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Age-adjusted D-Dimer cutoff levels to rule out deep vein thrombosis: a prospective outcome study. The adjust-DVT study

English title Age-adjusted D-Dimer cutoff levels to rule out deep vein thrombosis: a prospective outcome study. The adjust-DVT study
Applicant Righini Marc
Number 159510
Funding scheme Project funding (Div. I-III)
Research institution Hôpitaux Universitaires de Genève Service d'Angiologie et d'Hémostase
Institution of higher education University of Geneva - GE
Main discipline Clinical Cardiovascular Research
Start/End 01.10.2015 - 30.09.2020
Approved amount 136'600.00
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Keywords (3)

D-dimer measurement; Age-adjusted D-dimer cut-off; Deep vein thrombosis

Lay Summary (French)

Lead
Un taux de D-dimères inférieur à 500 microGr/L a été bien validé pour l'exclusion de la thrombose veineuse profonde. Une des limites de ce test est que la proportion de patients chez qui il permet d'exclure la thrombose diminue avec l'âge. Récemment un seuil adapté à l'âge a été validé de manière rétrospective. Ce seuil permettrait d'exclure la thrombose chez les patients de plus de 50 ans lorsque le taux de D-dimères est inférieur à l'âge X 10 ( thrombose exclue chez un patient de 78 ans si les D-dimères sont inférieurs à 780 microGr/L). Le but de l'étude ADJUST-DVT est de valider ce seuil de manière prospective.
Lay summary

La thrombose veineuse profonde est un problème clinique fréquent et demeure un challenge diagnostique. Les stratégies diagnostiques actuelles se basent sur l’utilisation séquentielle de l’évaluation de la probabilité clinique, le dosage des D-dimères et l’échographie de compression des membres inférieurs.

La thrombose veineuse profonde est un problème clinique fréquent et demeure un challenge diagnostique. Les stratégies diagnostiques actuelles se basent sur l’utilisation séquentielle de l’évaluation de la probabilité clinique, le dosage des D-dimères et l’échographie de compression des membres inférieurs.

Le dosage des D-dimères a été largement été utilisé dans les stratégies diagnostiques de la thrombose veineuse profonde et un test négatif (<500 µg/L) permet l’exclusion de la thrombose veineuse profonde avec une très bonne sécurité diagnostique. Malheureusement, l’intérêt clinique du test diminue chez les patients âgés, car le taux de D-dimères augmente de manière physiologique avec l’âge.

Il y a quelques années, nous avons dérivé et validé de manière rétrospective l’intérêt d’un seuil adapté à l’âge dans un collectif de 1712 patients avec une suspicion clinique d’embolie pulmonaire. Ce nouveau seuil est défini comme positif en multipliant l’âge du patient par 10 au dessus de 50 ans. Ainsi, un patient de 75 ans serait considéré comme ayant un D-dimère négatif si son taux de D-dimères est < 750 µg/L. 

La validation prospective de seuil adapté à l’âge chez les patients avec une suspicion d’embolie pulmonaire vient d’être publiée. Dans une étude prospective comportant plus de 3300 patients, et en comparaison avec le seuil usuel de 500 µg/L, le seuil adapté à l’âge augmentait de 5 fois la proportion de patients chez qui le diagnostic d’embolie pulmonaire était exclu par le dosage des D-dimères, sans nécessité d’examen d’imagerie (6.2% à 30%). Par ailleurs, aucun des patients de 75 ans et plus avec un taux de D-dimères en dessous du seuil adapté à l’âge n’a présenté d’événement thromboembolique veineux dans le suivi formel à trois mois (0% ; 95% CI:0 -1.9%).

Vu la similitude entre la thrombose veineuse profonde et l’embolie pulmonaire, il n’y a pas de raison de penser que ce nouveau seuil ne serait pas sûr dans l’exclusion de la thrombose veineuse profonde.

Nous envisageons donc une étude prospective dans laquelle ce nouveau seuil progressif (âge X 10 µg/L) serait utilisé pour l’exclusion de la thrombose veineuse profonde. Les patients avec D-dimères positifs seront investigués par une échographie veineuse, ce qui correspond à la stratégie habituelle en présence de thrombose veineuse profonde.

