Rathbun SW, Whitsett TL, Raskob GE. Negative D-dimer result to exclude recurrent deep venous thrombosis: a management trial. Ann Intern Med. 2004 Dec 7;141(11):839-45. doi: 10.7326/0003-4819-141-11-200412070-00007. — View Citation

Schulman S, Granqvist S, Holmstrom M, Carlsson A, Lindmarker P, Nicol P, Eklund SG, Nordlander S, Larfars G, Leijd B, Linder O, Loogna E. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N Engl J Med. 1997 Feb 6;336(6):393-8. doi: 10.1056/NEJM199702063360601. — View Citation

Tan M, Bornais C, Rodger M. Interobserver reliability of compression ultrasound for residual thrombosis after first unprovoked deep vein thrombosis. J Thromb Haemost. 2012 Sep;10(9):1775-82. doi: 10.1111/j.1538-7836.2012.04827.x. — View Citation

Tan M, Mol GC, van Rooden CJ, Klok FA, Westerbeek RE, Iglesias Del Sol A, van de Ree MA, de Roos A, Huisman MV. Magnetic resonance direct thrombus imaging differentiates acute recurrent ipsilateral deep vein thrombosis from residual thrombosis. Blood. 2014 Jul 24;124(4):623-7. doi: 10.1182/blood-2014-04-566380. Epub 2014 Jun 13. — View Citation

Tan M, Velthuis SI, Westerbeek RE, VAN Rooden CJ, VAN DER Meer FJ, Huisman MV. High percentage of non-diagnostic compression ultrasonography results and the diagnosis of ipsilateral recurrent proximal deep vein thrombosis. J Thromb Haemost. 2010 Apr;8(4):848-50. doi: 10.1111/j.1538-7836.2010.03758.x. No abstract available. — View Citation

van der Hulle T, Tan M, den Exter PL, van Roosmalen MJ, van der Meer FJ, Eikenboom J, Huisman MV, Klok FA. Recurrence risk after anticoagulant treatment of limited duration for late, second venous thromboembolism. Haematologica. 2015 Feb;100(2):188-93. doi: 10.3324/haematol.2014.112896. Epub 2014 Sep 26. — View Citation

Westerbeek RE, Van Rooden CJ, Tan M, Van Gils AP, Kok S, De Bats MJ, De Roos A, Huisman MV. Magnetic resonance direct thrombus imaging of the evolution of acute deep vein thrombosis of the leg. J Thromb Haemost. 2008 Jul;6(7):1087-92. doi: 10.1111/j.1538-7836.2008.02986.x. Epub 2008 Jul 1. — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Proportion of complete patients	Proportion of patients who completed the strategy	3 months
Secondary	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
Secondary	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
Secondary	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