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• W2008265412 abstract "Summaryd-Dimer measurement is a promising tool in the exclusion of venous thrombosis. New d-dimer assays have been introduced, but need clinical validation. Our objective was to evaluate the clinical usefulness of four relatively new d-dimer assays and a classical ELISA in outpatients suspected for deep venous thrombosis. In 537 patients, participants in a large prospective management study using a clinical probability score and a d-dimer measurement (Tina-quant®), additional samples were taken for d-dimer measurement using the Asserachrom ELISA®, the VIDAS New®, the STA-LIA® and the Miniquant® assay. Performances of each test were calculated using clinical data during a 3-month follow-up. Thrombosis was detected in 224 patients (42%). The area under the ROC curve was significantly higher for the Tina-quant as compared to the other assays. Using standard cut-off values, sensitivity, negative predictive value (NPV) and specificity of the Asserachrom were 97, 94 and 33%, respectively. For the VIDAS New, values were 100, 96 and 8%, respectively. The Tina-quant showed values of 99, 98 and 41%, respectively, and the STA-LIA 98, 95 and 32%. Values for the Miniquant were 95, 94 and 52%. The d-dimer assays in our study all show a high sensitivity and negative predictive value, but none of the assays reached an NPV of > 98% at standard cut-off values. d-Dimer assays with a low specificity still necessitate additional diagnostic tests in the majority of the patients. d-Dimer measurement is a promising tool in the exclusion of venous thrombosis. New d-dimer assays have been introduced, but need clinical validation. Our objective was to evaluate the clinical usefulness of four relatively new d-dimer assays and a classical ELISA in outpatients suspected for deep venous thrombosis. In 537 patients, participants in a large prospective management study using a clinical probability score and a d-dimer measurement (Tina-quant®), additional samples were taken for d-dimer measurement using the Asserachrom ELISA®, the VIDAS New®, the STA-LIA® and the Miniquant® assay. Performances of each test were calculated using clinical data during a 3-month follow-up. Thrombosis was detected in 224 patients (42%). The area under the ROC curve was significantly higher for the Tina-quant as compared to the other assays. Using standard cut-off values, sensitivity, negative predictive value (NPV) and specificity of the Asserachrom were 97, 94 and 33%, respectively. For the VIDAS New, values were 100, 96 and 8%, respectively. The Tina-quant showed values of 99, 98 and 41%, respectively, and the STA-LIA 98, 95 and 32%. Values for the Miniquant were 95, 94 and 52%. The d-dimer assays in our study all show a high sensitivity and negative predictive value, but none of the assays reached an NPV of > 98% at standard cut-off values. d-Dimer assays with a low specificity still necessitate additional diagnostic tests in the majority of the patients. Measurement of the concentration of d-dimers is a promising tool in the non-invasive diagnostic management of patients suspected for having deep venous thrombosis (DVT). Retrospective analyses show a high sensitivity and negative predictive value of d-dimer for the exclusion of venous thromboembolism (VTE) [1Bounameaux H. Schneider P.A. Reber G. De Moerloose P. Krahenbuhl B. Measurement of plasma d-dimer for diagnosis of deep venous thrombosis.Am J Clin Pathol. 1989; 91: 82-5Crossref PubMed Google Scholar, 2Bounameaux H. De Moerloose P. Perrier A. Reber G. Plasma measurement of d-dimer as diagnostic aid in suspected venous thromboembolism: an overview.Thromb Haemost. 1994; 71: 1-6Crossref PubMed Scopus (437) Google Scholar, 3D'Angelo A. D'Alessandro G. Tomassini L. Pittet J.L. Dupuy G. Crippa L. Evaluation of a new rapid quantitative d-dimer assay in patients with clinically suspected deep vein thrombosis.Thromb Haemost. 1996; 75: 412-6Crossref PubMed Scopus (0) Google Scholar, 4Elias A. Aptel I. Huc B. Chalé J.J. Nguyen F. Cambus J.P. Boccalon H. Boneu B. d-Dimer test and diagnosis of deep vein thrombosis. a comparative study of 7 assays.Thromb Haemost. 1996; 76: 518-22Crossref PubMed Scopus (0) Google Scholar, 5Freyburger G. Trillaud H. Labrouche S. Gauthier P. Javorschi S. Bernard P. Grenier N. d-Dimer strategy in thrombosis exclusion – a gold standard study in 100 patients suspected of deep venous thrombosis or pulmonary embolism: 8 DD methods compared.Thromb Haemost. 1998; 79: 32-7Crossref PubMed Google Scholar, 6Fünfsinn N. Caliezi C. Biasiutti F.D. Korte W. Z'Brun A. Baumgartner I. Ulrich M. Cottier C. Lämmle B. Wuillemin W.A. Rapid d-dimer testing and pre-test clinical probability in the exclusion of deep venous thrombosis in symptomatic outpatients.Blood Coagul Fibrinolysis. 2001; 12: 165-70Crossref PubMed Scopus (0) Google Scholar, 7Janssen M.C. Heebels A.E. De Metz M. Verbruggen H. Wollersheim H. Janssen S. Schuurmans M.M. Nováková I.R. Reliability of five rapid d-dimer assays compared to ELISA® in the exclusion of deep venous thrombosis.Thromb Haemost. 