Selective D‐dimer testing for the diagnosis of acute deep vein thrombosis: a validation study

The standard diagnostic algorithm for patients with clinically suspected deep vein thrombosis (DVT) starts with the Wells rule to determine pretest probability, followed by a quantitative D-dimer test in the case of an unlikely clinical probability [1,2]. In patients with a ‘DVT unlikely’ score (0–1 point) and a D-dimer level < 0.5 lg/mL, DVT can be safely ruled out [1,3,4]. In the remaining patients a proximal lower limb compression ultrasonography (CUS) is indicated. For patients with a ‘DVT likely’ score (≥2 points) and a normal CUS, a subsequently assessed Ddimer level ≥0.5 lg/mL is an indication for a repeated CUS after 1 week [2]. This strategy has high sensitivity but low specificity, resulting in a high number of CUS that are negative for DVT [2,4]. One of the main challenges in improving this algorithm is to safely diminish the number of required CUS. Recently, a diagnostic algorithm applying selective Ddimer thresholds depending on clinical probability was investigated in a randomized clinical trial, in which the original three risk categories by Wells were reintroduced [3]. In patients with a low risk score (0 points) the Ddimer threshold was increased to 1.0 lg/mL, while in patients with a moderate risk score (1–2 points) the threshold remained 0.5 lg/mL to rule out DVT without further imaging. In all other patients CUS was performed. Repeated CUS was indicated in patients with moderate or high risk scores and an initial negative CUS in combination with a D-dimer ≥0.5 lg/mL [1]. This strategy resulted in a relative reduction of 13.3% (95% CI 10.4–16.5%; absolute reduction 7.6%) of CUS with an absolute reduction of 22% in the number of D-dimer tests without compromising the safety of the algorithm. Nonetheless, due to two characteristics of this study, a validation study would be of interest. First, the overall DVT prevalence was 7%, which is lower than the 16– 39% reported in European studies [2,4]. Second, management in the reference group differed from the standard algorithm [1,2]: all patients underwent D-dimer testing at presentation regardless of the Wells score and in the case of a normal D-dimer test DVT was excluded. Therefore, we assessed the safety and performance of the selective D-dimer algorithm in a post-hoc analysis of a prospective DVT management study performed in the Netherlands from 2009 until 2010 with a higher DVT prevalence and compared the failure rate and number of required CUS with the standard algorithm [5]. Exclusion criteria were pregnancy, anticoagulant therapy and inability for followup. A diagnosis of DVT was established by CUS. The primary endpoint was the objective diagnosis of symptomatic venous thromboembolism. A rejected DVT diagnosis at baseline followed by an uneventful 3-month follow-up was the reference standard for the true absence of DVT. We calculated failure rates, the number of required CUS and D-dimer tests, test characteristics and predictive values. Of 606 eligible patients, 128 were excluded because of unavailable D-dimer test results due to diagnosis of DVT at the initially performed CUS and 89 patients were excluded because a D-dimer test result was not available due to protocol violation. The baseline characteristics of the remaining 389 patients and the 217 excluded patients are shown in Table 1. Of the included patients, overall DVT prevalence was 22% (79 diagnosed at baseline, eight after repeated CUS, none during follow-up). One patient died during follow-up in whom serial CUS was negative for DVT, with an unknown cause of death. Five patients were lost to follow-up, of which three were managed without CUS in both strategies. The excluded patients had a considerably higher DVT prevalence and higher Wells scores (Table 1). Using the standard algorithm, 45% of the patients had a ‘DVT unlikely’ and 55% a ‘DVT likely’ score, with a DVT prevalence of 11% and 28%. A D-dimer test was Correspondence: Tom van der Hulle, Department of Thrombosis and Hemostasis, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, the Netherlands. Tel.: +31 71 526 8132; fax: +31 71 526 6868. E-mail: t.van_der_hulle@lumc.nl