Bounameaux, Henri

Le Gal, Grégoire

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Intensive Care Med (2005) 31:1–2DOI 10.1007/s00134-004-2485-0 E D I T OR I A LGrgoire Le GalHenri BounameauxD-dimer for the diagnosisof pulmonary embolism:a call for sticking to evidenceAccepted: 7 October 2004Published online: 14 October 2004 Springer-Verlag 2004G. Le Gal · H. Bounameaux ())Division of Angiology and Hemostasis,Department of Internal Medicine,Faculty of Medicine and Geneva University Hospitals,1211 Geneva 14, Switzerlande-mail: henri.bounameaux@medecine.unige.chTel.: +41-22-3729292Fax: +41-22-3729299Critically ill patients are at high risk of venous throm-boembolism (VTE). However, the disease is often clini-cally silent, especially in these patients, and is not asso-ciated with any specific clinical sign or biologic mark-er. It is, therefore, particularly difficult to diagnose thiscondition in the ICU. D-dimers (DD) are cross-linkedfibrin derivatives that are produced upon fibrin degrada-tion by plasmin. The DD concentration rises in variousconditions in which coagulation and fibrinolysis are ac-tivated, e.g. in patients with VTE, but also in patients withcancer, myocardial infarction, infectious or inflammato-ry diseases, pregnancy and in the postoperative period.Practically, patients with acute VTE are very likely topresent with an elevated DD level, corresponding to avery high sensitivity to VTE, which in turn results in ahigh negative predictive value. On the other hand, as DDrise in various pathologic conditions [1], the proportion ofpatients with increased DD may be substantial in patientswithout VTE: the specificity (proportion of patients withnegative D-dimer test among those without VTE) of DDtesting is low, resulting in a poor positive predictive value(PPV, proportion of patients with VTE among those withpositive D-dimer tests).Although available DD assays are heterogeneous, anegative result usually allows the exclusion of acute VTE:in low clinical probability patients only for whole bloodagglutination assays [2] or even in all non-high clinicalprobability patients for the most sensitive tests (ELISA orimmunoturbidimetric assays) [3, 4]. Hence, DD testing iswidely used as a first-line test, at least in outpatients withsuspected VTE, as VTE can be ruled out in about 30% ofsuch patients without further invasive and/or expensivetesting.In this issue, Crowther et al. [5] report on a study usingsix different commercial DD assays in a prospective co-hort of 197 critically ill medical-surgical patients. The testwas performed upon admission to the ICU, and twiceweekly during the ICU stay. Bilateral compression ul-trasonography of the lower limbs was performed at thesame time points, as well as at the time of any suspicionof VTE. All patients had some kind of thrombo-prophy-laxis during their ICU stays. The results confirm the factthat DD testing is not useful for ruling out VTE in thissetting. Indeed, the proportion of patients with low DDconcentration decreases—and so does the clinical utilityof this test—in cancer patients, older subjects [6], inpa-tients [7] or pregnant women [8]. Among the medical-surgical critically ill patients included in the study byCrowther et al., only 3.6% had negative bedside D-dimertests (thereby ruling out VTE), which definitely precludesthe use of these tests in ICU patients. This proportion washigher (15.9%) in a previous study in ICU, but that studyincluded younger (62 vs 67 years) and less severely illpatients (APACHE II 20.2 vs 25.7) [9].The results also indicate that DD testing is not able toidentify correctly the ICU patients who have VTE. Ad-mittedly, the areas under the ROC curve differ signifi-cantly from 0.5 (which indicates that these tests have asignificant capacity to discriminate patients with andwithout the disease), but these curves show that DDtesting reaches sufficient specificity to identify patientswith VTE only for very high DD levels, that very fewpatients have. This observation is not surprising since thespecificity of DD is known to be not high enough—about40% at a 500 mg/l threshold and above 93% only forvalues above 4,000 mg/l when assayed by ELISA [10]—to2References1. Raimondi P, Bongard O, de MoerlooseP, Reber G, Waldvogel F, BounameauxH (1993) D-dimer concentration invarious clinical conditions: implicationfor the use of this test in the diagnosticapproach of venous thromboembolism.Thromb Res 69:125–1302. Wells PS, Anderson DR, Rodger M,Forgie M, Kearon C, Dreyer J, KovacsG, Mitchell M, Lewandowski B,Kovacs MJ (2003) Evaluation of D-di-mer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med349:1227–12353. Perrier A, Desmarais S, Miron MJ, deMoerloose P, Lepage R, Slosman D,Didier D, Unger PF, Patenaude JV,Bounameaux H (1999) Non-invasivediagnosis of venous thromboembolismin outpatients. Lancet 