1997; 77: 262-6Crossref PubMed Scopus (161) Google Scholar, 8Perrier A. Desmarais S. Miron M.J. De Moerloose P. Lepage R. Slosman D. Didier D. Unger P.F. Patenaude J.V. Bounameaux H. Non-invasive diagnosis of venous thromboembolism in outpatients.Lancet. 1999; 353: 190-5Abstract Full Text Full Text PDF PubMed Scopus (769) Google Scholar, 9Rowbotham B.J. Carroll P. Whitaker A.N. Bunce I.H. Cobcroft R.G. Elms M.J. Masci P.P. Bundesen P.G. Rylatt D.B. Webber A.J. Measurement of crosslinked fibrin derivatives – use in the diagnosis of venous thrombosis.Thromb Haemost. 1987; 57: 59-61Crossref PubMed Scopus (0) Google Scholar, 10Turkstra F. Van Beek E.J. Ten Cate J.W. Büller H.R. Reliable rapid blood test for the exclusion of venous thromboembolism in symptomatic outpatients.Thromb Haemost. 1996; 76: 9-11Crossref PubMed Scopus (116) Google Scholar, 11Wahlander K. Tengborn L. Hellstrom M. Olmarker A.H. Peterson L.E. Stigendal L. Larson G. Comparison of various d-dimer tests for the diagnosis of deep venous thrombosis.Blood Coagul Fibrinolysis. 1999; 10: 121-6Crossref PubMed Google Scholar, 12Wells P.S. Brill-Edwards P. Stevens P. Panju A. Patel A. Douketis J. Massicotte M.P. Hirsh J. Weitz J.I. Kearon C. Ginsberg J.S. A novel and rapid whole-blood assay for d-dimer in patients with clinically suspected deep vein thrombosis.Circulation. 1995; 91: 2184-7Crossref PubMed Google Scholar, 13Van Der Graaf F. Van Den Borne H. Van Der Kolk M. De Wild P.J. Janssen G.W. Van Uum S.H. Exclusion of deep venous thrombosis with d-dimer testing – comparison of 13 d-dimer methods in 99 outpatients suspected of deep venous thrombosis using venography as reference standard.Thromb Haemost. 2000; 83: 191-8Crossref PubMed Google Scholar]. Two management studies have proven the safety of withholding anticoagulants in patients with a normal d-dimer and a normal initial ultrasonography [14Bernardi E. Prandoni P. Lensing A.W. Agnelli G. Guazzaloca G. Scannapieco G. Piovella F. Verlato F. Tomasi C. Moia M. Scarano L. Girolami A. d-Dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study. The Multicentre Italian d-dimer Ultrasound Study Investigators Group.BMJ. 1998; 317: 1037-40Crossref PubMed Google Scholar, 15Kraaijenhagen R.A. Piovella F. Bernardi E. Verlato F. Beckers E.A. Koopman M.M. Barone M. Camporese G. Potter Van Loon B.J. Prins M.H. Prandoni P. Büller H.R. Simplification of the diagnostic management of suspected deep vein thrombosis.Arch Intern Med. 2002; 162: 907-11Crossref PubMed Google Scholar]. Various combinations of pretest clinical probability scores and a normal d-dimer test or even a normal d-dimer alone have been suggested to be accurate enough for the exclusion of VTE [8Perrier A. Desmarais S. Miron M.J. De Moerloose P. Lepage R. Slosman D. Didier D. Unger P.F. Patenaude J.V. Bounameaux H. Non-invasive diagnosis of venous thromboembolism in outpatients.Lancet. 1999; 353: 190-5Abstract Full Text Full Text PDF PubMed Scopus (769) Google Scholar, 16Janes S. Ashford N. Use of a simplified clinical scoring system and d-dimer testing can reduce the requirement for radiology in the exclusion of deep vein thrombosis by over 20%.Br J Haematol. 2001; 112: 1079-82Crossref PubMed Scopus (46) Google Scholar, 17Kearon C. Ginsberg J.S. Douketis J. Crowther M. Brill-Edwards P. Weitz J.I. Hirsh J. Management of suspected deep venous thrombosis in outpatients by using clinical assessment and d-dimer testing.Ann Intern Med. 2001; 135: 108-11Crossref PubMed Google Scholar, 18Anderson D.R. Wells P.S. Stiell I. MacLeod B. Simms M. Gray L. Robinson K.S. Bormanis J. Mitchell M. Lewandowski B. Flowerdew G. Management of patients with suspected deep vein thrombosis in the emergency department: combining use of a clinical diagnosis model with d-dimer testing.J Emerg Med. 2000; 19: 225-30Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 19Kruip M.J. Slob M.J. Schijen J.H. Van Der Heul C. Büller H.R. Use of a clinical decision rule in combination with d-dimer concentration in diagnostic workup of patients with suspected pulmonary embolism: a prospective management study.Arch Intern Med. 2002; 162: 1631-5Crossref PubMed Scopus (169) Google Scholar]. However, the choice for a diagnostic management strategy depends largely upon the reliability of the d-dimer test. Many d-dimer assays are available. The classical enzyme linked immunosorbent assays (ELISA®) are considered to be the golden standard in determining d-dimer [1Bounameaux H. Schneider P.A. Reber G. De Moerloose P. Krahenbuhl B. Measurement of plasma d-dimer for diagnosis of deep venous thrombosis.Am J Clin Pathol. 1989; 91: 82-5Crossref PubMed Google Scholar, 2Bounameaux H. De Moerloose P. Perrier A. Reber G. Plasma measurement of d-dimer as diagnostic aid in suspected venous thromboembolism: an overview.Thromb Haemost. 1994; 71: 1-6Crossref PubMed Scopus (437) Google Scholar, 4Elias A. Aptel I. Huc B. Chalé J.J. Nguyen F. Cambus J.P. Boccalon H. Boneu B. d-Dimer test and diagnosis of deep vein thrombosis. a comparative study of 7 assays.Thromb Haemost. 1996; 76: 518-22Crossref PubMed Scopus (0) Google Scholar, 5Freyburger G. Trillaud H. Labrouche S. Gauthier P. Javorschi S. Bernard P. Grenier N. d-Dimer strategy in thrombosis exclusion – a gold standard study in 100 patients suspected of deep venous thrombosis or pulmonary embolism: 8 DD methods compared.Thromb Haemost. 