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A Clinical Probability Assessment and D-dimer Measurement Should Be the Initial Step in the Investigation of Suspected Venous Thromboembolism* FREE TO VIEW

James Kelly; Beverley J. Hunt
Author and Funding Information

*From the Department of Haematology, Guy’s & St. Thomas’ Trust, London, UK.

Correspondence to: James Kelly, Department of Haematology, Fourth Floor, North Wing, St. Thomas’ Hospital, London, UK SE1 7EH; e-mail: jameskelly@northbrookfm.fsnet.co.uk



Chest. 2003;124(3):1116-1119. doi:10.1378/chest.124.3.1116
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Improved access to noninvasive investigation and a declining tolerance for diagnostic uncertainty has resulted in increasing numbers of patients who are referred with suspected venous thromboembolism (VTE), all of whom require objective testing to confirm or exclude the diagnosis. Hence, the proportion of patients with suspected VTE in whom the diagnosis is confirmed has fallen progressively from 30 to 35% in the 1970s and 1980s,13 to around 15 to 25% in the last decade.46 Indeed, prevalences of < 10% have been reported.7 This trend is not inappropriate for a potentially fatal disorder that can be effectively treated, but it has important resource implications.

The potential value of plasma d-dimers (d-ds) as an exclusionary test for VTE in an era of increasing numbers of negative imaging test 2results has been appreciated for more than a decade. However, although outcome studies performed in the last 5 years have shown that a negative d-d test result can be used to minimize the need for serial ultrasound testing in patients with suspected deep vein thrombosis (DVT),89 and to reduce the need for additional imaging in patients with suspected pulmonary embolism (PE) and nondiagnostic ventilation/perfusion (V̇/Q̇) scan results,1011 their role as an exclusionary first-line test has been uncertain.

The clinically useful d-d tests can be divided into two main groups that have important differences in performance characteristics. Rapid enzyme-linked immunosorbent assays (ELISAs) have very high sensitivity but low specificity, while modern latex agglutination tests tend to be somewhat less sensitive but more specific. More recently, highly sensitive latex agglutination tests have been developed, but they tend to have lower specificities so that their performance characteristics tend to resemble those of the ELISA assays. In the absence of an assay that is both highly sensitive and specific, two possible strategies for the initial use of d-d as an exclusionary tool are apparent. First, an assay chosen for high specificity could be used in combination with an additional factor such as low pretest probability (PTP), which identifies a subgroup with a low disease prevalence. This strategy is based on the concept that a test that had a sensitivity of, say, 90%, could not be used by itself to exclude VTE safely, but might be perfectly adequate when targeted to a subgroup of patients with a prior probability of, for example, only 5%. Second, an assay chosen for high sensitivity could be employed either as a stand-alone exclusionary test or in combination with an additional factor that identifies the major subgroup of patients in whom prevalence of VTE is not particularly high (ie, those with low or intermediate PTP).

The proper evaluation of these approaches requires clinical outcome studies that will investigate the safety of withholding imaging and treatment in patients with suspected VTE on the basis of these strategies, together with an assessment of their exclusionary efficiency. Ideally, patients categorized as being “VTE-negative” should have a 3-month event rate similar to that observed in patients with suspected DVT who have normal venogram or serial ultrasound findings, and in patients with suspected PE who have normal pulmonary angiograms or V̇/Q̇ scans. Given that such patients have a 3-month incidence of clinically apparent of VTE of 0.6 to 1.8%,1215 and that unsuspected PE is found in 1.5% of unselected patients undergoing routine contrast-enhanced helical thoracic CT scans,16 a 3-month event rate of ≤ 2% is considered to be acceptable.

