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An Evaluation of d-Dimer in the Diagnosis of Pulmonary Embolism: A Randomized Trial

Clive Kearon, MB, PhD; Jeffrey S. Ginsberg, MD; James Douketis, MD; Alexander G. Turpie, MB; Shannon M. Bates, MDCM; Agnes Y. Lee, MD; Mark A. Crowther, MD; Jeffrey I. Weitz, MD; Patrick Brill-Edwards, MD; Philip Wells, MD; David R. Anderson, MD; Michael J. Kovacs, MD; Lori-Ann Linkins, MD; Jim A. Julian, MMath; Laura R. Bonilla, MSc; Michael Gent, DSc, Canadian Pulmonary Embolism Diagnosis Study (CANPEDS) Group*
[+] Article and Author Information

From McMaster University and the Henderson Research Centre, Hamilton, Ontario, Canada; University of Ottawa, Ottawa, Ontario, Canada; Dalhousie University, Halifax, Nova Scotia, Canada; and University of Western Ontario, London, Ontario, Canada.


ClinicalTrials.gov identifier: NCT001825

Acknowledgments: Agen Biomedical Ltd., Brisbane, Australia, provided the d-dimer assays used in this research.

Grant Support: By the Canadian Institutes of Health Research (MT-14092). Drs. Kearon and Douketis were supported by the Heart and Stroke Foundation of Canada. Drs. Ginsberg, Weitz, and Crowther were supported by the Heart and Stroke Foundation of Ontario. Drs. Lee, Ginsberg, Weitz, and Wells were supported by the Canadian Institutes of Health Research. Dr. Bates was supported by the Canadian Institutes of Health Research University Industry Program (bioMerieux, Inc.). Dr. Kovacs was supported by the University of Western Ontario. Dr. Anderson was supported by Dalhousie University.

Potential Financial Conflicts of Interest: Consultancies: M.A. Crowther (Pfizer, Sanofi-Aventis, Leo Laboratories, AstraZeneca, Sandoz), J. Douketis (Agen Biomedical Ltd.); Honoraria: M.A. Crowther (Pfizer, Sanofi-Aventis, AstraZeneca, GlaxoSmithKline); Grants received: M.A. Crowther (Leo Laboratories, Sanofi-Aventis, Pfizer).

Corresponding Author: Clive Kearon, MB, PhD, Hamilton Health Sciences, Henderson Division, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada; e-mail, kearonc@mcmaster.ca.

Current Author Addresses: Drs. Kearon, Lee, Weitz, and Linkins: Henderson General Hospital, Hamilton Health Sciences Hospital, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada.

Drs. Ginsberg, Bates, and Brill-Edwards: McMaster University Medical Centre, Room 3W15, 1200 Main Street West, Hamilton, Ontario L8S 4L8, Canada.

Drs. Douketis and Crowther: St. Joseph's Hospital, Room L 208-4, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada.

Dr. Turpie: Hamilton General Hospital, Hamilton Health Sciences Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.

Dr. Wells: The Ottawa Hospital, Civic Parkdale Clinic, 467-737 Parkdale Avenue, Ottawa, Ontario K1Y 1J8, Canada.

Dr. Anderson: Queen Elizabeth II Health Sciences Centre, Room 430, Bethune Building, 1278 Tower Road, Halifax, Nova Scotia B3H 2Y9, Canada.

Dr. Kovacs: Victoria Hospital, 800 Commissioner's Road East, Room A2-401, London, Ontario N6A 4G5, Canada.

Mr. Julian, Ms. Bonilla, and Dr. Gent: Clinical Trials and Methodology Group, Henderson Research Centre, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada.

Author Contributions: Conception and design: C. Kearon, J.S. Ginsberg, M.J. Kovacs, P. Wells, D.R. Anderson.

Analysis and interpretation of the data: C. Kearon, J.S. Ginsberg, J.A. Julian, L.R. Bonilla, M. Gent.

Drafting of the article: C. Kearon, J.S. Ginsberg.

Critical revision of the article for important intellectual content: C. Kearon, J.S. Ginsberg, J. Douketis, A.G. Turpie, S.M. Bates, A.Y. Lee, M.A. Crowther, J.I. Weitz, P. Brill-Edwards, P. Wells, D.R. Anderson, M.J. Kovacs, L.-A. Linkins, J.A. Julian, L.R. Bonilla, M. Gent.

Final approval of the article: C. Kearon, J.S. Ginsberg, J. Douketis, A.G. Turpie, S.M. Bates, A.Y. Lee, M.A. Crowther, P. Brill-Edwards, P. Wells, D.R. Anderson, M.J. Kovacs, L.-A. Linkins, J.A. Julian, L.R. Bonilla, M. Gent.

Provision of study materials or patients: C. Kearon, J.S. Ginsberg, J. Douketis, A.G. Turpie, S.M. Bates, A.Y. Lee, M.A. Crowther, J.I. Weitz, P. Brill-Edwards, P. Wells, D.R. Anderson, M.J. Kovacs, L.-A. Linkins.