1998; 79: 32-7Crossref PubMed Google Scholar, 6Fünfsinn N. Caliezi C. Biasiutti F.D. Korte W. Z'Brun A. Baumgartner I. Ulrich M. Cottier C. Lämmle B. Wuillemin W.A. Rapid d-dimer testing and pre-test clinical probability in the exclusion of deep venous thrombosis in symptomatic outpatients.Blood Coagul Fibrinolysis. 2001; 12: 165-70Crossref PubMed Scopus (0) Google Scholar, 7Janssen M.C. Heebels A.E. De Metz M. Verbruggen H. Wollersheim H. Janssen S. Schuurmans M.M. Nováková I.R. Reliability of five rapid d-dimer assays compared to ELISA® in the exclusion of deep venous thrombosis.Thromb Haemost. 1997; 77: 262-6Crossref PubMed Scopus (161) Google Scholar, 9Rowbotham B.J. Carroll P. Whitaker A.N. Bunce I.H. Cobcroft R.G. Elms M.J. Masci P.P. Bundesen P.G. Rylatt D.B. Webber A.J. Measurement of crosslinked fibrin derivatives – use in the diagnosis of venous thrombosis.Thromb Haemost. 1987; 57: 59-61Crossref PubMed Scopus (0) Google Scholar, 13Van Der Graaf F. Van Den Borne H. Van Der Kolk M. De Wild P.J. Janssen G.W. Van Uum S.H. Exclusion of deep venous thrombosis with d-dimer testing – comparison of 13 d-dimer methods in 99 outpatients suspected of deep venous thrombosis using venography as reference standard.Thromb Haemost. 2000; 83: 191-8Crossref PubMed Google Scholar, 20Perrier A. Bounameaux H. Cost-effective diagnosis of deep vein thrombosis and pulmonary embolism.Thromb Haemost. 2001; 86: 475-87Crossref PubMed Scopus (100) Google Scholar, 21Brown M.D. Rowe B.H. Reeves M.J. Bermingham J.M. Goldhaber S.Z. The accuracy of the enzyme-linked immunosorbent assay d-dimer test in the diagnosis of pulmonary embolism: a meta-analysis.Ann Emerg Med. 2002; 40: 133-44Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar], but they are time-consuming and not suitable for emergency use. The early latex assays have too little sensitivity to be used in clinical practice [1Bounameaux H. Schneider P.A. Reber G. De Moerloose P. Krahenbuhl B. Measurement of plasma d-dimer for diagnosis of deep venous thrombosis.Am J Clin Pathol. 1989; 91: 82-5Crossref PubMed Google Scholar, 22Bounameaux H. De Moerloose P. Perrier A. Miron M.J. d-dimer testing in suspected venous thromboembolism: an update.QJM. 1997; 90: 437-42Crossref PubMed Google Scholar] and are replaced by newer latex assays with improved sensitivity and negative predictive value [5Freyburger G. Trillaud H. Labrouche S. Gauthier P. Javorschi S. Bernard P. Grenier N. d-Dimer strategy in thrombosis exclusion – a gold standard study in 100 patients suspected of deep venous thrombosis or pulmonary embolism: 8 DD methods compared.Thromb Haemost. 1998; 79: 32-7Crossref PubMed Google Scholar, 6Fünfsinn N. Caliezi C. Biasiutti F.D. Korte W. Z'Brun A. Baumgartner I. Ulrich M. Cottier C. Lämmle B. Wuillemin W.A. Rapid d-dimer testing and pre-test clinical probability in the exclusion of deep venous thrombosis in symptomatic outpatients.Blood Coagul Fibrinolysis. 2001; 12: 165-70Crossref PubMed Scopus (0) Google Scholar, 10Turkstra F. Van Beek E.J. Ten Cate J.W. Büller H.R. Reliable rapid blood test for the exclusion of venous thromboembolism in symptomatic outpatients.Thromb Haemost. 1996; 76: 9-11Crossref PubMed Scopus (116) Google Scholar, 12Wells P.S. Brill-Edwards P. Stevens P. Panju A. Patel A. Douketis J. Massicotte M.P. Hirsh J. Weitz J.I. Kearon C. Ginsberg J.S. A novel and rapid whole-blood assay for d-dimer in patients with clinically suspected deep vein thrombosis.Circulation. 1995; 91: 2184-7Crossref PubMed Google Scholar, 13Van Der Graaf F. Van Den Borne H. Van Der Kolk M. De Wild P.J. Janssen G.W. Van Uum S.H. Exclusion of deep venous thrombosis with d-dimer testing – comparison of 13 d-dimer methods in 99 outpatients suspected of deep venous thrombosis using venography as reference standard.Thromb Haemost. 2000; 83: 191-8Crossref PubMed Google Scholar, 16Janes S. Ashford N. Use of a simplified clinical scoring system and d-dimer testing can reduce the requirement for radiology in the exclusion of deep vein thrombosis by over 20%.Br J Haematol. 2001; 112: 1079-82Crossref PubMed Scopus (46) Google Scholar, 17Kearon C. Ginsberg J.S. Douketis J. Crowther M. Brill-Edwards P. Weitz J.I. Hirsh J. Management of suspected deep venous thrombosis in outpatients by using clinical assessment and d-dimer testing.Ann Intern Med. 2001; 135: 108-11Crossref PubMed Google Scholar, 23Chunilal S.D. Brill-Edwards P.A. Stevens P.B. Joval J.P. McGinnis J.A. Rupwate M. Ginsberg J.S. The sensitivity and specificity of a red blood cell agglutination d-dimer assay for venous thromboembolism when performed on venous blood.Arch Intern Med. 2002; 162: 217-20Crossref PubMed Google Scholar−25]. The negative predictive value and the sensitivity of the d-dimer assay represent its safety in the exclusion of thrombosis in case of a normal d-dimer. The specificity reflects its clinical usefulness from an economical point of view. A low specificity, which is the result of a lot of false-positive test results, still implies additional diagnostic procedures in the majority of the patients. The purpose of this study is to evaluate the accuracy in terms of sensitivity and negative predictive value and the clinical usefulness in terms of specificity