Screening for Deep Vein Thrombosis and Pulmonary Embolism in Outpatients with Suspected DVT or PE by the Sequential Use of Clinical Score: A Sensitive Quantitative D-Dimer Test and Noninvasive Diagnostic Tools

ABSTRACT

The requirement for a safe diagnostic strategy should be based on an overall posttest incidence of venous thromboembolism (VTE) of less than 1% during 3-month follow-up. The negative predictive value (NPV) during 3 months of follow-up is 98.1 to 99% after a normal venogram, 97 to 98% after a normal compression ultrasonography (CUS), and > 99% after serial CUS testing. Serial CUS testing is safe but 100 CUS must be repeated to find one or two CUS positive for deep vein thrombosis (DVT), which is not cost-effective and indicates the need to improve the diagnostic workup of DVT by the use of clinical score assessment and D-dimer testing. The NPV varies from 97.6 to 99.4% for low clinical score followed by a negative SimpiRED test, indicating the need for a first CUS. The NPV is 98.4 to 99.3% for a normal rapid enzyme-linked immunosorbent assay (ELISA) VIDAS D-dimer test result (< 500 ng/mL) irrespective of clinical score. The NPV is more than 99% for a negative CUS followed by either a negative SimpiRED test or an ELISA VIDAS test result of < 1000 ng/mL without the need to repeat a second CUS within 1 week. The sequential use of a sensitive, rapid ELISA D-dimer and clinical score assessment will safely reduce the need for CUS testing by 40 to 60%. Large prospective outcome studies demonstrate that with one negative examination with complete duplex color ultrasonography (CCUS) of the proximal and distal veins of the affected leg with suspected DVT, it is safe to withhold anticoagulant treatment, with a negative predictive value of 99.5%. This may indicates that CCUS is equal to serial CUS or the combined use of clinical score, D-dimer testing, and CUS. Pulmonary angiography is the gold standard for segmental pulmonary embolism (PE) but not for subsegmental PE. A normal perfusion lung scan and a normal rapid ELISA VIDAS D-dimer test safely excludes PE. Helical spiral computed tomography (CT) detects all clinically relevant PE and a large number of alternative diagnoses in symptomatic patients with suspected PE and can replace both the ventilation perfusion scan and pulmonary angiography to safely rule in PE and to rule out PE with an NPV of > 99%. The combination of clinical assessment, a rapid ELISA VIDAS D-dimer, followed by CUS will reduce the need for helical spiral CT by 40 to 50%.

KEYWORDS

Deep vein thrombosis - D-dimer assay - compression ultrasonography - clinical score - pulmonary embolism - venous thromboembolism - ventilation perfusion scan - spiral CT

REFERENCES

• 1 Michiels J J, Oortwijn W J, Naaborg R. Exclusion and diagnosis of deep vein thrombosis by a rapid ELISA D-dimer test, compression ultrasonography, and a simple clinical model.  Clin Appl Thromb Hemost. 1999;  5 171-180
• 2 Michiels J J, Freyburger G, van der Graaf F, Janssen M, Oortwijn W, van Beek EJR. Strategies for the safe and effective exclusion and diagnosis of deep vein thrombosis by the sequential use of clinical score, D-dimer testing and compression ultrasonography.  Sem Thromb Hemost. 2000;  26 657-667
• 3 Hull R, Hirsh J, Sackett D L et al.. Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis.  Circulation. 1981;  64 622-625
• 4 Pedersen L M, Lerche A, Jorgensen M, Urhammer S, Steenberg P, Jensen R. Follow-up study of patients with clinically suspected deep vein thrombosis and a normal venogram.  J Intern Med. 1993;  234 457-460
• 5 Cogo A, Lensing AWA, Prandoni P, Hirsch J. Distribution of thrombosis in patients with symptomatic deep vein thrombosis.  Arch Intern Med. 1993;  153 2777-2780
• 6 Cogo A, Lensing A W, Koopman M M et al.. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study.  BMJ. 1998;  316 17-20