Statistical expertise: J.A. Julian.

Obtaining of funding: C. Kearon, J.S. Ginsberg, P. Wells, D.R. Anderson, M.J. Kovacs.

Administrative, technical, or logistic support: J.A. Julian, L.R. Bonilla, M. Gent.

Collection and assembly of data: C. Kearon, J.S. Ginsberg, J.A. Julian, L.R. Bonilla, M. Gent.


Ann Intern Med. 2006;144(11):812-821. doi:10.7326/0003-4819-144-11-200606060-00007
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Patients were enrolled from July 1998 through October 2002. A total of 2591 patients met the inclusion criteria; 1126 of these were eligible, provided informed consent, were enrolled in the study, and had a standardized assessment of clinical probability of pulmonary embolism (Tables 1 and 2; Figure 1).

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Figure 2.
Diagnostic algorithm and patient outcomes for patients with a low clinical probability of pulmonary embolism.

High probability = ventilation–perfusion lung scan showed a high probability for pulmonary embolism; nondiagnostic = nondiagnostic ventilation–perfusion lung scan; normal = normal ventilation–perfusion lung scan; serial ultrasonography = serial bilateral ultrasonography of the proximal deep veins. *Ventilation–perfusion lung scan was not performed in 2 patients: 1 patient had a myocardial infarction, and radioisotope was not available for 1 patient. Neither patient was treated with anticoagulant therapy or had venous thromboembolism during follow-up. †Three patients did not have ventilation–perfusion lung scan, were not treated with anticoagulant therapy, and did not have venous thromboembolism at follow-up. ‡Patients with a nondiagnostic lung scan had bilateral venous ultrasonography of the proximal veins on the day of presentation and after 7 and 14 days (serial ultrasonography). §One patient started anticoagulant therapy for atrial fibrillation. ‖Two patients were judged to not have pulmonary embolism and were not treated: One had normal pulmonary angiography results, and 1 had normal serial venous ultrasonography results. Neither patient had venous thromboembolism during follow-up. ¶One patient had subsegmental pulmonary embolism on pulmonary angiography that was performed contrary to the protocol. **One patient who was treated for pulmonary embolism died suddenly on day 50, possibly from recurrent pulmonary embolism.

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Figure 3.
Diagnostic algorithm and outcomes for patients with a moderate or high probability of pulmonary embolism.

High probability = ventilation–perfusion lung scan showed a high probability for pulmonary embolism; nondiagnostic = nondiagnostic ventilation–perfusion lung scan; normal = normal ventilation–perfusion lung scan; serial ultrasonography = serial bilateral ultrasonography of the proximal deep veins. *Pulmonary embolism was diagnosed in 1 critically ill patient on the basis of presence of proximal deep venous thrombosis on ultrasonography; the patient did not have a ventilation–perfusion lung scan. †One patient was judged to not have pulmonary embolism on the basis of normal spiral computed tomography and venous ultrasonography results and was not treated. ‡Two patients did not have venous ultrasonography performed. Neither patient was treated with anticoagulant therapy or had venous thromboembolism during follow-up. §Three eligible patients were not randomly assigned: The physician chose to perform bilateral venography in 1 patient, and 2 patients were mistakenly sent for additional testing. None of these 3 patients was treated with anticoagulant therapy or had venous thromboembolism during follow-up. ‖Patients with high clinical probability were considered for pulmonary angiography or for venography followed by serial ultrasonography if the venography results were normal. Of 19 such patients, 2 had deep venous thrombosis on venography and were treated for pulmonary embolism. Moderate-probability patients were to have serial ultrasonography; of 121 such patients, 2 had ultrasonography results showing deep venous thrombosis that was subsequently treated. Five other patients were treated with anticoagulant therapy: 2 for initial pulmonary embolism despite nondiagnostic testing (not counted as pulmonary embolism in the analysis), 1 for atrial fibrillation, and 2 for temporary venous thromboembolism prophylaxis after major orthopedic surgery. None of these 9 treated patients had venous thromboembolism during follow-up. ¶One patient was treated with anticoagulant therapy for atrial fibrillation and did not have venous thromboembolism during follow-up. **One patient was treated with anticoagulant therapy because of a history of recurrent venous thromboembolism and congenital heart disease. This patient was diagnosed with pulmonary embolism during follow-up after stopping anticoagulant therapy.

