Portal de Periódicos da CAPES

Carta Acesso aberto Produção Nacional Revisado por pares

BIBTEX RIS

Clinical significance of a negative D‐dimer level in patients with confirmed venous thromboembolism. Findings from the RIETE Registry

2010; Elsevier BV; Volume: 9; Issue: 2 Linguagem: Inglês

10.1111/j.1538-7836.2010.04143.x

1538-7933

M.J. Soto, E Grau, Telma Gadelha, Gualtiero Palareti, H Bounameaux, J Villalta, Manuel Monréal,

Diagnosis and Treatment of Venous Diseases

Although it is unusual, some patients with acute venous thromboembolism (VTE) may test negative for D‐dimer [1Righini M. Perrier A. de Moerloose P. Bounameaux H. D‐dimer for venous thromboembolism diagnosis: twenty years after.J Thromb Haemost. 2008; 6: 1059-71Crossref PubMed Scopus (274) Google Scholar]. The sensitivity of D‐dimer testing for suspected VTE can be limited not only by the choice of the appropriate assay but also by some patient characteristics [2Dempfle C.E. Zips S. Ergul H. Heene D.L. Fibrin Assay Comparative Trial study groupThe 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 Scopus (127) Google Scholar, 3Schutgens R.E.G. Haas F.J.L.M. Biesma D.H. Reduced efficacy of clinical probability score and D‐dimer assay in elderly subjects suspected of having deep vein thrombosis.Br J Haematol. 2005; 129: 653-7Crossref PubMed Scopus (41) Google Scholar]. Using data from the RIETE Registry [4Lobo J.L. Zorrilla V. Aizpuru F. Grau E. Jiménez D. Palareti G. Monreal M. RIETE InvestigatorsD‐dimer levels and 15‐day outcome in acute pulmonary embolism. Findings from the RIETE Registry.J Thromb Haemost. 2009; 7: 1795-801Crossref PubMed Scopus (53) Google Scholar], we compared the sensitivities of different assays in, and the clinical characteristics of, VTE patients with negative D‐dimer findings at baseline and those who tested positive. D‐dimer testing was not routinely performed in RIETE, and the analyses were performed according to each hospital protocol. Patients were classified as having positive or negative test results, with the use of standard thresholds. Then, their clinical characteristics were compared. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated for categorical variables. The influence of a number of variables on the D‐dimer test result was tested with a chi‐square test for categorical variables, and with Student’s t‐test for continuous variables. A multivariate analysis was then carried out, with a forward stepwise logistic regression analysis. All analyses were performed with spss (version 16.0) for Windows, 2008 (SPSS, Chicago, IL, USA). Up to May 2009, 17 138 consecutive patients with objectively proven acute VTE underwent D‐dimer testing on admission. Of these, 742 (4.3%) tested negative. The pooled sensitivity of the various D‐dimer assays was 95.7% (95% CI 95.4–96.0), with some variation between the assays (Table 1). Whereas four assays (Vidas D‐dimer, IL Test D‐dimer, STA‐Liatest D‐D and Auto Dimertest Micro) exhibited a sensitivity > 96%, three other assays (Dimertest Latex, D‐Di Test and D‐Dimer Plus) had a sensitivity of < 90%.Table 1Sensitivity of different assays in the diagnosis of venous thromboembolism (only those used in at least 200 patients were considered)Patients, NPatients, positiveSensitivity (95% CI)IL Test D‐dimer (Instrumental Laboratory Spa, Milan, Italy)5263509896.9 (96.4–97.3)STA‐Liatest D‐D (Diagnostica Stago, Parsippany, NJ, USA)3440334697.3 (96.7–97.8)VIDAS D‐dimer (Biomerieux, Marcy l'Etoile, France)2477241897.6 (97.0–98.2)D‐Dimer Plus (Dade Behring, Marburg, Germany)1693150388.8 (87.3–90.3)Turbiquant D‐dimer (Dade Berhing)97593595.9 (94.7–97.1)Auto Dimertest Micro (Agen Biomedical, Melbourne, Australia)40840699.5 (98.8–100)Dimertest Latex (Agen Biomedical/Dade Behring)36432388.7 (85.5–92.0)Dimertest Gold EIA (Agen Biomedical)26725394.8 (92.1–97.4)NycoCard (Nycomed Pharma, Madrid, Spain)25423090.6 (87.0–94.1)D‐Di Test (Diagnostica Stago)24820783.5 (78.8–88.1)Other1749167795.9 (95.0–96.8)All patients171381639695.7 (95.4–96.0)CI, confidence interval. Open table in a new tab CI, confidence interval. VTE patients with negative D‐dimer test results were more often male, were significantly younger, were less likely to have cancer, recent immobility, recent bleeding or abnormal creatinine levels, and presented more often with deep vein thrombosis (DVT) alone (instead of pulmonary embolism) than those who tested positive (Table 2). Among patients presenting with DVT alone, distal (below‐knee) DVT was twice as frequent and upper‐extremity DVT three times more frequent than in patients with a positive D‐dimer test result. On multivariate analysis, among VTE patients, age < 70 years (OR 2.0; 95% CI 1.7–2.5) and initial presentation with DVT alone (OR 2.0; 95% CI 1.7–2.5) were independently associated with a higher risk for testing negative, whereas patients with active cancer (OR 0.8; 95% CI 0.6–0.9), recent bleeding (OR 0.4; 95% CI 0.2–0.96) or abnormal creatinine levels (OR 0.7; 95% CI 0.5–0.9) were at lower risk.Table 2Clinical characteristics of the 17 138 patients with acute venous thromboembolism (VTE), according to D‐dimer testingNegative N = 742 (%)Positive N = 16396 (%)P‐valueClinical characteristicsGender (males)396 (53)7939 (48)0.008Age < 70 years469 (63)7431 (45)< 0.001Body weight < 70 kg225 (30)5740 (35)0.009Inpatients171 (24)3955 (24)0.646Risk factors for VTEPrevious VTE132 (18)2498 (15)0.059Cancer99 (13)2977 (18)0.001Surgery87 (12)1881 (12)0.833Immobility ≥ 4 days146 (20)3814 (23)0.023Pregnancy8 (5.1)110 (3.9)0.449Estrogen therapy28 (3.8)644 (4.0)0.809Long‐term travel20 (2.8)354 (2.2)0.305None of the above311 (42)6280 (38)0.048Underlying diseasesRecent major bleeding5 (0.7)300 (1.8)0.020Chronic lung disease82 (11)1319 (9.9)0.294Chronic heart failure37 (5.0)964 (5.9)0.310Abnormal creatinine levels62 (8.4)2473 (15)< 0.001VTE characteristicsClinically overt PE242 (33)8454 (52)< 0.001In patients with DVTDistal DVT136 (32)1179 (16)< 0.001Upper‐extremity DVT60 (12)289 (3.7)< 0.001DVT, deep vein thrombosis; PE, pulmonary embolism. Open table in a new tab DVT, deep vein thrombosis; PE, pulmonary embolism. Several studies have shown that negative D‐dimer test results have the potential to exclude VTE in patients with a low clinical probability of VTE [5Wells 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 model’s utility with the SimpliRED D‐dimer.Thromb Haemost. 2000; 83: 416-20Crossref PubMed Scopus (1337) Google Scholar, 6Stein P.D. Hull R.D. Patel K.C. Olson R.E. Ghali W.A. Brant R. Biel R.K. Bharadia V. Kalra N.K. D‐dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review.Ann Intern Med. 2004; 140: 589-602Crossref PubMed Scopus (660) Google Scholar]. However, in those with a high clinical probability of VTE, a negative D‐dimer result does not exclude the diagnosis [7Arnason T. Wells P.S. Forster A.J. Appropriateness of diagnostic strategies for evaluating suspected venous thromboembolism.Thromb Haemost. 