353:190–1954. Perrier A, Roy PM, Aujesky D,Chagnon I, Howarth N, Gourdier AL,Leftheriotis G, Barghouth G, Cornuz J,Hayoz D, Bounameaux H (2004) Di-agnosing pulmonary embolism in out-patients with clinical assessment, D-di-mer measurement, venous ultrasoundand helical computed tomography: amulticenter management study. Am JMed 116:291–2995. Crowther MA, Cook DJ, Griffith LE,Meade M, Hanna S, Rabbat C, BatesSM, Johnston M, Guyatt G (2004)Neither baseline test of molecular hy-percoagulability nor D-dimer levelspredict deep venous thrombosis in crit-ically ill medical-surgical patients. In-tensive Care Med (http://dx.doi.org/10.1007/s00134-004-2467-2)6. Righini M, Bounameaux H, Perrier A(2004) Effect of age on the performanceof single detector helical computedtomography in suspected pulmonaryembolism. Thromb Haemost 91:296–2997. Miron MJ, Perrier A, Bounameaux H,de Moerloose P, Slosman DO, Didier D,Junod A (1999) Contribution of nonin-vasive evaluation to the diagnosis ofpulmonary embolism in hospitalizedpatients. Eur Respir J 13:1365–13708. Chabloz P, Reber G, Hohfeld P, deMoerloose P (2001) TAFI antigen andD-dimer levels during normal pregnan-cy and at delivery. Br J Haematol115:150–1529. Kollef MH, Zahid M, Eisenberg P(2000) Predictive value of a rapidsemiquantitative D-dimer assay in crit-ically ill patients with suspected venousthromboembolic disease. Crit Care Med28:414–42010. Perrier A, Desmarais S, Goehring C, deMoerloose P, Morabia A, Unger PF,Slosman D, Junod A, Bounameaux H(1997) D-dimer testing for suspectedpulmonary embolism in outpatients.Am J Respir Crit Care Med 156:492–49611. Palareti G, Legnani C, Cosmi B, ValdreL, Lunghi B, Bernardi F, Coccheri S(2003) Predictive value of D-dimer testfor recurrent venous thromboembolismafter anticoagulation withdrawal insubjects with a previous idiopathicevent and in carriers of congenitalthrombophilia. Circulation 108:313–31812. Eichinger S, Minar E, Bialonczyk C,Hirschl M, Quehenberger P, SchneiderB, Weltermann A, Wagner O, Kyrle PA(2003) D-dimer levels and risk of re-current venous thromboembolism.JAMA 290:1071–107413. Righini M, De Moerloose P, Reber G,Bounameaux H, Perrier A (2004) Po-tential role of D-dimer to rule in pul-monary embolism: a rebuttal. J ThrombHaemost 2:367–368 (Author’s reply369–370)ensure a clinically interesting PPV. This is even more truewhen the prevalence of the disease is low. The prevalencewas only 5/197 (2.5%) upon ICU admission in the presentstudy. Consequently, specificity should have been par-ticularly high to allow correct identification of the casesby a positive test.The authors have also evaluated the capacity of fourhypercoagulability tests (protein C, protein S, activatedprotein C resistance ratio and antithrombin) and of D-dimer to predict the occurrence of VTE during a meanICU stay of 12 days, as recently suggested by two groups[11, 12]. Eventually, they found that none of these testswas able to predict VTE occurrence, as demonstrated byareas under the ROC curves that were not significantlydifferent from 0.5.Although this is an original result, it could have beenanticipated, especially for DD testing [13]. Indeed, if DDlevels are highly sensitive to the presence of a clot andeven of a hypercoagulable state, as already said, theirspecificity for the diagnosis of VTE in patients suspectedof having this is poor. Moreover, because of the low in-cidence—here 11.6% over 12 days, mostly asymptom-atic—a high PPV was not to be expected.In conclusion, thanks to its high sensitivity for thepresence of VTE, DD testing allows, with some certainty,the exclusion of the disease when negative (i.e. when theconcentration is below a validated diagnostic threshold) inpatients who are suspected of having it, if those patientshave (1) a low clinical probability when whole bloodagglutination assays are used or (2) a low or intermediateclinical probability when highly sensitive tests such asELISA or some immunoturbidimetric assays are used.Due to its poor specificity and to the relatively lowprevalence of the disease in patients suspected of havingit, DD testing can not be used to establish the diagnosis inthese patients nor to predict VTE occurrence in at-riskpatients. Moreover, because they have only little chanceof being negative in critically ill patients, the use of thesetests should be discouraged in such patients. New biologictests must be applied for validated indications in appro-priate patient populations. All divergent uses are likely toresult in financial losses and, more importantly, in clini-cally useless or even misleading information.

D-dimer for the diagnosis of pulmonary embolism: a call for sticking to evidence

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D-dimer for the diagnosis of pulmonary embolism: a call for sticking to evidence

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