The four outcome studies published to date (Table 1 ) have validated the safety of withholding imaging and treatment in patients with suspected DVT or PE, low PTP and a negative d-d assay (SimpliRED,5,7,17 AGEN Biomedical, Brisbane, Australia; or VIDAS,18 BioMerieux, Marcy l’Etoile, France). Imaging and treatment were withheld in a total of 773 patients in these studies on this basis, with only two confirmed episodes of VTE (0.3%) over the next 3 months. In one of these studies,7 this approach allowed the immediate exclusion of PE in 47% of outpatients. One test, the SimpliRED test, differs from other d-d assays in that it can be performed using a drop of capillary blood either at the patient’s bedside or on venous whole blood in the laboratory,4 and it provides a qualitative result requiring a subjective interpretation for the presence or absence of agglutination. Overall, sensitivity has been approximately 85 to 90%, and specificity has been approximately 70%.45,19 By contrast, the VIDAS d-d test, the most extensively validated rapid ELISA assay, has consistently demonstrated a sensitivity of 96 to 100%6,19 and a specificity of approximately 40%.6,19 The sensitivity of the SimpliRED assay has varied quite markedly between studies, and it has been suggested that this might be accounted for by the experience of the personnel performing the test, with studies in which the test was performed by experienced laboratory staff demonstrating sensitivities of > 90%.4 Nevertheless, these outcome studies indicate that the sensitivity of this assay is perfectly adequate when applied to a low-prevalence population. The advantages of SimpliRED are therefore that it is rapid, potentially suitable for near-patient testing, and among the most specific of the d-d assays. The disadvantages are its imperfect sensitivity and the subjective element in its interpretation. Regarding the latter concern, two new d-d assays that are potentially suitable for near-patient testing and that provide an objective result are undergoing evaluation. A novel qualitative immunochromatographic assay called Simplify (AGEN), which produces an easily interpreted colored line when positive,20 and the Cardiac d-d assay (Roche Diagnostics; Mannheim, Germany), which is performed on the Cardiac Reader instrument (which is also used for measuring troponin T levels) and provides a quantitative result.21

Three recent outcome studies (Table 1) have validated the safety of withholding imaging and treatment in patients with suspected DVT or PE and low or intermediate PTP by using the following two highly sensitive latex agglutination immunoturbidimetric tests: the Tinaquant assay2223 (Roche; Frankfurt am Main, Germany); and the MDA d-d assay24 (BioMerieux). In total, VTE was regarded as being excluded in 553 patients on this basis, in whom two episodes of VTE (0.4%) occurred over the next 3 months. In one of these studies, this approach allowed the exclusion of DVT in 51% of outpatients.24

The use of d-d in a stand-alone capacity has been investigated in only one study (Table 1) . Imaging and treatment were withheld in 159 of 444 outpatients (36%) with suspected PE and negative VIDAS d-d assay results, irrespective of the PTP, and no cases of VTE occurred during 3 months of follow-up.6 The proportion of patients in this study with a high PTP and a negative d-d assay result was not stated, but, given that only 11% of the entire cohort with suspected PE were categorized as having high PTP, and that the likelihood of a negative d-d test falls as PTP rises,5,25 the absolute number in this subgroup must have been very small. Indeed, the proportion of all patients with suspected VTE who have a high PTP and negative d-d assay result has only been around 2% in other studies.5,25 Furthermore, assuming a PE prevalence of 60% in the high-PTP subgroup, and a sensitivity and specificity of the VIDAS assay of 98% and 40%, respectively, the Bayes theorem indicates an expected 7% posterior probability of PE in the presence of a high PTP and negative VIDAS test result, rising to 28% if the prior probability is increased to 80%, and the sensitivity of the assay decreased to 96%. Therefore, while this study suggests that the VIDAS may be a safe stand-alone exclusionary test for PE, this outcome should be replicated in additional investigations before this approach is widely adopted in clinical practice.

These outcome studies therefore have validated the safety of a strategy of excluding VTE if PTP is low in combination with a negative d-d test result using assays with similar or greater sensitivity than the SimpliRED test, or if PTP is low or intermediate in combination with a negative d-d test result using selected highly sensitive assays such as VIDAS, Tinaquant, or the MDA d-d. However, clear conclusions about the comparative exclusionary efficiency of these strategies cannot be drawn as the prevalences of VTE have varied markedly between studies, and these approaches have not been compared in the same population of patients.