2007; 97: 195-201Crossref PubMed Scopus (40) Google Scholar]. Our findings confirm that D‐dimer testing alone is not sensitive enough to rule out VTE. Indeed, one in every 23 patients with symptomatic, objectively confirmed, acute VTE tested negative. Exclusion is only possible in association with a low (less sensitive D‐dimer assays) or low–intermediate (highly sensitive assays) prior clinical probability [8Ceriani E. Combescure C. Le Gal G. Nendaz M. Perneger T. Bounameaux H. Perrier A. Righini M. Clinical prediction rules for pulmonary embolism: a systematic review and meta‐analysis.J Thromb Haemost. 2010; 8: 957-70Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar]. As expected, there was some variation among the different D‐dimer assays, but the mean sensitivity for each test was consistent with previous reports, and the overall sensitivity was 95.7% [9Galle C. Papazyan J.P. Miron M.J. Slosman D. Bounameaux H. Perrier A. Prediction of pulmonary embolism extent by clinical findings, D‐dimer level and deep vein thrombosis shown by ultrasound.Thromb Haemost. 2001; 86: 1156-60Crossref PubMed Scopus (76) Google Scholar, 10De Monye W. Sanson B.J. MacGillavry M.R. Pattynama P.M. Büller H.R. van den Berg‐Huysmans A.A. Huisman M.V. ANTELOPE Study GroupEmbolus location affects the sensitivity of a rapid quantitative D‐dimer assay in the diagnosis of pulmonary embolism.Am J Respir Crit Care Med. 2002; 165: 345-8Crossref PubMed Scopus (100) Google Scholar]. Even with some highly sensitive assays (such as the Vidas assay), the sensitivity was below 98%, if the final diagnosis of VTE was accepted as the reference standard. Only a second‐generation latex agglutination test, the Auto Dimertest Micro (Agen Biomedical), exhibited a sensitivity over 98%. Unfortunately, it was performed in a small proportion of patients, and the 95% CIs do largely overlap. In contrast, one of the less sensitive assays (D‐Dimer Plus) was the fourth most frequently used (in 1693 patients). Several investigators have previously found a lower specificity of D‐dimer testing in elderly patients, and in those with cancer, recent bleeding or renal insufficiency [11Karami‐Djurabi R. Klok F.A. Kooiman J. Velthuis S.I. Nijkeuter M. Huisman M.V. D‐dimer testing in patients with suspected pulmonary embolism and impaired renal function.Am J Med. 2009; 122: 1050-3Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 12Douoma R.A. Le Gal G. Söhne M. Righini M. Kamphuisen P.W. Perrier A. Kruip M.J.H.A. Bounameaux H. Büller H.R. Roy P.M. Potential of an age‐adjusted D‐dimer cut‐off value to improve the exclusion of pulmonary embolism in older patients: a retrospective analysis of three large cohorts.BMJ. 2010; 340: c1475Crossref Scopus (251) Google Scholar]. Our findings confirm and extend these observations. In fact, in these clinical settings, the usefulness of D‐dimer testing is very limited. Overall, our findings suggest that negative D‐dimer levels should be interpreted with caution in some patients (such as those with suspected arm DVT), in order to avoid false‐negative results. Our findings also emphasize the need to associate the D‐dimer result with a previously assessed clinical probability, in order to reduce the number of false‐negative test results, especially when less sensitive assays are used. This study has several limitations. First, although consecutive patients were enrolled in RIETE, not all patients in the registry had a D‐dimer sample drawn, which means that we cannot exclude the possibility of selection bias with respect to D‐dimer testing. Although this limits the nature of the