Performance of Age-Adjusted D-Dimer Cut-off Values to Rule Out Venous Thromboembolism in Patients with Non-High Pre-Test Probability

D-dimer levels below a well defined cut-off level enable to safely rule out VTE in patients with a low or intermediate pre-test probability (PTP), with a high negative predictive value (NPV). As ageing is associated with increased concentrations of coagulation activation markers, including D-dimer, the question was raised of their usefulness to rule out VTE in elderly patients. Various attempts were made in the recent years to address that issue. In that connection, we firstly managed the data of the 644 out-patients with a low or intermediate PTP (Wells' scores for DVT or PE) (C.Legnani et al. 2010) that were included in a multicenter management study of a D-dimer assay. We then intended to validate our results in a cohort of 1042 consecutive patients with a non-high PTP, evaluated using another D-dimer assay.

In the first part of the study, D-dimer levels, evaluated using the HemosIL D-dimer HS500 assay (Instrumentation Laboratory), were above the usually used cut-off value (500 ng/mL) in all 88 patients with VTE (100%) and in 299 of the 556 patients without VTE (53.8%). With a 13.7% prevalence of VTE, the test NPV was 100% as well as its sensitivity. If the overall test specificity was 46.2%, it significantly decreased in an age-dependent manner over 70 years, related to a high percentage of increased D-dimer levels in elderly patients, particularly in those above 80 y. ROC-analysis of test results obtained in the different age groups allowed us to propose an age-adjustment of the cut-off value by increasing the usually used value (500 ng/mL) by 100 ng/mL per 10 year-increment in patients aged over 59 years e.g. 600 ng/mL in patients between 60 et 69 years old, 700 ng/mL in patients between 70 et 79 years old. When used, such an age-adjusted cut-off value yielded to significantly improve test specificity, particularly in very old patients with an overall NPV=56.1% vs. 46.2% using the fixed cut-off value. However, an 84 y old patient, with D-dimer level (625 ng/mL) above 500 ng/mL but below the age-adjusted cut-off value, was missed, but the overall NPV remained high (99.6%).

To validate that strategy, we then evaluated data from 1,042 consecutive out-patients with a non high PTP. A standardized diagnostic procedure was applied to assess VTE, with a 3 month-follow up. In this cohort D-dimer levels were evaluated using the Vidas D-dimer assay (BioMérieux). As the result, D-dimer levels were above the cut-off value (500 ng/mL) in all of the 67 patients with confirmed VTE (100%) and in 536 patients without VTE (55.0%), leading to a NPV=99.4% and a sensitivity=95.7%. When applied, our proposed age-adjusted cut-off value leaded to improve the test specificity, with an overall NPV=62.2% vs. 55.1% using the fixed cut-off value. Even if three additional patients, with D-dimer levels above 500 ng/mL but below the age-adjusted cut-off value, were missed, the overall NPV remained high (99.0%).

To use an age-adjusted cut-off value for D-dimer, calculated by increasing the traditional cut-off value (500 ng/mL) by 100 ng/mL per 10 year-increment in those patients aged over 59 years old, leaded to a significant increased in the test specificity, but correlatively to slightly decreased NPV and sensitivity, as some patients with D-dimer levels above 500 ng/mL but below the age-adjusted cut-off value could be misdiagnosed. However such a strategy was found to be safe, in our studied populations, as the NPV remained above 99%.

No relevant conflicts of interest to declare.