of four relatively new different d-dimer assays (VIDAS New®, Tina-quant®, STA-LIA® and Miniquant®) and a classical ELISA® in symptomatic outpatients suspected for DVT. In total, 537 eligible patients entered the current study. Exclusion criteria were pregnancy, previous deep venous thrombosis in the ipsilateral leg without documentation of recanalization, a concomitant clinical suspicion of pulmonary embolism (PE), the use of unfractionated heparin, low molecular weight heparin or any form of oral anticoagulant in the past month, geographic impossibility for follow-up and life expectancy less than 3 months. The patients participated in a prospective multicentre cohort study in outpatients with suspected DVT [26Schutgens R.E.G. Ackermark P. Haas F.J.L.M. Nieuwenhuis H.K. Peltenburg H.G. Pijlman A.H. Pruijm M. Oltmans R. Kelder J.C. Biesma D.H. Combination of a normal D–dimer concentration and a non-high clinical probability score is a safe strategy to exclude deep venous thrombosis.Circulation. 2003; 107: 593-7Crossref PubMed Scopus (0) Google Scholar] and belonged to two of the four participating centers. Patients were categorized according to their d-dimer concentration (using the Tina-quant®d-dimer assay) and their clinical probability score, according to Wells et al.[27Wells P.S. Anderson D.R. Bormanis J. Guy F. Mitchell M. Gray L. Clement C. Robinson K.S. Lewandowski B. Value of assessment of pretest probability of deep-vein thrombosis in clinical management.Lancet. 1997; 350: 1795-8Abstract Full Text Full Text PDF PubMed Scopus (981) Google Scholar]. In patients with a normal d-dimer concentration and a non-high clinical score, no further testing was done. Patients with a normal d-dimer concentration and a high clinical score underwent a single compression ultrasonography (CUS). In the case of an abnormal d-dimer concentration, serial CUS was performed. Primary outcome was the development of venous thromboembolism (DVT or PE) during a 3-month follow-up period. d-Dimer concentration was measured immediately using the Tina-quant®d-dimer assay (Roche, Mannheim, Germany), which is a fully automated quantitative immunoturbidimetric latex assay adapted for the Integra 700 (Roche, Mannheim, Germany). Additional samples were taken within 2 h of presentation and frozen at −70 °C until further study analysis. The mean storage duration was 724 days (range 75–1296). The other d-dimer determinations were done using the Asserachrom® ELISA® (Diagnostica Stago, Asnières, France), the VIDAS d-dimer New® ELISA (BioMerieux, Marcy l'Etoile, France), the STA-LIA® fully automated quantitative immunoturbidimetric latex assay measured with the STA-R® (Diagnostica Stago) and the Miniquant® fully automated quantitative immunoturbidimetric latex assay measured with the Miniquant™-1 analyzer (Biopool, Umeå, Sweden). All d-dimer assays were performed according to the manufacturer's instructions by technicians who were unaware of the clinical outcomes of the patients. Test results for all d-dimer assays but the Miniquant® are reported as fibrin equivalent units (FEU) mg L−1; results of the Miniquant® are reported as d-dimer equivalent units in mg L−1. The cut-off value as recommended by the manufacturers was 0.5 FEU mg L−1 for the Asserachrom, the VIDAS New, the Tina-quant® and the STA-LIA®d-dimer assays, and 0.25 mg L−1 for the Miniquant® assay. For detection of DVT, ultrasonography using real-time B-mode with compression was done with a 7.5-MHz and/or a 5.0-MHz transducer. Two areas of the leg were examined: the common femoral vein at the inguinal ligament and the popliteal vein at the knee-joint line traced down to the point of the trifurcation of the calf veins. Veins were scanned in the transverse plane only. Lack of compressibility was the sole criterion for an abnormal result; a vein was considered fully compressible if no residual lumen was seen. If a patient was suspected for PE after entering the prospective management study, a ventilation-perfusion scintigraphy was performed using routine methods. A normal scintigraphy ruled out PE, where a high probability scan confirmed the diagnosis. An intermediate probability scintigraphy was followed by pulmonary angiography. Sensitivity, negative predictive value (NPV) and specificity of the five d-dimer assays were calculated in relation to the results of the clinical outcomes, i.e. having venous thromboembolism at presentation or during follow-up. For calculation of 95% confidence intervals (CI), the exact binomial method was used. The Fisher's exact test was used for comparison of the sensitivity, NPV and specificity between the d-dimer assays. Receiver operator characteristics (ROC) curves were constructed by plotting sensitivity (true positive fraction) vs. 1-specificity (false positive fraction) using Analyze-it® Software for Microsoft Excel (Leeds, UK). The area under the curve (AUC) was then calculated and compared using the Hanley and McNeil method [28Hanley J.A. McNeil B.J. A method of comparing the areas under receiver operating characteristic curves derived from the same cases.Radiology. 