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Comment on Stein article
Pitfalls of using D-dimer for exclusion of venous thromboembolism
D-dimer test in patients with cancer
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Stephen J. Wolf, MD Denver Health Medical Center
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stephen.wolf{at}dhha.org Stephen J. Wolf
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I read with great interest the recent article by Stein and colleagues entitled “D-dimer for the Exclusion of Acute Venous Thrombosis and Pulmonary Embolism”(1). This systematic review provides clinicians with a thorough compilation of the data published to date for application of the D-dimer in the setting of suspected deep vein thrombosis and pulmonary embolism (PE). Unfortunately, the authors’ conclusions are misleading and only continue to muddy the waters as to the utility of the D-dimer assay in this particular setting. The authors imply in their conclusion that radiographic evaluation of patients for suspected PE is not indicated in the setting of a negative quantitative rapid ELISA D-dimer assay. This conclusion is based on the assumption that negative likelihood ratios of less than 0.1 “result in large and often conclusive changes from pre- to post-test probability”(1). Of the seven types of D-dimer assays evaluated in this review, the only negative likelihood ratio found to be less than 0.1 for the evaluation of PE was with the quantitative rapid ELISA D-dimer assay. The authors fail to address the issue that the upper 95% confidence limit was 4.15. This is a negative likelihood ratio that would seemingly increase the likelihood of disease. Even at its stated negative likelihood ratio of 0.05, a negative quantitative rapid ELISA D-dimer result would not exclude PE in all patients regardless of pretest probability. Patients with high pretest probabilities account for 10% - 13% of those evaluated for PE(2- 4), and the incidence of PE in this population has been found to be any where from 39% – 87%(2-5). Applying a D-dimer assay with a negative likelihood ratio of 0.05 to these pretest probabilities would yield post- test probabilities of 9% – 25%, a number clearly too high to abort the work-up of disease. Stephen J. Wolf, MD Department of Emergency Medicine Denver Health Medical Center Denver, Colorado 1. Stein PD, Hull RD, Patel KC, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med. 2004;140(8):589-602. 2. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). The PIOPED Investigators. Jama. 1990;263(20):2753-9. 3. 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(12):997-1005. 4. Wells PS, Anderson DR, Rodger M, et al. 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(3):416-20. 5. Perrier A, Desmarais S, Miron MJ, et al. Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet. 1999;353(9148):190-5. Conflict of Interest:None declared |
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John T. Philbrick, MD University of Virginia, Steven Heim and Joel M. Schectman
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jtp9b{at}virginia.edu John T. Philbrick, et al.
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To the editor: We read with interest the systematic review by Stein et al. (1) on D- dimer tests for deep venous thrombosis and pulmonary embolism. Although we acknowledge that their conclusion, “a negative quantitative rapid ELISA result is as diagnostically useful as a normal lung scan or negative duplex ultrasonography finding,” is technically correct, we believe that the issues surrounding this use of D-dimer are more complex. For a “rule- out” test, a high sensitivity is not the only important test characteristic. Specificity also plays a key role and limits the use of D -dimer for venous thromboembolism in at least two ways. First, the likelihood ratio for a negative test (calculated as (1- sensitivity)/specificity) is inversely proportional to specificity. Few tests have invariable sensitivity and specificity numbers. Instead, these indices of test performance vary with the clinical characteristics of patient populations. This is particularly true for the specificity of D- dimer. There is a very long list of conditions other than thromboembolism that cause “elevated” d-dimer levels. When large numbers of patients with these conditions - which include cancer, trauma, surgery, and advanced age - are included in a study, specificity will be very low, the likelihood ratio for a negative test will not be as small as reported by Stein (1), and sometimes D-dimer levels of those with venous thromboembolism will be indistinguishable from those without.