 

 

 

Direct link to Lay Summary Last update: 25.03.2015

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Number Title Start Funding scheme
146287 Sequential use of the left rule, D-dimer measurement and complete ultrasonography to rule out deep vein thrombosis during pregancy: a prospective management study 01.02.2014 Project funding (Div. I-III)

Abstract

Suspected deep vein thrombosis (DVT) is a frequent clinical problem and remains a diagnostic challenge. The diagnostic approach of DVT relies on sequential diagnostic tests, such as the assessment of clinical probability, plasma D-dimer measurement, and compression ultrasonography (CUS). Clinical probability has a fair predictive accuracy either evaluated implicitly or by clinical prediction rules and is useful for identifying patients with a low prevalence of DVT who can be usually fully investigated by non invasive tests. The D-dimer test has been extensively evaluated in the exclusion of DVT, particularly in outpatients. ELISA D-dimer and second-generation latex agglutination (immuno-turbidimetric tests) have a remarkably high sensitivity and have been proved safe first-line tests in association with clinical probability to rule out DVT in outcome studies. The clinical usefulness of D-dimer is defined by the proportion of patients in whom DVT may be ruled out by a normal result and it is determined by the specificity. However, ELISA and second-generation latex agglutination (immuno-turbidimetric tests) tests have a quite limited overall specificity of around 35% to 40%. Therefore, many investigators tried to increase the D-dimer thresholds in particular in elderly patients to increase the rate of patients in whom the diagnosis could be excluded by this easy and inexpensive test. Several studies have shown that D-dimer levels increase with age, which turns in a decreased specificity of the D-dimer test at the usual threshold in the elderly, and thus to a less useful test to exclude both DVT and pulmonary embolism (PE) in older patients. For example, ELISA D-dimer is able to rule out PE in 60% of patients aged less than 40 years, but in only 5% of patients above the age of 80. In this study, raising the cutoff value to various points between 600 microg/L and 1000 microg/L increased specificity, but this came at the cost of safety with more false negative test results. In this analysis, however, no stratification was made for clinical probability and the sample was small.Recently, we retrospectively assessed the value of a progressive cutoff adjusted to age in a wide sample of 1712 patients with suspected PE. This “new” cutoff was defined for D-Dimer test positivity in each patient by multiplying patient’s age by 10.4 All patients with a D-Dimer level below 500 microg/L, and all patients above 50 years whose D-Dimer levels were inferior to their age multiplied by 10 were considered as having a negative D-Dimer test. The exact derivation and validation of this “new” D-dimer cutoff is described hereafter. Using the conventional cutoff, the VIDAS® D-Dimer test was negative (below 500 microg/L) in 512/1712 patients (29.9%) and none had PE during initial workup or the three-month follow-up period. Using the cutoff adjusted to age (cutoff for D-Dimer test positivity equals age multiplied by ten, in microg/L), the figure was as follows. D-Dimer levels were below the adjusted cutoff in 615/1712 patients (35.9%, number needed to test 2.8). This represented a statistically significant 20.1% increase in the number of patients in whom the D-Dimer test was considered as negative, p=0.0002. Of these 615 patients, 5 had PE during initial workup (0.8%, 95 percent confidence interval 0.4 to 1.9%).Our team recently published a prospective outcome validation study of the age-adjusted cutoff in patients with a clinically suspected PE. The study included more than 3300 patients with suspected PE and showed that the three-month thromboembolic risk in patients with an nonhigh (or unlikely) clinical probability and a D-Dimer level between 500 microg/L and the age-adjusted cutoff was of 0.3% (95% CI: 0.1 % to 1.7%). These results were in line with the one found in patients with a D-dimer level below the usual cutoff of 500 microg/L: 0.1% (95% CI: 0.0% to 0.7%). Moreover, in patients above 75 years the age-adjusted cutoff allowed to increase five-fold the number of patients in whom PE could be excluded without imaging test a with thromboembolic events in the three-month follow-up.As PE and DVT are often considered as a similar disease, we plan a prospective outcome study in which this progressive or “new” cutoff (age X 10 µg/L) will be used in patients with suspected DVT. In this multicentre study, clinical probability will be assessed by the Wells score and an ELISA D-dimer test (Vidas D-dimer Exclusion® test (Biomérieux, Marcy l’Etoile, Paris, France) or an immuno-turbidimetric test Innovance D-dimer (Siemens, Munich, Germany) will be performed. Patients with a nonhigh or “unlikely” clinical probability with the Wells score and a normal “new” D-dimer cutoff will be considered as not having DVT, and will be followed for three-months to assess possible VTE recurrences. The main outcome will be the rate of thromboembolic events during a formal 3-month follow-up in patients not anticoagulated on the basis of this strategy. Patients with a D-dimer measurement above the age-adjusted cutoff will be investigated with CUS as currently admitted.
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