1983; 148: 839-43Crossref PubMed Google Scholar]. Agreement between two methods to classify a patient having a negative or positive test result was estimated by calculation of the kappa coefficient: a value of > 0.81 represents an excellent concordance, 0.80–0.61 a good concordance, 0.60–0.41 a moderate concordance, 0.40–0.21 a mediocre concordance, 0.20–0 a poor concordance and <0 very poor concordance [29Fermanian J. Mesure de l'accord entre deux juges. Cas qualitatif.Rev Epidem Et. Santé Publications. 1984; 32: 140-7PubMed Google Scholar]. The study population consisted of 537 patients. VTE was diagnosed in 224 patients (prevalence 42%): 210 patients had DVT at presentation, 11 patients had DVT detected by the second CUS, and three developed VTE during follow-up (one DVT and two PE). Both cases of PE were detected by ventilation-perfusion scintigraphy. Figure 1 shows the ROC curves displaying sensitivity and specificity for the different d-dimer assays at different cut-off levels. Using the Asserachrom ELISA® as the reference test, the AUC of the VIDAS, STA-LIA® and Miniquant® assays were not different (P = 0.6, P= 0.8 and P= 0.1, respectively) (Table 1). The AUC of the Tina-quant® was significantly higher compared with the other assays; P= 0.003 for comparison with the Asserachrom, P= 0.004 with the VIDAS, P < 0.0001 with the STA-LIA® and P= 0.01 with the Miniquant®.Table 1Comparison of the area under ROC curves (AUC) for the five d-dimer assays, reported as P-valuesAUC (95% CI)VIDAS NewTina-quantSTA-LIAMiniquantAsserachrom0.879 (0.850–0.908)0.60.0030.80.1VIDAS New0.887 (0.859–0.916)0.0040.70.2Tina-quant0.922 (0.900–0.945)<0.00010.01STA-LIA0.883 (0.854–0.911)0.07Miniquant0.902 (0.874–0.930) Open table in a new tab The performance of the different d-dimer assays is given in Table 2, showing sensitivity, NPV and specificity with 95% confidence intervals according to different cut-off values for each assay. Given the cut-off values as recommended by the manufacturers, all d-dimer assays had a sensitivity of 95% or higher and an NPV of 94% or higher. The highest NPV (98%) was seen with the Tina-quant®; this was not significantly different as compared to the Asserachrom (P = 0.08), the VIDAS New® (P = 0.4) and the STA-LIA® (P = 0.2), but higher as compared to the Miniquant® (P = 0.047). The highest sensitivity (100%) was seen with the VIDAS New® assay: this was not statistically different as compared to the Asserachrom (P = 0.07), the Tina-quant® (P = 1.0) and the STA-LIA® (P = 0.2), but higher as compared to the Miniquant® (P = 0.006). Sensitivity of the Miniquant® (95%) was lower as compared to the Tina-quant® (P = 0.02). By changing the cut-off values, only in the Tina-quant® an NPV of 100% could be reached. Slight (not statistically significant) improvements of the NPV were seen in the Asserachrom and STA-LIA® assays by lowering the cut-off values, but they led to significant reductions in specificity. A low specificity was seen for the VIDAS New®d-dimer assay: its specificity of 8% was lower than the other d-dimer assays that showed values of 32–52% (P < 0.0001 when compared to the Asserachrom). The number of patients with a negative VIDAS New®d-dimer test result was 27/537 as compared to 110/537 negative Asserachrom tests (P < 0.0001), 131/537 negative Tina-quant® tests (P < 0.0001), 106/537 negative STA-LIA® tests (P < 0.0001) and 174/537 negative Miniquant® tests (P < 0.0001).Table 2Clinical performance of the different d-dimer assays. Values are reported as percentage and their 95% confidence intervals. Cut-off values as recommended by the manufacturers have been given in boldd-Dimer assayCut-off value (mg L−1)SensitivityNegative predictive valueSpecificityAsserachrom1.0 FEU88 (84–93)89 (85–93)68 (63–73)0.5 FEU97 (94–99)94 (87–97)33 (28–38)0.4 FEU99 (96–100)96 (89–99)24 (20–29)0.3 FEU99 (97–100)96 (85–99)13 (10–17)0.2 FEU100 (98–100)95 (75–100)6 (4–9)VIDAS New1.0 FEU98 (96–100)96 (90–99)29 (24–34)0.5 FEU100 (98–100)96 (81–100)8 (6–12)0.4 FEU100 (98–100)93 (66–100)4 (2–7)0.3 FEU100 (98–100)88 (47–100)2 (1–5)0.2 FEU100 (98–100)0 (0–100)0 (0–12)Tina-quant1.0 FEU93 (89–96)94 (90–96)70 (65–75)0.5 FEU99 (97–100)98 (95–100)41 (36–47)0.4 FEU100 (98–100)99 (94–100)31 (26–36)0.3 FEU100 (98–100)100 (94–100)18 (14–22)0.2 FEU100 (98–100)100 (74–100)4 (2–7)STA-LIA1.0 FEU94 (90–97)93 (89–96)60 (55–66)0.5 FEU98 (95–99)95 (89–99)32 (27–37)0.4 FEU99 (97–100)98 (91–100)25 (20–30)0.3 FEU100 (98–100)98 (89–100)15 (11–19)0.2 FEU100 (98–100)–0 (0–1)Miniquant0.590 (86–94)91 (86–94)72 (67–77)0.2595 (91–98)94 (89–97)52 (47–58)0.296 (93–98)94 (88–97)43 (37–48)0.1595 (91–97)93 (87–97)35 (29–40)0.198 (96–100)93 (83–98)17 (13–21) Open table in a new tab Table 3 shows the kappa coefficients between the five d-dimer assays. The concordance of the Asserachrom with the Tina-quant® and the STA-LIA® is good, with the Miniquant® moderate and with the VIDAS New® mediocre. The concordance of the VIDAS New® with the other d-dimer assays was mediocre or worse. Concordance between the Tina-quant, STA-LIA® and Miniquant® was good.Table 3Kappa coefficients between the five d-dimer assaysVIDAS NewTina-quantSTA-LIAMiniquantAsserachrom0.330.630.700.59VIDAS New0.240.310.18Tina-quant0.700.72STA-LIA0.62For the calculation of the accuracy indices, quantitative d-dimer results lower than the cut-off value were considered to be negative. Cut-off values for the Asserachrom, VIDAS New, Tina-quant® and STA-LIA® were 0.5 FEU mg L−1. The cut-off value for the Miniquant® was 0.25 d-dimer equivalent units mg L−1. Open table in a new tab For the calculation of the accuracy indices, quantitative d-dimer results lower than the cut-off value were considered to be negative. Cut-off values for the Asserachrom, VIDAS New, Tina-quant® and STA-LIA® were 0.5 FEU mg L−1. The cut-off value for the Miniquant® was 0.25 d-dimer equivalent units mg L−1. The diagnostic strategy in patients suspected for DVT or PE is being challenged by the development of highly sensitive d-dimers and the revival of the pretest clinical probability score. Recent studies have demonstrated the safety of withholding anticoagulant treatment in patients with a normal d-dimer and a normal single ultrasound [14Bernardi E. Prandoni P. Lensing A.W. Agnelli G. Guazzaloca G. Scannapieco G. Piovella F. Verlato F. Tomasi C. Moia M. Scarano L. Girolami A. d-Dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study. The Multicentre Italian d-dimer Ultrasound Study Investigators Group.BMJ. 1998; 317: 1037-40Crossref PubMed Google Scholar, 15Kraaijenhagen R.A. Piovella F. Bernardi E. Verlato F. Beckers E.A. Koopman M.M. Barone M. Camporese G. Potter Van Loon B.J. Prins M.H. Prandoni P. Büller H.R. Simplification of the diagnostic management of suspected deep vein thrombosis.Arch Intern Med. 2002; 162: 907-11Crossref PubMed Google Scholar]. Even the combination of a low clinical score and a normal d-dimer concentration can be considered a safe strategy to exclude thrombosis and to withhold anticoagulant therapy in patients suspected for venous thromboembolism [8Perrier A. Desmarais S. Miron M.J. De Moerloose P. Lepage R. Slosman D. Didier D. Unger P.F. Patenaude J.V. Bounameaux H. Non-invasive diagnosis of venous thromboembolism in outpatients.Lancet. 1999; 353: 190-5Abstract Full Text Full Text PDF PubMed Scopus (769) Google Scholar, 15Kraaijenhagen R.A. Piovella F. Bernardi E. Verlato F. Beckers E.A. Koopman M.M. Barone M. Camporese G. Potter Van Loon B.J. Prins M.H. Prandoni P. Büller H.R. Simplification of the diagnostic management of suspected deep vein thrombosis.Arch Intern Med. 2002; 162: 907-11Crossref PubMed Google Scholar, 16Janes S. Ashford N. Use of a simplified clinical scoring system and d-dimer testing can reduce the requirement for radiology in the exclusion of deep vein thrombosis by over 20%.Br J Haematol. 2001; 112: 1079-82Crossref PubMed Scopus (46) Google Scholar, 17Kearon C. Ginsberg J.S. Douketis J. Crowther M. Brill-Edwards P. Weitz J.I. Hirsh J. Management of suspected deep venous thrombosis in outpatients by using clinical assessment and d-dimer testing.Ann Intern Med. 2001; 135: 108-11Crossref PubMed Google Scholar, 19Kruip M.J. Slob M.J. Schijen J.H. Van Der Heul C. Büller H.R. Use of a clinical decision rule in combination with d-dimer concentration in diagnostic workup of patients with suspected pulmonary embolism: a prospective management study.Arch Intern Med. 2002; 162: 1631-5Crossref PubMed Scopus (169) Google Scholar, 30Cornuz J. Ghali W.A. Hayoz D. Stoianov R. Depairon M. Yersin B. Clinical prediction of deep venous thrombosis using two risk assessment methods in combination with rapid quantitative d-dimer testing.Am J Med. 2002; 112: 198-203Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 31Wells P.S. Anderson D.R. Rodger M. Stiell I. Dreyer J.F. Barnes D. Forgie M. Kovacs G. Ward J. Kovacs M.J. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and d-dimer.Ann Intern Med. 2001; 135: 98-107Crossref PubMed Google Scholar, 32Wells P.S. Anderson D.R. Rodger M. Ginsberg J.S. Kearon C. Gent M. Turpie A.G. Bormanis J. Weitz J. Chamberlain M. Bowie D. Barnes D. Hirsh J. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED d-dimer.Thromb Haemost. 2000; 83: 416-20Crossref PubMed Google Scholar]. When trying to replace accepted strategies like venography or serial ultrasound, their failure rates of, respectively, 1.3% [33Hull R. Hirsh J. Sackett D.L. Taylor D.W. Carter C. Turpie A.G. Powers P. Gent M. Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis.Circulation. 1981; 64: 622-5Crossref PubMed Google Scholar] and 0.6–0.7% [34Birdwell B.G. Raskob G.E. Whitsett T.L. Durica S.S. Comp P.C. George J.N. Tytle T.L. McKee P.A. The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis.Ann Intern Med. 1998; 128: 1-7Crossref PubMed Google Scholar, 35Cogo A. Lensing A.W. Koopman M.M. Piovella F. Siragusa S. Wells P.S. Villalta S. Büller H.R. Turpie A.G. Prandoni P. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study.BMJ. 1998; 316: 17-20Crossref PubMed Google Scholar] may not be exceeded by the new diagnostic strategy. Therefore, a highly sensitive d-dimer test is mandatory for the exclusion of thrombosis in every new diagnostic strategy. Differences between d-dimer assays are thought to be caused by antibody specificity, especially concerning the preference for high- or low-molecular-weight fibrin derivates and for cross-linked and non-cross-linked fibrin derivates [36Dempfle C. Schraml M. Besenthal I. Hansen R. Gehrke J. Korte W. Risch M. Quehenberger P. Handler S. Minar E. Schulz I. Zerback R. The Fibrin Assay Comparison Trial (FACT): evaluation of 23 quantitative d-dimer assays as basis for the development of d-dimer calibrators. FACT Study Group.Thromb Haemost. 