Diagnosis Exclusion of Recurrent Deep Vein Thrombosis of the Lower Limbs

NCT ID: NCT03868956

Last Updated: 2025-11-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 466 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-17
• Study Completion Date: 2023-01-30

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.

Conditions

Deep Vein Thrombosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Diagnostic strategy

Colour doppler ultrasound (CDUS) with or without D-dimer test to rule-in or rule-out deep vein thrombosis recurrence

Group Type: EXPERIMENTAL

Colour doppler ultrasound with or without D-dimer test

Intervention Type: DIAGNOSTIC_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

Interventions

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

Intervention Type: DIAGNOSTIC_TEST

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Centre Hospitalier Universitaire de Saint Etienne

OTHER

Sponsor Role: collaborator

Investigation network on venous thrombo-embolism

UNKNOWN

Sponsor Role: collaborator

Centre Hospitalier Intercommunal de Toulon La Seyne sur Mer

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Antoine Elias, MD

Role: STUDY_DIRECTOR

Centre Hospitalier Intercommunal Toulon La Seyne sur Mer

Locations

Centre Hospitalier de Vichy

Vichy, Allier, France

Centre Hospitalier Universitaire de Nice

Nice, Alpes-Maritimes, France

Centre Hospitalier de Carcassonne

Carcassonne, Aude, France

Centre d'angiologie

Carcassonne, Aude, France

APHM La Timone

Marseille, Bouches Du Rhône, France

Cabinet libéral Pung

Aubagne, Bouches-du-Rhône, France

Cabinet libéral Dias

Istres, Bouches-du-Rhône, France

Cabinet libéral Sidoli

Marseille, Bouches-du-Rhône, France

Cabinet libéral El Haddad

Marseille, Bouches-du-Rhône, France

Cabinet libéral De Mari

Ajaccio, Corse Du Sud, France

Cabinet libéral Secondi

Ajaccio, Corse Du Sud, France

Centre Hospitalier Universitaire Bocage

Dijon, Cote d'Or, France

Centre Hospitalier Universitaire François Mitterrand

Dijon, Côte d'Or, France

Centre hospitalier Universitaire Cavale Blanche

Brest, Finistère, France

Centre Hospitalier Universitaire de Nîmes

Nîmes, Gard, France

Centre Hospitalier d'Auch

Auch, Gers, France

Cabinet libéral Cazaux

Auch, Gers, France

Hôpital Saint André

Bordeaux, Gironde, France

Centre de medicine vasculaire interventionnel

Langon, Gironde, France

Cabinet libéral Casanova

Bastia, Haute Corse, France

Cabinet libéral Bonavita

Bastia, Haute-Corse, France

Cabinet libéral Bourrinet

Balma, Haute-Garonne, France

Centre Hospitalier Universitaire Rangueil

Toulouse, Haute-Garonne, France

Clinique Rive Gauche

Toulouse, Haute-Garonne, France

Cabinet libéral Wagner

Lourdes, Hautes-Pyrénées, France

Cabinet libéral Esteve

Tarbes, Hautes-Pyrénées, France

Centre Hospitalier Universitaire de Montpellier

Montpellier, Hérault, France

Centre Hospitalier Universitaire de Rennes

Rennes, Ille-et-Vilaine, France

Centre Hospitalier Universitaire de Grenoble

Grenoble, Isère, France

Centre Hospitalier Universitaire d'Angers

Angers, Maine-et-Loire, France

Centre Hospitalier Universitaire de Nancy

Nancy, Meurthe Et Moselle, France

Espace Artois Santé

Arras, Pas-de-Calais, France

Centre Hospitalier Universitaire Nord

Saint-Étienne-de-Montluc, Pays de la Loire Region, France

Centre Hospitalier Universitaire de Clermont-Ferrand

Clermont-Ferrand, Puy-de-Dôme, France

Hôpital Edouard Herriot

Lyon, Rhône, France

Centre Hospitalier Universitaire d'Amiens

Amiens, Somme, France

Cabinet libéral Besancon - polyclinique des Fleurs

Ollioules, Var, France

Clinique des Fleurs

Ollioules, Var, 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

Centre Hospitalier Intercommunal Toulon La Seyne sur Mer

Toulon, Var, France

Hôpital Saint Joseph

Paris, , France

Centre d'explorations vasculaires

Paris, Île-de-France Region, France

Countries

France

References

Prandoni P, Cogo A, Bernardi E, Villalta S, Polistena P, Simioni P, Noventa F, Benedetti L, Girolami A. A simple ultrasound approach for detection of recurrent proximal-vein thrombosis. Circulation. 1993 Oct;88(4 Pt 1):1730-5. doi: 10.1161/01.cir.88.4.1730.