The clinical assessment of VTE has now come full circle in the diagnostic management of VTE. Diagnosis was necessarily made clinically prior to the 1970s, but interest in the discriminatory value of the clinical assessment, other than to alert the clinician to the need for objective testing, was abandoned when the advent of imaging demonstrated that clinical diagnosis was frequently incorrect.12 In more recent years, clinical assessment in the form of scoring systems, while unable to exclude or confirm the presence of VTE, has gained favor as a method of stratifying PTP into low-probability, intermediate-probability, or high-probability groups. This has facilitated a Bayesian approach to diagnosis, which has proved valuable in an era of predominantly noninvasive imaging in which results often are presented in terms of probabilities rather than binary answers.

This was first recognized in the PIOPED study published in 1990,3 in which V̇/Q̇ scanning and pulmonary angiography were compared in 755 patients with suspected PE. An empirical assessment of PTP was found to supplement the data derived from V̇/Q̇ scans significantly and to refine the posterior probability of underlying PE. For example, the overall prevalence of PE in patients with low-probability results of V̇/Q̇ scans was 14%, but it increased to 40% if the PTP was considered to be high, while it decreased to 4% if the PTP was considered to be low. Formal scoring systems for DVT and PE have since been devised, and those of Wells and colleagues2526 are the most extensively validated, allowing the classification of around half of patients as having low PTP, in whom the prevalence of VTE is approximately 5%. Points are allocated on the basis of risk factors, clinical features, and the presence or absence of a likely alternative diagnosis using all the available information, with the final score determining the PTP. However, correct use requires careful consideration of the latter factor, which introduces an element of subjectivity into the assessment. More recently, the Geneva score has been shown to categorize patients with suspected PE with an accuracy similar to that of the Wells score25 and has been externally validated.2728 While this system avoids the subjective element of the Wells score, it has been validated only in outpatients and cannot be applied without the measurement of arterial blood gases. Furthermore, there is also good evidence that an empirical assessment, usually prompted by a checklist of signs, symptoms, and risk factors, allows the equally accurate categorization of the PTP to formal scoring systems,3,6,27,29 although fewer patients tend to be classified as having low PTP.3,27,29 Hence, when assessing PTP, the standardized approach offered by the use of formal scoring systems such as those of Wells and colleagues,2526 which is subject to exclusions,5,7 therefore may be preferable to an empirical assessment, particularly as relatively inexperienced staff are often the first to encounter patients with suspected VTE, although this may not be of critical importance.

In conclusion, imaging and treatment may safely be withheld in patients presenting with suspected VTE who have a low PTP and a negative d-d test result using most modern tests, an approach that is most effective when using one of the more specific assays; or in patients with low or intermediate PTP using selected highly sensitive assays. Future studies should allow a direct comparison of the exclusionary efficiency of these alternative approaches in the same patient population.

Abbreviations: d-d = d-dimer; DVT = deep vein thrombosis; ELISA = enzyme-linked immunosorbent assay; PE = pulmonary embolism; PTP = pretest probability; V̇/Q̇ = ventilation/perfusion; VTE = venous thromboembolism

Table Graphic Jump Location
Table 1. Clinical Management Studies Assessing the Validity of Excluding VTE on the Basis of Negative D-dimers and Various Categories of PTP
* 

Values given as No. (% of total).