• 7 Birdwell B G, Raskob G E, Whitsett T L et al.. The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis.  Ann Intern Med. 1998;  128 1-7
• 8 Kearon C, Julian J A, Math M, Newman T E, Ginsberg J S. Non-invasive diagnosis of deep vein thrombosis.  Ann Intern Med. 1998;  128 663-677
• 9 Wells P, Hirsh J, Anderson D R et al.. Accuracy of clinical assessment of deep-vein thrombosis.  Lancet. 1995;  345 1326-1330
• 10 Wells P, Anderson D R, Bormanis J et al.. Value of assessment of pre-test probability of deep-vein thrombosis in clinical management.  Lancet. 1997;  350 1795-1798
• 11 Michiels J J, Schroyens W, De Maeseneer M, Kasbergen A A, Oudega R. The rehabilitation of clinical assessment in the diagnosis of deep vein thrombosis.  Sem Vasc Med. 2002;  1 1-5
• 12 Miron M J, Perrier A, Boumameaux H. Clinical assessment of suspected deep vein thrombosis: comparison between a score and empirical assessment.  J Intern Med. 2000;  247 249-254
• 13 Kraaijenhagen R A, Piovelli F, Bernardi E et al.. Simplification of the diagnostic management of suspected deep vein thrombosis.  Arch Intern Med. 2002;  162 907-911
• 14 Tick L W, Ton E, van Voorthuizen Th et al.. Practical diagnostic management of patients with clinically suspected deep vein thrombosis by clinical probability test, compression ultrasonography and D-dimer test.  Am J Med. 2002;  113 630-635
• 15 Cornuz 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;  112 198-203
• 16 Constans J, Nelzy M L, Salmi L R et al.. Clinical prediction of lower limb deep vein thrombosis in symptomatic hospitalized patients.  Thromb Haemost. 2001;  86 985-990
• 17 Anderson D R, Kovacs M J, Kovacs G et al.. Combined use of clinical assessment and D-dimer to improve the management of patients presenting to the emergency department with suspected deep vein thrombosis (the EDITED Study).  J Thromb Haemost. 2003;  1 645-651
• 18 Wells P, Brill-Edwards P, Stevens P et al.. A novel and rapid whole-blood assay for D-dimer in patients with clinically suspected deep vein thrombosis.  Circulation. 1995;  91 2184-2187
• 19 Blättler W, Martinez I, Blättler I K. Diagnosis of deep vein thrombosis and alternative diseases in symptomatic outpatients.  Eur J Intern Med. 2004;  15 305-311
• 20 Bates S M, Kearon C, Crowther M et al.. A diagnostic strategy involving a quantitative latex-D-dimer assay reliable excludes deep vein thrombosis.  Ann Intern Med. 2003;  138 787-794
• 21 Wells P S, Anderson D R, Rodger M et al.. Evaluation of D-dimer in the diagnosis of suspected deep vein thrombosis.  N Engl J Med. 2003;  349 1227-1235
• 22 Kearon C, Ginsberg J S, Douketis J et al.. Management of suspected deep vein thrombosis in outpatients by using clinical assessment and D-dimer testing.  Ann Intern Med. 2001;  135 108-111
• 23 Freyburger G, Trillaud H, Labrouche S et al.. D-dimer strategy in thrombosis exclusion. A gold standard study in 100 patients suspected of deep vein thrombosis or pulmonary embolism: 8 DD methods compared.  Thromb Haemost. 1998;  79 31-37
• 24 Van Der Graaf F, van den Borne H, van der Kolk M et al.. Exclusion of deep vein thrombosis with D-dimer testing.  Thromb Haemost. 2000;  83 191-198
• 25 Perrier A, Desmarais S, Miron M J et al.. Non-invasive diagnosis of venous thrombo-embolism in outpatients.  Lancet. 1999;  353 190-195
• 26 Michiels J J, Kasbergen HAA, Trienekens P H. Evidence for safe exclusion of deep vein thrombosis (DVT) by the rapid ELISA VIDAS D-dimer test at cut-off levels of 500 and 1000 ng/ml in 1046 consecutive outpatients with suspected DVT.  Blood. 2004;  301a , (abstract 1059)
• 27 Schutgens REG, Ackermark P, Haas FJLM et al.. Combination of a normal D-dimer concentration and a non-high pretest clinical probability score is a safe strategy to exclude deep venous thrombosis.  Circulation. 2003;  107 593-597
