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d-Dimer for the Exclusion of Acute Venous Thrombosis and Pulmonary Embolism : A Systematic Review

Paul D. Stein, MD; Russell D. Hull, MBBS, MSc; Kalpesh C. Patel, MBBS; Ronald E. Olson, PhD; William A. Ghali, MD, MPH; Rollin Brant, PhD; Rita K. Biel, BSc; Vinay Bharadia, MSc; and Neeraj K. Kalra, MD
[+] Article and Author Information

From Saint Joseph Mercy-Oakland, Pontiac, Michigan; Wayne State University, Detroit, Michigan; University of Calgary, Calgary, Alberta, Canada; and Oakland University, Rochester, Michigan.


Acknowledgments: The authors thank Natasha Burke, BSc, Adrian Jorgenson, BSc, and Jeanne Sheldon, BA, University of Calgary, for their assistance in preparing the manuscript and Trupti Patel, BS, for her help in analyzing the data.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Paul D. Stein, MD, Saint Joseph Mercy-Oakland, 44555 Woodward Avenue, Suite 107, Pontiac, MI 48341; e-mail, steinp@trinity-health.org.

Current Author Addresses: Dr. Stein: Saint Joseph Mercy-Oakland, 44555 Woodward Avenue, Suite 107, Pontiac, MI 48341.

Dr. Hull and Ms. Biel: Thrombosis Research Unit, University of Calgary, 601 South Tower, Foothills Hospital, 1403 29 Street Northwest, Calgary, Alberta T2N 2T9, Canada.

Dr. Patel: 712 Indian Creek Drive, Wilkes Park, PA 18702.

Dr. Olson: Office of the Vice Provost for Research and Graduate Studies, Oakland University, 520 O'Dowd Hall, Rochester, MI 48309-4401.

Dr. Ghali: University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta T2N 4N1, Canada.

Dr. Brant: University of Calgary, 3310 Hospital Drive Northwest, Calgary, Alberta T2N 1N4, Canada.

Mr. Bharadia: University of Victoria, Cornett Building A238, 3800 Finnerty Road (Ring Road), Victoria, British Columbia V8P 5C2, Canada.

Dr. Kalra: Detroit Medical Center, Wayne State University, 4201 St. Antoine Street, Detroit, MI 48201.

Author Contributions: Conception and design: P.D. Stein, R.D. Hull, V. Bharadia.

Analysis and interpretation of the data: P.D. Stein, R.D. Hull, R.E. Olson, W.A. Ghali, R. Brant, R.K. Biel, V. Bharadia, N.K. Kalra.

Drafting of the article: P.D. Stein, R.D. Hull, R.E. Olson, R. Brant, R.K. Biel, V. Bharadia.

Critical revision of the article for important intellectual content: P.D. Stein, R.D. Hull, R.E. Olson, W.A. Ghali, R. Brant, V. Bharadia.

Final approval of the article: P.D. Stein, R.D. Hull, W.A. Ghali.

Provision of study materials or patients: P.D. Stein, R.D. Hull, V. Bharadia.

Statistical expertise: P.D. Stein, R.D. Hull, R.E. Olson, W.A. Ghali, R. Brant.

Obtaining of funding: P.D. Stein, R.D. Hull.

Administrative, technical, or logistic support: P.D. Stein, R.D. Hull, R.K. Biel, V. Bharadia.

Collection and assembly of the data: P.D. Stein, R.D. Hull, K.C. Patel, R.K. Biel, V. Bharadia, N.K. Kalra.


Ann Intern Med. 2004;140(8):589-602. doi:10.7326/0003-4819-140-8-200404200-00005
Text Size: A A A

Background: Despite extensive literature, the diagnostic role of d-dimer for deep venous thrombosis (DVT) or pulmonary embolism (PE) remains unclear, reflecting multiple d-dimer assays and concerns about differing sensitivities and variability.

Purpose: To systematically review trials that assessed sensitivity, specificity, likelihood ratios, and variability among d-dimer assays.

Data Sources: Studies in all languages were identified by searching PubMed from 1983 to January 2003 and EMBASE from 1988 to January 2003.

Study Selection: The researchers selected prospective studies that compared d-dimer with a reference standard. Studies of high methodologic quality were included in the primary analyses; sensitivity analysis included additional weaker studies.

Data Extraction: Two authors collected data on study-level factors: d-dimer assay used, cutoff value, and whether patients had suspected DVT or PE.