Reference Type: BACKGROUND

PMID: 8403319 (View on PubMed)

Prandoni P, Lensing AW, Bernardi E, Villalta S, Bagatella P, Girolami A; DERECUS Investigators Group. The diagnostic value of compression ultrasonography in patients with suspected recurrent deep vein thrombosis. Thromb Haemost. 2002 Sep;88(3):402-6.

Reference Type: BACKGROUND

PMID: 12353067 (View on PubMed)

Ageno W, Squizzato A, Wells PS, Buller HR, Johnson G. The diagnosis of symptomatic recurrent pulmonary embolism and deep vein thrombosis: guidance from the SSC of the ISTH. J Thromb Haemost. 2013 Aug;11(8):1597-602. doi: 10.1111/jth.12301. No abstract available.

Reference Type: BACKGROUND

PMID: 23682905 (View on PubMed)

Aguilar C, del Villar V. Combined D-dimer and clinical probability are useful for exclusion of recurrent deep venous thrombosis. Am J Hematol. 2007 Jan;82(1):41-4. doi: 10.1002/ajh.20754.

Reference Type: BACKGROUND

PMID: 16947316 (View on PubMed)

Bates SM, Jaeschke R, Stevens SM, Goodacre S, Wells PS, Stevenson MD, Kearon C, Schunemann HJ, Crowther M, Pauker SG, Makdissi R, Guyatt GH. Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e351S-e418S. doi: 10.1378/chest.11-2299.

Reference Type: BACKGROUND

PMID: 22315267 (View on PubMed)

Fraser DG, Moody AR, Morgan PS, Martel AL, Davidson I. Diagnosis of lower-limb deep venous thrombosis: a prospective blinded study of magnetic resonance direct thrombus imaging. Ann Intern Med. 2002 Jan 15;136(2):89-98. doi: 10.7326/0003-4819-136-2-200201150-00006.

Reference Type: BACKGROUND

PMID: 11790060 (View on PubMed)

Geersing GJ, Zuithoff NP, Kearon C, Anderson DR, Ten Cate-Hoek AJ, Elf JL, Bates SM, Hoes AW, Kraaijenhagen RA, Oudega R, Schutgens RE, Stevens SM, Woller SC, Wells PS, Moons KG. Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis. BMJ. 2014 Mar 10;348:g1340. doi: 10.1136/bmj.g1340.

Reference Type: BACKGROUND

PMID: 24615063 (View on PubMed)

Goodacre S, Sampson F, Thomas S, van Beek E, Sutton A. Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis. BMC Med Imaging. 2005 Oct 3;5:6. doi: 10.1186/1471-2342-5-6.

Reference Type: BACKGROUND

PMID: 16202135 (View on PubMed)

Hamadah A, Alwasaidi T, LE Gal G, Carrier M, Wells PS, Scarvelis D, Gonsalves C, Forgie M, Kovacs MJ, Rodger MA. Baseline imaging after therapy for unprovoked venous thromboembolism: a randomized controlled comparison of baseline imaging for diagnosis of suspected recurrence. J Thromb Haemost. 2011 Dec;9(12):2406-10. doi: 10.1111/j.1538-7836.2011.04533.x.

Reference Type: BACKGROUND

PMID: 21985174 (View on PubMed)

Hassen S, Barrellier MT, Seinturier C, Bosson JL, Genty C, Long A, Pernod G. High percentage of non-diagnostic compression ultrasonography results and the diagnosis of ipsilateral recurrent proximal deep vein thrombosis: a rebuttal. J Thromb Haemost. 2011 Feb;9(2):414-6; author reply 417-8. doi: 10.1111/j.1538-7836.2010.04137.x. No abstract available.

Reference Type: BACKGROUND

PMID: 21070594 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 1633039 (View on PubMed)

Hull RD, Carter CJ, Jay RM, Ockelford PA, Hirsch J, Turpie AG, Zielinsky A, Gent M, Powers PJ. The diagnosis of acute, recurrent, deep-vein thrombosis: a diagnostic challenge. Circulation. 1983 Apr;67(4):901-6. doi: 10.1161/01.cir.67.4.901.

Reference Type: BACKGROUND

PMID: 6825247 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26867832 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16432085 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19228281 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16378830 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17367489 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15583225 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 9010144 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20398187 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22726359 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24928859 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25261098 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18433464 (View on PubMed)

Other Identifiers

2019-A00136-51

Identifier Type: OTHER

Identifier Source: secondary_id

2018-CHITS-04

Identifier Type: -

Identifier Source: org_study_id