(2) Thus, unless care is taken by the clinician to order D-dimer only in patients free of conditions known to cause elevated levels, results will not be diagnostically useful for venous thromboembolism. Second, it is important to remember that a low specificity leads to a high false positive rate. To illustrate this, we performed some calculations using the sensitivity and specificity values for deep venous thrombosis from Stein (1), assuming a disease prevalence of 20 percent. For the quantitative rapid ELISA, Stein’s favored D-dimer assay (sensitivity 0.91, specificity 0.43), the false positive rate is 46 percent. However, for the whole blood assay (sensitivity 0.82, specificity 0.70), the false positive rate is only 24 percent. Although the high sensitivity of the quantitative ELISA gives it an apparent advantage as a rule-out test, its corresponding low specificity results in almost half of tested patients having a false positive result. This can lead to problems. The availability of a simple blood test to rule-out venous thromboembolism may lead physicians to order the test more often with a positive result likely to influence physicians to order additional tests to rule out thromboembolism. Goldstein et al (3) found that, in an inpatient setting, ordering D-dimer as the initial diagnostic strategy for patients with suspected pulmonary embolism resulted in more lung scans and CT pulmonary angiography being ordered than those managed without the test. We believe there is a place for D-dimer in the management of patients with suspected venous thromboembolism, such as selected emergency room settings.(4) However, D-dimer’s role will always be limited due to its low specificity. In choosing to use the test, clinicians will need to consider whether patients have conditions likely to cause false positive results and, if so, go straight to imaging studies. In addition, clinicians will need to respect the pitfalls of low specificity and refrain from ordering D-dimer on increasingly wider ranges of patients just because the test is cheap and easy to perform. References 1. Stein PD, Hull RD, Patel KC, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism. Ann Intern Med. 2004;140:589-602. 2. Brotman DJ, Segal JB, Jani JT, Petty BG, Kickler TS. Limitations of D- dimer testing in unselected inpatients with suspected thromboembolism. Am J Med. 2003:114:276-282. 3. Goldstein NM, Kollef MH, Ward S, Gage BF. The impact of the introduction of a rapid D-dimer assay on the diagnostic evaluation of suspected pulmonary embolism. Arch Intern Med. 2001;161:567-71. 4. Wells PS, Anderson DR, Roger M et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003;349:1227- 35. Conflict of Interest:None declared |
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Fabio Puglisi, MD, PhD Clinical Oncology, University of Udine, Italy, Edda Federico
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fabio.puglisi{at}med.uniud.it Fabio Puglisi, et al.
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We read with great interest the systematic review by Stein et al about the accuracy of D-dimer assays for diagnosing deep venous thrombosis (DVT) and pulmonary embolism (PE). In the discussion, the Authors pointed out that the clinical utility of D- dimer test may vary among patients with different diseases. In particular, a higher value of the assay can be expected when the probability of having DVT/PE is lower, such as in outpatient setting. We agree with this remark but, in our opinion, another important point should be emphasized. DVT and PE are common complication in patients with cancer and D-dimer test is probably of limited diagnostic usefulness. In fact, malignancies are often associated with elevated values of D-dimer because of tumor- induced activation of intravascular coagulation (1). Accordingly, different studies evaluating the role of D-dimer in patients with cancer and suspected DVT/PE found a low specificity and negative predictive value of the test (2-4). A note of caution is hence needed before applying the results of this systematic review to patients with high probability of elevated levels of D-dimer (low specificity for DVT/PE), such as patients with cancer. References 1. Rocha E, Paramo JA, Fernandez FJ, Cuesta B, Hernandez M, Paloma MJ, Rifon J. Clotting activation and impairment of fibrinolysis in malignancy. Thromb Res. 1989;54:699-707. 2. Lee AY, Julian JA, Levine MN, Weitz JI, Kearon C, Wells PS, Ginsberg JS. Clinical utility of a rapid whole-blood D-dimer assay in patients with cancer who present with suspected acute deep venous thrombosis. Ann Intern Med. 1999;131:417-23. 3. Schutgens RE, Esseboom EU, Haas FJ, Nieuwenhuis HK, Biesma DH. Usefulness of a semiquantitative D-dimer test for the exclusion of deep venous thrombosis in outpatients. Am J Med. 2002;112:617-21. 4. Gomes MP, Deitcher SR. Diagnosis of venous thromboembolic disease in cancer patients. Oncology (Huntingt). 2003;17:126-35. Conflict of Interest:None declared |
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