Data Synthesis: For DVT, the enzyme-linked immunosorbent assay (ELISA) and quantitative rapid ELISA dominate the rank order for these values: sensitivity, 0.96 (95% confidence limit [CL], 0.91 to 1.00), and negative likelihood ratio, 0.12 (CL, 0.04 to 0.33); and sensitivity, 0.96 (CL, 0.90 to 1.00), and negative likelihood ratio, 0.09 (CL, 0.02 to 0.41), respectively. For PE, the ELISA and quantitative rapid ELISA also dominate the rank order for these values: sensitivity, 0.95 (CL, 0.85 to 1.00), and negative likelihood ratio, 0.13 (CL, 0.03 to 0.58); and sensitivity, 0.95 (CL, 0.83 to 1.00), and negative likelihood ratio, 0.13 (CL, 0.02 to 0.84), respectively. The ELISA and quantitative rapid ELISA have negative likelihood ratios that yield a high certainty for excluding DVT or PE. The positive likelihood values, which are in the general range of 1.5 to 2.5, do not greatly increase the certainty of diagnosis. Sensitivity analyses do not affect these findings.

Limitations: Although many studies evaluated multiple d-dimer assays, findings are based largely on indirect comparisons of test performance characteristics across studies.

Conclusion: The ELISAs in general dominate the comparative ranking among the d-dimer assays for sensitivity and negative likelihood ratio. For excluding PE or DVT, a negative result on quantitative rapid ELISA is as diagnostically useful as a normal lung scan or negative duplex ultrasonography finding.

Figures

Grahic Jump Location
Figure 1.
Reports evaluated for inclusion in the review.

*Studies that did not meet the third, fourth, or tenth inclusion criteria were labeled as tier 3 studies and were included in sensitivity analyses. † 49 studies of deep venous thrombosis (DVT), 31 studies of pulmonary embolism (PE); of these studies, 2 reported both DVT and PE as separate cohorts. ‡ 70 studies of DVT, 41 studies of PE; of these studies, 3 reported both DVT and PE. ELISA = enzyme-linked immunosorbent assay.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Boxplots of the findings for sensitivity and specificity among thed-dimer assays for patients with suspected deep venous thrombosis.

The top and bottom of each box represent the upper and lower quartiles of the values for the sample, and the white bars represent the medians. Bars extend above and below each box to the maximal and minimal value in the sample or, if there are extreme data points, to limits based on the interquartile range, defined as the distance from the lower quartile to the upper quartile. Outliers beyond these limits are plotted separately. ELISA = enzyme-linked immunosorbent assay; Quantitative latex assay = quantitative latex agglutination assay; semi-quantitative latex assay = semi-quantitative latex agglutination assay; whole-blood assay = whole-blood agglutination assay.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Boxplots of the findings for sensitivity and specificity among thed-dimer assays for patients with suspected pulmonary embolism.

The top and bottom of each box represent the upper and lower quartiles of the values for the sample, and the white bars represent the medians. Bars extend above and below each box to the maximal and minimal value in the sample or, if there are extreme data points, to limits based on the interquartile range, defined as the distance from the lower quartile to the upper quartile. Outliers beyond these limits are plotted separately. * One study only. ELISA = enzyme-linked immunosorbent assay; Quantitative latex assay = quantitative latex agglutination assay; semi-quantitative latex assay = semi-quantitative latex agglutination assay; whole-blood assay = whole-blood agglutination assay.

Grahic Jump Location

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Comments

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D-dimer test in patients with cancer
Posted on April 20, 2004
Fabio Puglisi
Clinical Oncology, University of Udine, Italy
Conflict of Interest: None Declared

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

Pitfalls of using D-dimer for exclusion of venous thromboembolism
Posted on April 30, 2004
John T. Philbrick
University of Virginia
Conflict of Interest: None Declared

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

Comment on Stein article
Posted on June 1, 2004
Stephen J. Wolf
Denver Health Medical Center
Conflict of Interest: None Declared

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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Summary for Patients

Ability of Different d-Dimer Tests To Exclude Deep Venous Thrombosis and Pulmonary Embolism

The summary below is from the full report titled “d-Dimer for the Exclusion of Acute Venous Thrombosis and Pulmonary Embolism. A Systematic Review.” It is in the 20 April 2004 issue of Annals of Internal Medicine (volume 140, pages 589-602). The authors are P.D. Stein, R.D. Hull, K.C. Patel, R.E. Olson, W.A. Ghali, R. Brant, R.K. Biel, V. Bharadia, and N.K. Kalra.

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