conclusions that can be drawn, data captured and reported in the registry reflect ‘real‐world’ practices and outcomes in the treatment of VTE. Enrolled patients were treated according to standard practice, and prospective follow‐up was completed for all patients. Objective criteria were strictly applied for the diagnosis of initial and recurrent VTE, along with quality control and audit measures. Second, we cannot exclude the possibility that the patients who tested negative for D‐dimer and were subsequently diagnosed with VTE were at particularly high risk of having the disease (corresponding to a high clinical probability), and were therefore unduly submitted to imaging, irrespective of the D‐dimer test result. Finally, a wide variety of D‐dimer assays were used in different centers, under different conditions, and it is well established that the operating characteristics of D‐dimer assays vary significantly. A negative D‐dimer finding with an assay that has a very high sensitivity is more likely to be a true‐negative result than a negative D‐dimer finding with a less sensitive assay. Consequently, the characteristics of the patients who have false‐negative results are likely to differ as well. We express our gratitude to Sanofi‐Aventis Spain for supporting this Registry with an unrestricted educational grant. We also express our gratitude to Bayer Schering Pharma for supporting this Registry. Bayer Schering Pharma’s support was limited to the international part of RIETE (excluding patients from Spain), which accounts for 11.94% of the total patients included in the RIETE Registry. We thank the Registry Coordinating Center, S&H Medical Science Service, for quality control, and S. Ortiz, Universidad Autónoma de Madrid and Statistical Advisor S&H Medical Science Service for statistical analysis of the data presented in this article. Coordinator of the RIETE Registry: M. Monreal (Spain). RIETE Steering Committee Members: H. Decousus (France), P. Prandoni (Italy), and B. Brenner (Israel). RIETE National Coordinators: R. Barba (Spain), P. Di Micco (Italy), K. Rivron‐Guillot (France), M. Bosevski (R. Macedonia), and H. Bounameaux (Switzerland). RIETE Registry Coordinating Center: S&H Medical Science Service. Spain: J. I. Arcelus, R. Barba, A. Blanco, M. Barrón, I. Casado, J. M. Casas, E. Cisneros, E. Chaves, J. del Toro, M. Durán, C. Falgá, C. Fernández‐Capitán, F. Gabriel, P. Gallego, F. García‐Bragado, S. Gómez‐Zorilla, E. Grau, R. Guijarro, M. Guil, J. Gutiérrez, M. R. Gutiérrez, L. Hernández, D. Hernández‐Huerta, M. Jiménez, M. P. Jiménez, J. M. Lasso, J. L. Lobo, L. López, A. Lorenzo, J. M. Luque, M. Lladó, O. Madridano, P. J. Marchena, J. J. Martín‐Villasclaras, M. Monreal, M. Morales, M. D. Nauffal, J. A. Nieto, M. J. Núñez, M. Oribe, J. M. Pedrajas, L. Pérez‐Jiménez, R. Rabuñal, A. Riera‐Mestre, M. A. Rodríguez, V. Roldán, P. Román, V. Rosa, S. Rubio, A. Ruiz‐Gamietea, N. Ruíz‐Giménez, J. C. Sahuquillo, A. Samperiz, J. F. Sánchez Muñoz‐Torrero, X. Solanich, S. Soler, M. J. Soto, G. Tiberio, J. A. Todolí, C. Tolosa, J. Trujillo, F. Uresandi, V. Valdés, R. Valle, J. Vela, G. Vidal, and J. Villalta. Brazil: T. Gadelha. France: H. Boccalon, D. Farge‐Bancel, I. Mahe, and K. Rivron‐Guillot. Israel: B. Brenner. Italy: A. Barillari, G. Barillari, M. Ciammaichella, P. Di Micco, F. Dalla Valle, R. Duce, R. Maida, S. Pasca, C. Piovella, R. Poggio, P. Prandoni, R. Quintavalla, A. Schenone, E. Tiraferri, and A. Visonà. Republic of Macedonia: M. Bosevski. Switzerland: H. Bounameaux.