Clinical trial NCT02384135: Age-adjusted D-dimer Cutoff Levels to Rule Out Deep Vein Thrombosis: a Prospective Outcome Study
Official title: Age-adjusted D-dimer Cutoff Levels to Rule Out Deep Vein Thrombosis: a Prospective Outcome Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Deep Vein Thrombosis
D-dimer
Lead sponsor: University Hospital, Geneva
Sponsor class: OTHER
Collaborators: name: The Ottawa Hospital
name: University Medical Center Groningen
First posted: 2015-03-10
Enrollment: 3300
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: Prospective validation of an age-adjusted D-dimer cut-off to rule out deep vein thrombosis (DVT)

Detailed description: 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%.3 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, the investigators 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. 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. 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%).

In a recently published a prospective outcome validation study of the age-adjusted cutoff in patients with a clinically suspected PE.13 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 5 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.

As PE and DVT are often considered as a similar disease, the investigators 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 (Table 1) 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.

Eligibility criteria: Inclusion Criteria:

* All outpatients admitted to the emergency ward for suspected DVT will be included in the study, provided they correspond to the following diagnostic and exclusion criteria and they have signed an informed consent form.

Exclusion Criteria:

* DVT suspicion raised more than 48 hours after admission to the hospital
* Pregnancy.
* Patients anticoagulated for a disease other than venous thromboembolism (for instance, atrial fibrillation)
* Concommitant PE suspicion
* Life expectancy less than 3 months
* Absence of informed consent
* Incapacity to deliver informed consent

Primary outcomes:
measure: Three-month thromboembolic risk in patient with D-dimer levels between the usual cut-off and the age-adjusted cut-off
timeFrame: three-month follow-up
Secondary outcomes:
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Calgary/Alberta
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: Monfort
country: Canada
facility: Hôpital Monfort
state: Ontario
city: Montreal
country: Canada
facility: Hopital Maisonneuve-Rosemont
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Saskatoon
country: Canada
facility: Royal University Hospital
state: Saskatchewan
city: Vancouver
country: Canada
facility: Providence Health Care
state: Vancouver/British Columbia
city: Kingston, Ontario
country: Canada
facility: Kingston General Hospital
city: Ottawa
country: Canada
facility: The Ottawa Hospital
city: Thunder Bay, Ontario
country: Canada
facility: Thunder Bay regional Health Sciences center
city: Toronto, Ontario
country: Canada
facility: University Health network
city: Brest
country: France
facility: Grégoire LE GAL
city: Geneva
country: Switzerland
facility: Marc Righini
city: Geneva
country: Switzerland
facility: Geneva University Hospital
city: Geneva
country: Switzerland
facility: University Hospital of Geneva
Study officials:
affiliation: University Hospital, Geneva
name: Marc Righini, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ottawa University Hospital
name: Grégoire Le Gal, MD
role: PRINCIPAL_INVESTIGATOR
References: