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. PURPOSE: 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. DATA SOURCES: 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. STUDY SELECTION: 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). DATA EXTRACTION: 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. DATA SYNTHESIS: 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. LIMITATIONS: Unmeasured variables could have affected the risk for recurrent VTE. The study population was predominantly white. CONCLUSION: 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.