Age-adjusted D-dimer Cut-off Levels to Rule Out Pulmonary Embolism (ADJUST)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2013 by University Hospital, Geneva
Sponsor:
Collaborators:
University Hospital, Brest
University Hospital, Angers
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Information provided by (Responsible Party):
Marc Righini, University Hospital, Geneva
ClinicalTrials.gov Identifier:
NCT01134068
First received: May 28, 2010
Last updated: April 18, 2013
Last verified: April 2013
  Purpose

Suspected pulmonary embolism (PE) is a frequent clinical problem and remains a diagnostic challenge. The diagnostic approach of PE relies on sequential diagnostic tests, such as plasma D-dimer measurement, multi-slice computed tomography (MSCT) and pulmonary angiography. In addition, the diagnostic workup is usually stratified according to the clinical probability of pulmonary embolism. Clinical probability has a fair predictive accuracy either evaluated implicitly or by clinical prediction rules1 and is useful for identifying patients with a low prevalence of pulmonary embolism who can be usually fully investigated by non invasive tests.The D-dimer test has been extensively evaluated in the exclusion of pulmonary embolism, 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 pulmonary embolism in outcome studies. The clinical usefulness of D-dimer is defined by the proportion of patients in whom pulmonary embolism 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 and 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 PE in older patients. Indeed, 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 80.8 In this study, raising the cut-off value to various points between 600 ng/ml and 1000 ng/ml 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 cut-off adjusted to age in a wide sample of 1712 patients. This "new" cut-off 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 500mg/ml, 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 cut-off is described hereafter. Using the conventional cutoff, the VIDAS® D-Dimer test was negative (below 500 mg/ml) 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 mg/ml), 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%).

These data suggest that adopting this progressive cut-off in patients above 50 years, could increase of about 20% the number of patients in whom PE could be excluded without further testing, with an acceptable safety profile as the three-month thromboembolic rate remained very low.

Therefore, the investigators plan a prospective outcome study in which this progressive or "new" cut-off (age X 10 ng/ml) in patients above 50 years will be used. In this multicentre study, clinical probability will be assessed by the simplified revised Geneva revised score (Table 1) and an ELISA D-dimer test will be performed [Vidas D-Dimer Exclusion® test (Biomérieux, Marcy l'Etoile, Paris, France)]. Patients with a non high clinical probability with the simplified revised Geneva score and a normal "new" D-dimer cut-off with the Vidas D-dimer Exclusion®, (Biomerieux, Marcy l'Etoile, France) will be considered as not having PE, 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 positive D-dimers will be investigated with MSCT as currently admitted.


Condition Intervention Phase
Pulmonary Embolism
Other: Evaluation of a modified DD cut-off to rule out PE
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Age-adjusted D-dimer Cut-off Levels to Rule Out Pulmonary Embolism: a Prospective Outcome Study.

Resource links provided by NLM:


Further study details as provided by University Hospital, Geneva:

Primary Outcome Measures:
  • The main outcome is the rate of thromboembolic events during a formal 3-month follow-up in patients not anticoagulated on the basis of a PE ruled out by the association mentioned here above. [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Prospective validation of the simplified revised Geneva score. [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 5000
Study Start Date: October 2010
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Intervention Details:
    Other: Evaluation of a modified DD cut-off to rule out PE
    Evaluation of a modified DD cut-off to rule out PE
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

All outpatients admitted to the emergency ward for suspected pulmonary embolism defined as acute onset of new or worsening shortness of breath or chest pain without another obvious etiology 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:

  • PE suspicion raised more than 24 hours after admission to the hospital
  • Absence of informed consent
  • Incapacity to deliver informed consent
  • Life expectancy less than 3 months
  • Geographic inaccessibility for follow-up
  • Pregnancy.
  • Patients anticoagulated for a disease other than venous thromboembolism (for instance, atrial fibrillation)
  • Patients allergic to contrast medium
  • Impaired renal function (creatine clearance less than 30 ml/min as calculated by the Cockroft formula).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01134068

Contacts
Contact: Marc Righini, MD 0041 22 372 92 94 marc.righini@hcuge.ch
Contact: Grégoire Le Gal, Prof gregoire.legal@chu-brest.fr

Locations
France
Angers University Hospital Recruiting
Angers, France
Contact: Pierre-Marie Roy, Prof       PMR@chu-angers.fr   
Grégoire Le Gal Recruiting
Brest, France, 02
Contact: Grégoire Le Gal, Prof       gregoire.legal@chu-brest.fr   
Netherlands
Amsterdam University hospital Recruiting
Amsterdam, Netherlands
Contact: Renée Douma, MD         
Principal Investigator: Renée Douma, MD         
Switzerland
Geneva University Hospital Recruiting
Geneva, Switzerland, 1205
Contact: Marc Righini, MD       marc.righini@hcuge.ch   
Contact: Grégoire Le Gal, Prof       gregoire.legal@chu-brest.fr   
Principal Investigator: Marc Righini, MD         
Sponsors and Collaborators
Marc Righini
University Hospital, Brest
University Hospital, Angers
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Investigators
Principal Investigator: Marc Righini, MD Geneva University Hospital
Principal Investigator: Grégoire Le Gal, Prof University Hospital, Brest
Principal Investigator: Renée Douma, MD Amsterdam University Hospital
Principal Investigator: Pierre-Marie Roy, Prof Angers University Hospital
  More Information

No publications provided by University Hospital, Geneva

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Marc Righini, MD, University Hospital, Geneva
ClinicalTrials.gov Identifier: NCT01134068     History of Changes
Other Study ID Numbers: ADJUST
Study First Received: May 28, 2010
Last Updated: April 18, 2013
Health Authority: Switzerland: Ethikkommission

Keywords provided by University Hospital, Geneva:
D-dimer
Pulmonary embolism
Diagnostic strategy
Safety of ruling PE with and age-adjusted DD cut-off

Additional relevant MeSH terms:
Embolism
Pulmonary Embolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases

ClinicalTrials.gov processed this record on August 18, 2014