References

Ramsay, LE (1983) Impact of venography on the diagnosis and management of deep vein thrombosis.BMJ286,698-699. [PubMed] [CrossRef]
 
Simpson, FG, Robinson, PJ, Bark, M, et al Prospective study of thrombophlebitis and “pseudothrombophlebitis.”Lancet1980;1,331-333. [PubMed]
 
The PIOPED investigators. Value of the ventilation-perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED).JAMA1990;263,2753-2759. [PubMed]
 
Chunilal, SD, Brill-Edwards, PA, Stevens, PB, et al The sensitivity and specificity of a red blood cell agglutination d-dimer assay for venous thromboembolism when performed on venous blood.Arch Intern Med2002;162,217-220. [PubMed]
 
Kearon, C, Ginsberg, JS, Douketis, J, et al Management of suspected deep venous thrombosis in outpatients by using clinical assessment and d-dimer testing.Ann Intern Med2001;135,108-111. [PubMed]
 
Perrier, A, Desmarais, S, Miron, M, et al Non-invasive diagnosis of venous thromboembolism in outpatients.Lancet1999;353,190-195. [PubMed]
 
Wells, PS, Anderson, DR, Rodger, M, et al 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 Med2001;135,98-107. [PubMed]
 
Bernardi, E, Prandoni, P, Lensing, AW, et al D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study.BMJ1998;317,1037-1040. [PubMed]
 
Kraaijenhagen, RA, Piovella, F, Bernardi, E, et al Simplification of the diagnostic management of suspected deep vein thrombosis.Arch Intern Med2002;162,907-911. [PubMed]
 
Perrier, A, Desmarais, S, Goehring, C, et al D-dimer testing for suspected pulmonary embolism in outpatients.Am J Respir Crit Care Med1997;156,492-496. [PubMed]
 
de Groot, MR, van Marwijk,, Kooy, M, et al The use of a rapid d-dimer blood test in the diagnostic work up of pulmonary embolism.Thromb Haemost1999;82,1588-1592. [PubMed]
 
Hull, R, Hirsh, J, Sackett, DL, et al Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis.Circulation1981;64,622-625. [PubMed]
 
Lensing, AW, Hirsh, J, Buller, HR Diagnosis of venous thromboembolism. Colman, RW Hirsh, J Marder, VJet al eds.Haemostasis and thrombosis: basic principles and clinical practice1993,1297-1321 JB Lippincott. Philadelphia, PA:
 
Van Beek, EJ, Brouwers, EM, Song, B, et al Clinical validity of a normal pulmonary angiogram in patients with suspected pulmonary embolism: a critical review.Clin Radiol2001;56,838-842. [PubMed]
 
Hull, RD, Raskob, GE, Coates, G, et al Clinical validity of a normal perfusion lung scan in patients with suspected pulmonary embolism.Chest1990;97,23-26. [PubMed]
 
Gosselin, MV, Rubin, GD, Leung, AN, et al Unsuspected pulmonary embolism: prospective detection on routine helical CT scans.Radiology1998;208,209-215. [PubMed]
 
Janes, 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 Haematol2001;112,1079-1082. [PubMed]
 
Kruip, MJ, Slob, MJ, Schijen, JH, et al Use of a clinical decision rule in combination with d-dimer concentration in diagnostic work up of patients with suspected pulmonary embolism.Arch Intern Med2002;162,1631-1635. [PubMed]
 
Perrier, A, Bounameaux, H Cost-effective diagnosis of deep vein thrombosis and pulmonary embolism.Thromb Haemost2001;86,475-487. [PubMed]
 
Legnani, C, Fariselli, S, Cini, M, et al Accuracy of a new rapid bedside assay for d-dimer detection (Simplify D-dimer) in the diagnostic work-up for deep vein thrombosis (DVT) [abstract]. Pathophysiol Haemost Thromb. 2002;;32 ,.:S2
 
Bucek, RA, Quehenberger, P, Feliks, I, et al Results of a new rapid D-dimer assay (cardiac d-dimer) in the diagnosis of deep vein thrombosis.Thromb Res2001;103,17-23. [PubMed]
 
Schutgens, RE, Ackermark, P, Haas, FJ, et al Combination of a normal d-dimer concentration and a non-high pretest clinical probability score is a safe strategy to exclude deep vein thrombosis.Circulation2003;107,593-597. [PubMed]
 
Leclercq, MG, Lutisan, JG, van Marwijk,, Kooy, M, et al Ruling out clinically suspected pulmonary embolism by assessment of clinical probability and d-dimer levels: a management study.Thromb Haemost2003;89,97-103. [PubMed]
 
