After > 10 years of intensive research, plasma d-dimer measurement is increasingly accepted as a first-line test in patients with suspected pulmonary embolism.1–4
Adoption of d-dimer was faster in suspected deep venous thrombosis, probably because clinicians are less fearful of a false-negative result in that context than when a potentially fatal disease such as pulmonary embolism is suspected. Nevertheless, as carefully reviewed in a recent editorial in CHEST by Kelly and Hunt,,3
and in a recent review of outcome studies in suspected pulmonary embolism,5
the evidence is now convincing: highly or even less sensitive d-dimer assays combined with clinical probability assessment are safe instruments to rule out pulmonary embolism. However, it is now well recognized that d-dimer assays are not a homogeneous group and exhibit vastly different characteristics: they recognize different epitopes of d-dimer and use different technologies (latex, enzyme-linked immunosorbent assay [ELISA], immunoturbidimetry) that impact on the diagnostic characteristics and performance of each individual assay.3
The safety of ruling out pulmonary embolism based on a d-dimer concentration below the predefined cutoff value depends on the sensitivity of the test, ie, the proportion of patients with pulmonary embolism in whom d-dimer is elevated. Indeed, if that proportion approaches 100% (the true figure lies between 96% and 99% for ELISA and immunoturbidimetric assays), the probability of a false-negative test result is very low, and a negative test result is strong evidence that the patient does not have pulmonary embolism. However, although d-dimer is highly specific for cross-linked fibrin, fibrin is generated and degraded in a wide variety of clinical situations. Therefore, the specificity of highly sensitive d-dimer assays for pulmonary embolism is only approximately 40% in outpatients. This has two consequences. First, a d-dimer result above the threshold value is of no value for ruling in pulmonary embolism. More importantly, since only negative d-dimer results are useful for clinical decision making, the proportion of patients with a negative result among those without a pulmonary embolus (ie, specificity) determines the clinical usefulness of the test. Consider a prevalence of pulmonary embolism of 20%, a usual figure in the published literature. In a hypothetical cohort of 100 patients, 80 patients would not have the disease. If the specificity of d-dimer is 40%, d-dimer will be negative in 32 patients. Therefore, the number of patients who must be tested in order to rule out one pulmonary embolism among the entire cohort would be three. In contrast, if the specificity decreases to 12%, only 10 patients will benefit and the number needed to test will rise to 10. Hence, if the specificity of d-dimer varies across patient subgroups, the clinical usefulness of that test may depend on the patient population in whom it is being used.