2001; 85: 671-8Crossref PubMed Google Scholar]. Other causes of discrepancies between d-dimer assays are time-dependent of neo-epitope expression in the course of fibrin formation and dissolution, assay format, purity or heterogeneity of the calibrator, matrix effects of plasma on epitope presentation and interference by irrelevant analytes [37Ellis D.R. Eaton A.S. Plank M.C. Butman B.T. Ebert R.F. A comparative evaluation of ELISAs for d-dimer and related fibrin(ogen) degradation products.Blood Coagul Fibrinolysis. 1993; 4: 537-49Crossref PubMed Google Scholar]. In our study, ROC curve analysis showed a significantly higher AUC for the Tina-quant®d-dimer assay as compared to the other four assays. At standard cut-off values, the Tina-quant® also had the highest NPV with 98% (although not statistically different), with a high sensitivity of 99%. The performance of the Tina-quant® in our study was comparable with previous reports [1Bounameaux H. Schneider P.A. Reber G. De Moerloose P. Krahenbuhl B. Measurement of plasma d-dimer for diagnosis of deep venous thrombosis.Am J Clin Pathol. 1989; 91: 82-5Crossref PubMed Google Scholar, 5Freyburger G. Trillaud H. Labrouche S. Gauthier P. Javorschi S. Bernard P. Grenier N. d-Dimer strategy in thrombosis exclusion – a gold standard study in 100 patients suspected of deep venous thrombosis or pulmonary embolism: 8 DD methods compared.Thromb Haemost. 1998; 79: 32-7Crossref PubMed Google Scholar, 13Van Der Graaf F. Van Den Borne H. Van Der Kolk M. De Wild P.J. Janssen G.W. Van Uum S.H. Exclusion of deep venous thrombosis with d-dimer testing – comparison of 13 d-dimer methods in 99 outpatients suspected of deep venous thrombosis using venography as reference standard.Thromb Haemost. 2000; 83: 191-8Crossref PubMed Google Scholar]. Using standard cut-off values, the Miniquant® reached a sensitivity of 95% with an NPV of 94%, which is comparable with previous reports [38Gosselin R.C. Owings J.T. Utter G.H. Jacoby R.C. Larkin E.C. A new method for measuring d-dimer using immunoturbidometry: a study of 255 patients with suspected pulmonary embolism and deep vein thrombosis.Blood Coagul Fibrinolysis. 2000; 11: 715-21Crossref PubMed Scopus (0) Google Scholar, 39Shitrit D. Levi H. Huerta M. Rudensky B. Bargil-Shitrit A. Gutterer N. Appropriate indications for venous duplex scanning based on d-dimer assay.Ann Vasc Surg. 2002; 16: 304-8Abstract Full Text PDF PubMed Scopus (12) Google Scholar, 40Shitrit D. Heyd J. Raveh D. Rudensky B. Diagnostic value of the d-dimer test in deep vein thrombosis: improved results by a new assay method and by using discriminate levels.Thromb Res. 2001; 102: 125-31Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. It had significant lower values of sensitivity and NPV as compared to the Tina-quant® and a significant lower sensitivity as compared to the VIDAS New®. Results of the STA-LIA® assay showed a high sensitivity of 98% and NPV of 95%. This is higher than a previous report that found a sensitivity of 89% and NPV of 86% [41Bucek R.A. Quehenberger P. Feliks I. Handler S. Reiter M. Minar E. Results of a new rapid d-dimer assay (cardiac d-dimer) in the diagnosis of deep vein thrombosis.Thromb Res. 2001; 103: 17-23Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar] but comparable with other reports [42Duet M. Benelhadj S. Kedra W. Vilain D. Ajzenberg C. Elkharrat D. Drouet L. Soria C. Mundler O. A new quantitative d-dimer assay appropriate in emergency: reliability of the assay for pulmonary embolism exclusion diagnosis.Thromb Res. 1998; 91: 1-5Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 43Escoffre-Barbe M. Oger E. Leroyer C. Grimaux M. Le Moigne E. Nonent M. Bressollette L. Abgrall J.F. Soria C. Amiral J. Ill P. Clavier J. Mottier D. Evaluation of a new rapid d-dimer assay for clinically suspected deep venous thrombosis (Liatest d-dimer).Am J Clin Pathol. 1998; 109: 748-53Crossref PubMed Scopus (0) Google Scholar, 44Oger E. Leroyer C. Bressollette L. Nonent M. Le Moigne E. Bizais Y. Amiral J. Grimaux M. Clavier J. Ill P. Abgrall J.F. Mottier D. Evaluation of a new, rapid, and quantitative D-Dimer test in patients with suspected pulmonary embolism.Am J Respir Crit Care Med. 1998; 158: 65-70Crossref PubMed Google Scholar]. The VIDAS New® had an excellent sensitivity of 100% and an NPV of 96%, which was better than a previous report [45Larsen T.B. Stoffersen E. Christensen C.S. Laursen B. Validity of d-dimer tests in the diagnosis of deep vein thrombosis: a prospective comparative study of three quantitative assays.J Intern Med. 2002; 252: 36-40Crossref PubMed Scopus (0) Google Scholar] but comparable with a study from de Moerloose et al. [46De Moerloose P. Bounameaux H. Perrier A. Reber G. Performances of the VIDAS d-dimer new assay for the exclusion of venous thromboembolism.Thromb Haemost. 