• 28 Elias A, Mallard L, Elias M et al.. A single complete ultrasound investigation of the venous network for diagnostic management of patients with a clinically suspected first episode of deep vein thrombosis of the lower limbs.  Thromb Haemost. 2003;  89 221-227
• 29 Schellong S M, Schwarz T, Halbritter K et al.. Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis.  Thromb Haemost. 2003;  89 228-234
• 30 Stevens S M, Elliott G, Chan K J, Egger M J, Ahmed K M. Withholding anticoagulation after a negative result on duplex ultrasonography for suspected symptomatic deep vein thrombosis.  Ann Intern Med. 2004;  140 985-991
• 31 The PIOPED Investigators . Value of the ventilation/perfusion scan in acute pulmonary embolism.  JAMA. 1990;  263 2753-2759
• 32 Oudkerk M, van Beek EJ, van Putten WL, Buller HR. Cost-effectiveness analysis of various strategies in the diagnostic management of pulmonary embolism.  Arch Intern Med. 1993;  153 947-954
• 33 Henry J W, Relyea B, Stein P D. Continuing risk of thromboemboli among patients with normal pulmonary angiograms.  Chest. 1995;  107 1735-1738
• 34 Hull R D, Hirsh J, Carter C J et al.. Pulmonary angiography, ventilation lung scanning, and venography for clinically suspected pulmonary embolism with abnormal perfusion lung scan.  Ann Inter Med. 1983;  98 891-899
• 35 Diffin D C, Leyendecker J R, Johnson S P, Zucker R J, Grebe P J. Effect of anatomic distribution of pulmonary emboli on inter-observer agreement in the interpretation of pulmonary angiography.  AJR Am J Roentgenol. 1998;  171 1085-1089
• 36 Michiels J J, Perrier A, Bounameaux H. Should a normal D-dimer rule out angiographic pulmonary embolism or unfavourable outcome in patients left untreated?.  Thromb Haemost. 2001;  85 753-754
• 37 Michiels J J, Schroyens W, De Backer W, Van Der Planken M, Hoogsteden H, Pattynama PMT. Non-invasive exclusion and diagnosis of pulmonary embolism by sequential use of the rapid ELISA D-dimer assay, clinical score and spiral CT.  Int Angiol. 2003;  22 1-14
• 38 Hoellerich V L, Wigton R S. Diagnosing pulmonary embolism using clinical findings.  Arch Intern Med. 1986;  146 1699-1704
• 39 Celi A, Palla A, Petruzzelli S et al.. Prospective study of a standardized questionnaire to improve clinical estimate of pulmonary embolism.  Chest. 1989;  95 332-337
• 40 Wells PS, Ginsberg JS, Anderson DR et al.. Use of a clinical model for safe management of patients with suspected pulmonary embolism.  Ann Intern Med. 1998;  129 997-1005
• 41 Sanson B J, Lijmer J G, MacGilevry M R, Turkstra F, Prins M H, Büller H R. Comparison of a clinical probability estimate and two clinical models in patients with suspected pulmonary embolism.  Thromb Haemost. 2000;  83 199-203
• 42 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 a D-dimer.  Ann Intern Med. 2001;  135 98-107
• 43 Wicki J, Perneger T V, Junod A F, Bounameaux H, Perrier A. Assessing clinical probability of pulmonary embolism in the emergency ward.  Arch Intern Med. 2001;  161 92-97
• 44 Bounameaux H, Slosman D, de Moerloose P, Reber G. Diagnostic value of plasma D-dimer in suspected pulmonary embolism.  Lancet. 1988;  2 628-629
• 45 Bounameaux H, Schneider P A, Slosman D, de Moerloose P, Reber G. Plasma D-dimer in suspected pulmonary embolism: a comparison with pulmonary angiography and ventilation-perfusion scintigraphy.  Blood Coagul Fibrinolysis. 1990;  1 577-579
• 46 Bounameaux H, Cirefici P, de Moerloose Ph. Measurement of D-dimer in plasma as diagnostic aid in suspected pulmonary embolism.  Lancet. 1991;  337 196-200
• 47 Rowbotham B J, Egerton-Vermont J, Whitaker A N et al.. Plasma cross linked fibrin degradation products in pulmonary embolism.  Thorax. 1990;  45 684-687
• 48 Goldhaber S Z, Simons G R, Elliott G et al.. Quantitative plasma D-dimer levels among patients undergoing pulmonary angiography for suspected pulmonary embolism.  JAMA. 1993;  270 2819-2822
