Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism.
BACKGROUND
In patients with a first unprovoked venous thromboembolism (VTE), an elevated d-dimer level after anticoagulation is stopped is a risk factor for recurrent VTE. However, questions remain about the utility of measuring d-dimer in clinical practice.


OBJECTIVE
To determine whether the timing of testing, patient age, and the cut point used to define a positive or negative result affect the ability of d-dimer testing to distinguish risk for recurrent disease.


METHODS
Comprehensive search of electronic databases (MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials) until July 2010, supplemented by reviewing conference abstracts and contacting content experts.


METHODS
7 prospective studies that investigated an association between d-dimer, measured after stopping anticoagulation, and disease recurrence in patients with a first unprovoked VTE (proximal deep venous thrombosis, pulmonary embolism, or both).


METHODS
Patient-level databases were obtained, transferred to a central database, checked, completed with further information provided by study investigators, and pooled into a single database.


RESULTS
1818 patients with a first unprovoked VTE were followed for a mean of 26.9 months (SD, 19.1). A study-stratified multivariate Cox regression model, which included patient age, sex, hormone therapy use at the time of the index event, body mass index, timing of postanticoagulation d-dimer testing, and inherited thrombophilia as possible confounders, indicated that the hazard ratio for d-dimer status (positive vs. negative) was 2.59 (95% CI, 1.90 to 3.52). Only male sex had a significant effect on risk for recurrent VTE independent of d-dimer status. The Cox regression model and the log-rank test confirmed that the risk for recurrent VTE was higher in patients with a positive d-dimer result than in those with a negative result, regardless of the timing of postanticoagulation d-dimer testing or patient age. No study- or assay-specific d-dimer effect was found, and reassessing the analysis after recoding data according to specific quantitative d-dimer cut points (500 µg/L and 250 µg/L) did not change the results.


CONCLUSIONS
Unmeasured variables could have affected the risk for recurrent VTE. The study population was predominantly white.


CONCLUSIONS
In patients with a first unprovoked VTE who have their d-dimer level measured after stopping anticoagulation, the timing of d-dimer testing, patient age, and the assay cut point used do not affect the ability of d-dimer to distinguish patients with a higher or lower risk for recurrent VTE.
McMaster University, Hamilton, Ontario, Canada. jdouket@mcmaster.ca
James
J
Douketis
Alberto
A
Tosetto
Maura
M
Marcucci
Trevor
T
Baglin
Mary
M
Cushman
Sabine
S
Eichinger
Gualtiero
G
Palareti
Daniela
D
Poli
R Campbell
RC
Tait
Alfonso
A
Iorio
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012008:Recurrence; D012307:Risk Factors; D012737:Sex Factors; D013997:Time Factors; D054556:Venous Thromboembolism / Q000097:blood* / Q000188:drug therapy; D028761:Withholding Treatment; D055815:Young Adult
D000925:Anticoagulants; D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; C036309:fibrin fragment D