2001; 85: 185-6Crossref PubMed Scopus (36) Google Scholar]. It is well known that the d-dimer tests have positive results in case of various comorbid conditions, such as infections and malignancy. Due to these frequent false-positive test results, the specificity of the d-dimer is low. It is the specificity that determines the usefulness of the d-dimer as an exclusion criterion for thrombosis. A low specificity of a d-dimer implies that CUS will still be necessary in the majority of the patients. Although the sensitivity and NPV of the VIDAS New® were high, a remarkably low specificity of 8% was found. This low specificity is in disagreement with two previous reports on the VIDAS New®[45Larsen T.B. Stoffersen E. Christensen C.S. Laursen B. Validity of d-dimer tests in the diagnosis of deep vein thrombosis: a prospective comparative study of three quantitative assays.J Intern Med. 2002; 252: 36-40Crossref PubMed Scopus (0) Google Scholar, 46De Moerloose P. Bounameaux H. Perrier A. Reber G. Performances of the VIDAS d-dimer new assay for the exclusion of venous thromboembolism.Thromb Haemost. 2001; 85: 185-6Crossref PubMed Scopus (36) Google Scholar] that found a specificity of 42% and 33%, respectively, at the same cut-off level. Furthermore, the kappa coefficients of the VIDAS New® compared to the other four assays were mediocre to poor. This is in disagreement with the kappa coefficients for the original VIDAS compared to the STA-LIA®, Asserachrom and Tina-quant® as found by van der Graaf et al. [13Van Der Graaf F. Van Den Borne H. Van Der Kolk M. De Wild P.J. Janssen G.W. Van Uum S.H. Exclusion of deep venous thrombosis with d-dimer testing – comparison of 13 d-dimer methods in 99 outpatients suspected of deep venous thrombosis using venography as reference standard.Thromb Haemost. 2000; 83: 191-8Crossref PubMed Google Scholar]. As the VIDAS New® assay is fully automated and not dependent on technician skills, it is not likely that variables in the analytic process have lead to the large number of false-positive results in our study. A previous report has seen no effect of transportation or storage at room temperature on the results of the VIDAS d-dimer assay [47Caliezi C. Reber G. Lämmle B. De Moerloose P. Wuillemin W.A. Agreement of d-dimer results measured by a rapid ELISA® (VIDAS) before and after storage during 24h or transportation of the original whole blood samples.Thromb Haemost. 2000; 83: 177-8Crossref PubMed Scopus (12) Google Scholar]. We showed recently that freezing of samples or type of chemical analyzer had no influence on d-dimer concentration [48Schutgens R.E. Haas F.J. Ruven H.J. Spannagl M. Horn K. Biesma D.H. No influence of heparin plasma and other (pre) analytic variables on d-dimer determinations.Clin Chem. 2002; 48: 1611-3Crossref PubMed Scopus (15) Google Scholar]. A considerable improvement of the performance of the VIDAS New® was achieved after raising the cut-off level to 1.0 FEU mg L−1, resulting in a sensitivity of 98%, an NPV of 96%, and a specificity of 29%. The d-dimer assays in our study all showed generally high sensitivity and NPV. In general, the sensitivity could be improved by lowering the cut-off values, but the subsequent decrease in specificity makes the assays less useful in clinical practice. Despite changes in cut-off values none of the tests reached an NPV of > 98%, except for the Tina-quant. Using standard cut-off values, none of the tests reached an NPV of > 98%. When the use of d-dimer is restricted to patients with a low clinical probability score only, it has been shown for the SimpliRed® and Tina-quant® assay that the NPV of the d-dimer assay will further increase [18Anderson D.R. Wells P.S. Stiell I. MacLeod B. Simms M. Gray L. Robinson K.S. Bormanis J. Mitchell M. Lewandowski B. Flowerdew G. Management of patients with suspected deep vein thrombosis in the emergency department: combining use of a clinical diagnosis model with d-dimer testing.J Emerg Med. 2000; 19: 225-30Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 26Schutgens R.E.G. Ackermark P. Haas F.J.L.M. Nieuwenhuis H.K. Peltenburg H.G. Pijlman A.H. Pruijm M. Oltmans R. Kelder J.C. Biesma D.H. Combination of a normal D–dimer concentration and a non-high clinical probability score is a safe strategy to exclude deep venous thrombosis.Circulation. 2003; 107: 593-7Crossref PubMed Scopus (0) Google Scholar, 30Cornuz J. Ghali W.A. Hayoz D. Stoianov R. Depairon M. Yersin B. Clinical prediction of deep venous thrombosis using two risk assessment methods in combination with rapid quantitative d-dimer testing.Am J Med. 2002; 112: 198-203Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar]. It is therefore to be expected that the combination of a clinical probability score and the other d-dimer tests from our study will also increase the NPV and be a safe strategy to exclude DVT in outpatients. In conclusion, the d-dimer assays in our study all show a high sensitivity and negative predictive value. However, using standard cut-off values, none of the assays reached an NPV of > 98%. For exclusion of DVT, we therefore recommend combining the d-dimer assay with other non-invasive tests in order to reach failure rates less than 1.0%. The use of d-dimer assays with a very low specificity might not be worthwhile from an economical point of view, as a positive test will necessitate additional testing in the majority of the patients." @default.
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