Bates, SM, Kearon, C, Crowther, M, et al A diagnostic strategy involving a quantitative latex d-dimer assay reliably excludes deep venous thrombosis.Ann Intern Med2003;138,787-794. [PubMed]
 
Wells, PS, Anderson, DR, Rodger, M, et al Derivation of a simple clinical model to categorise patients probability of pulmonary embolism: increasing the model’s utility with the SimpliRED D-dimer.Thromb Haemost2000;83,416-420. [PubMed]
 
Wells, PS, Hirsh, J, Anderson, DR, et al A simple clinical model for the diagnosis of deep vein thrombosis combined with impedance plethysmography: potential for an improvement in the diagnostic process.J Intern Med1998;243,15-23. [PubMed]
 
Wicki, J, Perneger, TV, Junod, AF, et al Assessing clinical probability of pulmonary embolism in the emergency ward.Arch Intern Med2001;161,92-97. [PubMed]
 
Chagnon, I, Bounameaux, H, Aujesky, D, et al Comparison of two clinical prediction rules and implicit assessment among patients with suspected pulmonary embolism.Am J Med2002;113,269-275. [PubMed]
 
Miron, MJ, Perrier, A, Bounameaux, H Clinical assessment of suspected deep vein thrombosis: comparison between a score and empirical assessment.J Intern Med2000;247,249-254. [PubMed]
 
Wells, P, Hirsh, J, Anderson, DR, et al Accuracy of clinical assessment of deep-vein thrombosis.Lancet1995;1,1326-1330
 

Figures

Tables

Table Graphic Jump Location
Table 1. Clinical Management Studies Assessing the Validity of Excluding VTE on the Basis of Negative D-dimers and Various Categories of PTP
* 

Values given as No. (% of total).

References

Ramsay, LE (1983) Impact of venography on the diagnosis and management of deep vein thrombosis.BMJ286,698-699. [PubMed] [CrossRef]
 
Simpson, FG, Robinson, PJ, Bark, M, et al Prospective study of thrombophlebitis and “pseudothrombophlebitis.”Lancet1980;1,331-333. [PubMed]
 
The PIOPED investigators. Value of the ventilation-perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED).JAMA1990;263,2753-2759. [PubMed]
 
Chunilal, SD, Brill-Edwards, PA, Stevens, PB, et al The sensitivity and specificity of a red blood cell agglutination d-dimer assay for venous thromboembolism when performed on venous blood.Arch Intern Med2002;162,217-220. [PubMed]
 
Kearon, C, Ginsberg, JS, Douketis, J, et al Management of suspected deep venous thrombosis in outpatients by using clinical assessment and d-dimer testing.Ann Intern Med2001;135,108-111. [PubMed]
 
Perrier, A, Desmarais, S, Miron, M, et al Non-invasive diagnosis of venous thromboembolism in outpatients.Lancet1999;353,190-195. [PubMed]
 
Wells, PS, Anderson, DR, Rodger, M, et al 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 Med2001;135,98-107. [PubMed]
 
Bernardi, E, Prandoni, P, Lensing, AW, et al D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study.BMJ1998;317,1037-1040. [PubMed]
 
Kraaijenhagen, RA, Piovella, F, Bernardi, E, et al Simplification of the diagnostic management of suspected deep vein thrombosis.Arch Intern Med2002;162,907-911. [PubMed]
 
Perrier, A, Desmarais, S, Goehring, C, et al D-dimer testing for suspected pulmonary embolism in outpatients.Am J Respir Crit Care Med1997;156,492-496. [PubMed]
 
de Groot, MR, van Marwijk,, Kooy, M, et al The use of a rapid d-dimer blood test in the diagnostic work up of pulmonary embolism.Thromb Haemost1999;82,1588-1592. [PubMed]
 
Hull, R, Hirsh, J, Sackett, DL, et al Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis.Circulation1981;64,622-625. [PubMed]
 
