XXVI Congresso Nazionale FCSA Bologna 5-7 Novembre 2015 Il D-dimero: vantaggi e limiti Gualtiero Palareti Cardiovascular diseases University of Bologna, Italy
Degradation of stabilized fibrin
DD= Methodolgical problems Analytical errors Lack of standardization Two different measure units Different sensitivity among assays
DD: Leading causes of analytical errors (from Lippi et al. Clin Chem Lab Med 2014) Pre-analytical errors (identification, reagent deterioration, etc) Analyzer malfunction Spurious hemolysis Hyperbilirubinemia Turbidity Heterophile antibodies HAMAs Rheumatoid factor Clotted samples
Olson et al. Arch Pathol Lab Med 2013
Naturally occurring changes in DD levels = a) increasing with age b) higher in females c) increasing during pregnancy
From Tripodi, Clin Chem 2011
Why to perform D-dimer assay? To help diagnostic processes To help guiding treatment
Conventional reference values (95 percentile of healthy subjects) OR Decision thresholds (concentration with the best diagnostic sensitivity and possibly- with high specificity for a predetermined clinical scope)
D-dimer testing in clinical practice Validated indication for: Diagnosis and monitoring of DIC Strategies for VTE Diagnosis/Exclusion Emergent: Individual risk stratification for VTE recurrence Others Exclusion of clinical conditions (Cerebr. VT, Aortic Dissection) Prognostic value of high levels in VTE patients Diagnostic value in stroke patients Possible use to regulate prophylaxis in medical patients Other
Patients with isolated headache may have CVT. D-dimers have a high NPV in patients with isolated headache
D-dimer for VTE exclusion: high NPV in subjects with suspected VTE and non-high clinical probability
Pre test clinical probability Diagnostic procedure suggested for Emergency Dept. Low or intermediate High D-dimer Complication at 3 m. = 0.1% (0.0-0.7%) PE (Wells, Ann Intern Med 2001) = 0.6% (0.0-3.1%) DVT (Kearon, Ann Intern Med 2001) Below cutoff Above cutoff CUS or CT Negative Positive In pts with low or intermediate pre test clinical probability In pts with high pre test clinical probability Treatment No treatment Additional imaging
The Christopher Study; JAMA 2006;295:172-9
Why DD should not be performed in VTE-suspected patients with high clinical probability?
D-dimers for exclusion of VTE: D-dimers must be used with caution (possible false negative results) if: Symptoms present for > 2 weeks Heparin treatment already started Patients receive anticoagulants ( VKA) Cut-off values not validated by specific clinical studies Low-sensitivity assays
Conditions in which DD testing for VTE exclusion is almost useless: Elderly Pregnancy In-patients Cancer Post-surgery Acute infections Etc.
Age-adjusted cut-off levels Age correction = patients > 50 ys for VTE exclusion age multiplied by 10 for FEU assays (Douma et al., BMJ 2010; Douma et al., Haematologica 2012) or by 5 for non-feu assays (Cini et al., Int J Lab Hematol. 2014) Age correction = patients => 60 years 750 ng/ml for assays with results expressed as FEU (Haas et al., Am J Hematol. 2009) or 375 ng/ml for non-feu assays (Cini et al., Int J Lab Hematol. 2014)
JTH 2013 Different cut-off levels in relation to the clinical probability (retrospective study) D-dimer thresholds and results at 3 mo.: Standard (up to 6 points) < 0.5 ug ml no CT-scan Complications = 0.88% (CI 0.29 2.1%) Variable according to probability - Low (< 2 points) < 1.0 ug ml = - Intermediate (2 6 points) < 0.5 ug ml Complications = 2.1% (CI 1.2 3.4%); 11% less CT-scan
DD and the risk of VTE recurrence
ACCP 2012 Duration of AC in patients with a first unprovoked VTE - AC should be given for not less than 3 mo. - With low-moderate bleeding risk an extended AC is suggested over 3 months of therapy (Grade 2B) - With high bleeding risk 3 months of AC are recommended over extended therapy (Grade 1B)
Problems in clinical practice: 1) The risk of bleeding is very difficult to predict 2) The case-fatality rate of major bleeding should not be overlooked 3) What to do in patients with weak risk factors?
T&H 2013 The case-fatality rate of recurrent VTE decreases over time during anticoagulation, while that of major bleeding remains stable
Arch Intern Med 2010
The target of many Italian clinical studies: to identify subjects at high or low risk of recurrence and to give them or avoid indefinite AC Residual vein thrombosis D-dimer after AC is stopped
The «Vienna» and DASH scores to assess the individual risk of VTE recurrence include DD assessed at ~ 30 days from AC is stopped
Changes regarding management in the DULCIS study 1 y AC if Residual VT was present Serial DD measurements Different DD cut-off levels according to age/sex
Patients with altered DD in DULCIS study (age-adjusted cut-offs)
Comparison of results calculated according to different DD cut-off systems (Palareti et al., Int J Lab Haematol 2015) 52.6% 54.5% 51.9% % recurrent events 44.1% 33.2% 26.0% 26.0% 75.7% Age 1 = 750 or 375 ng/ml for FEU or non-feu assays in pts => 60 y Age 2 = age x 10 or x 5 for FEU or non-feu assays in pts => 50 y
Blood 2014
Targets for future clinical research To define an effective and easy to perform management of patients after 1st VTE To adopt simplified DD cut-off levels To lower the recurrence rates in elderly patients To lower the bleeding rates in patients who resume anticoagulation (NOA at low dose)
The next «McLean» study