• 49 Van Beek EJR, van den Ende B, Berkmans R J et al.. A comparative analysis of D-dimer assays in patients with clinically suspected pulmonary embolism.  Thromb Haemost. 1993;  70 408-413
• 50 Van Beek EJR, Schenk E, Michel B C et al.. The role of plasma D-dimer concentration in the exclusion of pulmonary embolism.  Br J Haematol. 1996;  92 725-732
• 51 Perrier A, Bounameaux H, Morabia A et al.. Diagnosis of pulmonary embolism by a decision analysis-based strategy including clinical probability, D-dimer levels, and ultrasonography: a management study.  Arch Intern Med. 1996;  156 531-536
• 52 Perrier A, Desmarais S, Goehring C et al.. D-dimer testing for suspected pulmonary embolism in outpatients.  Am J Respir Crit Care Med. 1997;  156 492-496
• 53 Opinions regarding the diagnosis and management of venous thromboembolic disease. ACCP Consensus Committee on Pulmonary Embolism. American College of Chest Physicians.  Chest. 1998;  113 499-504
• 54 De Moerloose P, Desmarais S, Bounameaux H et al.. Contribution of a new rapid, individual and quantitative automated Vidas D-dimer ELISA to exclude pulmonary embolism.  Thromb Haemost. 1996;  75 11-13
• 55 Kruip M J, Slob M J, Schijen FHEM, 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.  Arch Intern Med. 2002;  162 1631-1635
• 56 Ferretti G R, Bosson J-L, Buffaz P D et al.. Acute pulmonary embolism: role of helical CT in 164 patients with intermediate probability at ventilation-perfusion scintigraphy and normal results at duplex of the legs.  Radiology. 1997;  205 453-458
• 57 Ost D, Rozenshstein A, Saffran L, Snider A. The negative predictive value of spiral computed tomography for the diagnosis of pulmonary embolism in patients with non-diagnostic ventilation-perfusion scans.  Am J Med. 2001;  110 16-21
• 58 Lomis NNT, Yoon H C, Miller F J. Clinical outcomes of patients after a negative spiral CT pulmonary angiogram in the evaluation of acute pulmonary embolism.  J Vasc Interv Radiol. 1999;  10 707-712
• 59 Garg K, Sieler H, Welsh C H, Johnston R, Russ P. Clinical validity of helical CT being interpreted as negative for pulmonary embolism. Implications for patient treatment.  AJR Am J Roentgenol. 1999;  172 1627-1631
• 60 Goodman L R, Lipchik R J, Kuzo R S, McAuliffe T L, O'Brien D J. Subsequent pulmonary embolism: risk after a negative helical CT pulmonary angiogram. Prospective comparison with scintigraphy.  Radiology. 2000;  215 535-542
• 61 Göttsäter A, Berg A, Centegard J, Frennby B, Nirhov N, Nyman U. Clinically suspected pulmonary embolism: is it safe to withhold anticoagulation after a negative spiral CT?.  Eur Radiol. 2001;  11 65-72
• 62 Tillie-Leblond I, Mastora I, Radenne F et al.. Risk of pulmonary embolism after a negative spiral CT angiogram in patients with pulmonary disease: 1 year clinical follow-up study.  Radiology. 2002;  223 461-467
• 63 Van Strijen MJL, de Monyé W, Schiereck J et al.. Helical CT as the primary diagnostic test in suspected pulmonary embolism: prospective ANTELOPEW multicenter trial in 512 patients.  Ann Intern Med. 2003;  138 307-314
• 64 Musset D, Parent F, Meyer G et al.. Diagnostic strategy for patients with suspected pulmonary embolism: a prospective multicenter outcome study.  Lancet. 2002;  360 1914-1920
• 65 Perrier A, Roy P-M, Aujesky D et al.. Bounameaux. Diagnosing pulmonary embolism in outpatients with clinical assessment, D-Dimer measurement, venous ultrasound, and helical computed tomography: a multicenter study.  Am J Med. 2004;  116 291-299
• 66 Verschuren Fr, Hainaut P, Thys Fr et al.. ELISA D-dimer measurement for the clinical suspicion of pulmonary embolism in the emergency department: one-year observational study of the safety profile and physician'S prescription.  Acta Clin Belg. 2003;  58 233-240