Lensing, AW, Hirsh, J, Buller, HR Diagnosis of venous thromboembolism. Colman, RW Hirsh, J Marder, VJet al eds.Haemostasis and thrombosis: basic principles and clinical practice1993,1297-1321 JB Lippincott. Philadelphia, PA:
 
Van Beek, EJ, Brouwers, EM, Song, B, et al Clinical validity of a normal pulmonary angiogram in patients with suspected pulmonary embolism: a critical review.Clin Radiol2001;56,838-842. [PubMed]
 
Hull, RD, Raskob, GE, Coates, G, et al Clinical validity of a normal perfusion lung scan in patients with suspected pulmonary embolism.Chest1990;97,23-26. [PubMed]
 
Gosselin, MV, Rubin, GD, Leung, AN, et al Unsuspected pulmonary embolism: prospective detection on routine helical CT scans.Radiology1998;208,209-215. [PubMed]
 
Janes, 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 Haematol2001;112,1079-1082. [PubMed]
 
Kruip, MJ, Slob, MJ, Schijen, JH, et al Use of a clinical decision rule in combination with d-dimer concentration in diagnostic work up of patients with suspected pulmonary embolism.Arch Intern Med2002;162,1631-1635. [PubMed]
 
Perrier, A, Bounameaux, H Cost-effective diagnosis of deep vein thrombosis and pulmonary embolism.Thromb Haemost2001;86,475-487. [PubMed]
 
Legnani, C, Fariselli, S, Cini, M, et al Accuracy of a new rapid bedside assay for d-dimer detection (Simplify D-dimer) in the diagnostic work-up for deep vein thrombosis (DVT) [abstract]. Pathophysiol Haemost Thromb. 2002;;32 ,.:S2
 
Bucek, RA, Quehenberger, P, Feliks, I, et al Results of a new rapid D-dimer assay (cardiac d-dimer) in the diagnosis of deep vein thrombosis.Thromb Res2001;103,17-23. [PubMed]
 
Schutgens, RE, Ackermark, P, Haas, FJ, et al Combination of a normal d-dimer concentration and a non-high pretest clinical probability score is a safe strategy to exclude deep vein thrombosis.Circulation2003;107,593-597. [PubMed]
 
Leclercq, MG, Lutisan, JG, van Marwijk,, Kooy, M, et al Ruling out clinically suspected pulmonary embolism by assessment of clinical probability and d-dimer levels: a management study.Thromb Haemost2003;89,97-103. [PubMed]
 
Bates, SM, Kearon, C, Crowther, M, et al A diagnostic strategy involving a quantitative latex d-dimer assay reliably excludes deep venous thrombosis.Ann Intern Med2003;138,787-794. [PubMed]
 
Wells, PS, Anderson, DR, Rodger, M, et al Derivation of a simple clinical model to categorise patients probability of pulmonary embolism: increasing the model’s utility with the SimpliRED D-dimer.Thromb Haemost2000;83,416-420. [PubMed]
 
Wells, PS, Hirsh, J, Anderson, DR, et al A simple clinical model for the diagnosis of deep vein thrombosis combined with impedance plethysmography: potential for an improvement in the diagnostic process.J Intern Med1998;243,15-23. [PubMed]
 
Wicki, J, Perneger, TV, Junod, AF, et al Assessing clinical probability of pulmonary embolism in the emergency ward.Arch Intern Med2001;161,92-97. [PubMed]
 
Chagnon, I, Bounameaux, H, Aujesky, D, et al Comparison of two clinical prediction rules and implicit assessment among patients with suspected pulmonary embolism.Am J Med2002;113,269-275. [PubMed]
 
Miron, MJ, Perrier, A, Bounameaux, H Clinical assessment of suspected deep vein thrombosis: comparison between a score and empirical assessment.J Intern Med2000;247,249-254. [PubMed]
 
Wells, P, Hirsh, J, Anderson, DR, et al Accuracy of clinical assessment of deep-vein thrombosis.Lancet1995;1,1326-1330
 
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