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D-dimer Should Be Viewed with Caution
Posted on June 15, 2006
Abdul-Karim Elhabyan
Charleston Area Medical Center
Conflict of Interest: None Declared

In their prospective study evaluating D-dimer as a tool to rule-out pulmonary embolism (PE), Kearon et al1 described as a primary finding the low incidence of PE when D-dimer is used as a stand-alone test to rule-out disease among patients with low clinical probability. We agree with the authors that it is essential for physicians to interpret the real value of D-dimer as a test to diagnose VTE and we also applaud their efforts towards clarifying its place. Although interesting, we believe that the conclusions of the authors should be viewed with caution based on the following observations of their methodology:

First, all randomized patients with negative D-dimer and a non- diagnostic V/Q scan should be included in the final analysis. The three cases of venous thromboembolism (VTE) excluded due to deviations in the protocol (refer to figure 2 of the article) should count as new occurrences of VTE in the cohort. If as the conclusion suggests no additional tests were conducted, these new enrollment cases would likely not have been discovered. Due to the fact that these new cases of VTE occurred after randomization and after additional diagnostic testing, it is only reasonable to include them in the final analysis. Thus, there should be 4 VTE cases in the additional testing group, which would result in a prevalence of 2.2%. Although including these initially excluded VTE cases does not confirm a significant difference between the two groups (no additional versus additional testing), it does however increase the prevalence of VTE to be higher than the a priori 1% expected by the authors (which was later readjusted to be 2.1% after restarting the study). The higher, but expected, prevalence of VTE in the additional testing group is troublesome. The prevalence should be similar between the no additional versus additional testing groups. Thus, readers should be cautioned about withholding additional diagnostic testing until more convincing evidence is presented.

Second, even with the use of the most sensitive D-dimer assay (ELISA); this test has demonstrated to only increase the rate of subsequent testing to rule-out PE without any benefits regarding its diagnostic capability.2 The failure of D-dimer to rule-out disease has been also reported by others, and in our opinion the authors of this study failed to explain this noteworthy dissimilarity between their results and previous publications.

References:

1. Kearon C, Ginsberg JS, Douketis J, Turpie AG, Bates SM, Lee AY, Crowther MA, Weitz JI, Brill-Edwards P, Wells P, Anderson DR, Kovacs MJ, Linkins LA, Julian JA, Bonilla LR, Gent M; Canadian Pulmonary Embolism Diagnosis Study (CANPEDS) Group. An evaluation of D-dimer in the diagnosis of pulmonary embolism: a randomized trial. Ann Intern Med. 2006; 6:812-21. (PMID: 16754923)

2. Ray P, Bellick B, Birolleau S, Marx JS, Arock. Referent D-dimer enzyme-linked immunosorbent assay testing is of limited value in the exclusion of thromboembolic disease: result of a practical study in an ED. Am J Emerg Med. 2006; 24:313-8. (PMID: 16635704)

Conflict of Interest:

None declared

Won't it be the normal expectant result.?
Posted on June 19, 2006
Jeevan P Marasinghe
Registrar in Obstetrics and Gynaecology,Professorial unit,Teaching Hospital ,Peradeniya,Sri Lanka.
Conflict of Interest: None Declared

Dear Sir, I read the article on the evaluation of D-Dimer in the diagnosis of pulmonary embolism with great enthusiasm. There Kearon C et al(1) have tried to emphasize the relative less importance of performing additional investigations in patients who are suspected to have pulmonary embolism with a negative D -Dimer test. The idea is of course brilliant and would save valuable resources and manpower which can be utilized to needy patients.

There they have randomly allocated 456 patients out of 1126 who were negative for D- dimer test into a low probability group and moderate or high probability group. Their control intervention for the low probability group was ventilation perfusion lung scan followed by ultrasonography of the proximal deep veins of the legs. The control intervention for the moderate or high probability group was ultrasonography of the proximal deep veins of the legs. Then they have looked for the prevalence of pulmonary embolism in low probability group and moderate or high probability group with additional diagnostic testing and without additional diagnostic testing. Then they have concluded that in patients with a low probability of pulmonary embolism who have negative D-Dimer results ,additional diagnostic testing can be withheld.

But according to Roy PM et al.(2)in patients with a high pretest probability, ventilation perfusion lung scan ,spiral computed tomography and ultrasonography of leg veins have a greater than 85% of posttest probability of pulmonary embolism. In patients with a low probability of pulmonary embolism, these tests have only 5% post test probability of pulmonary embolism. Not only the D-Dimer test but also magnetic resonance angiography ,quantitative latex D-Dimer test can only exclude pulmonary embolism in patients with a low probability of pulmonary embolism only. Helical CT appears to a rapid and non invasive diagnostic test in patients with moderate to high risk of pulmonary embolism.(3)So the findings by Kearon C et al seems to be the proven expected in the diagnosis of pulmonary embolism.

References (1)Clive Kearon,Ginberg JS,Douketis J et al.An evaluation of D-Dimer in the diagnosis of pulmonary embolism. Annals of Internal Medicine. 2006 Jun 6;144(11):812-21.

(2)Roy PM,Colombert I,Durieux P et al.Systemic review and meta analysis of strategies for the diagnosis of suspected pulmonary embolism.BMJ 2005 Jul 30;331(7511):259.

(3)Rahimtoola A,Berjin JD.Acute pulmonary embolism: an update of diagnosis and management.Curr Probl Cardiol 2005 Feb;30(2):61-114.

Conflict of Interest:

None declared

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