Articles
6 June 2006

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

Publication: Annals of Internal Medicine
Volume 144, Number 11

Abstract

Background:

It may be safe to omit additional diagnostic testing in selected patients with suspected pulmonary embolism (PE) who have a negative d-dimer test, but this approach has never been evaluated in a randomized, controlled trial.

Objective:

To determine if additional diagnostic testing can be safely withheld in patients with suspected PE who have negative erythrocyte agglutination d-dimer test results.

Design:

Randomized comparisons in 2 subgroups of a prospective multicenter study.

Setting:

7 university hospitals.

Patients:

1126 outpatients or inpatients with suspected PE; of these, 456 patients with negative erythrocyte agglutination d-dimer test results were randomly assigned to the intervention groups. Patients were classified into 2 clinical probability groups: those with a low clinical probability of PE (low-probability group) and those with a moderate or high clinical probability of PE, a nondiagnostic ventilation–perfusion lung scan, and no evidence of proximal deep venous thrombosis on bilateral ultrasonography (moderate- or high-probability group).

Interventions:

The experimental intervention for both probability groups was no further diagnostic testing for PE. The control intervention for the low-probability group was a ventilation–perfusion lung scan followed by ultrasonography of the proximal deep veins of the legs on the same day. If the lung scan was nondiagnostic, ultrasonography of the legs was repeated 7 and 14 days later. The control intervention for the moderate- or high-probability group was ultrasonography of the proximal deep veins of the legs after 7 and 14 days. In the control and experimental groups, anticoagulation was withheld or withdrawn if PE was not diagnosed.

Measurements:

Symptomatic venous thromboembolism (VTE) during 6 months of follow-up.

Results:

Prevalence of VTE was 15.2% in the 1126 enrolled patients. In the low-probability group, VTE occurred during follow-up in 0 of 182 patients who had no additional diagnostic testing and in 1 of 185 patients who had additional testing (difference, −0.5 percentage point [95% CI, −3.0 to 1.6 percentage points]). In the moderate- or high-probability group, VTE occurred during follow-up in 1 of 41 patients who had no additional diagnostic testing and in 0 of 41 patients who had additional testing (difference, 2.4 percentage points [CI, −6.4 to 12.6 percentage points]).

Limitations:

The authors could not enroll 2000 patients as originally planned; 3 randomly assigned patients did not receive the allocated intervention, and 7 received inadequate follow-up. Personnel who performed follow-up evaluations were not blinded to the results of diagnostic testing at enrollment or to allocation group assignments.

Conclusion:

In patients with a low probability of PE who have negative d-dimer results, additional diagnostic testing can be withheld without increasing the frequency of VTE during follow-up. Low clinical probability and negative d-dimer results occur in 50% of outpatients and in 20% of inpatients with suspected PE.
*For other persons and institutions who participated in this study, see the Appendix.

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Abdul-Karim Elhabyan 15 June 2006
D-dimer Should Be Viewed with Caution

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

Jeevan P Marasinghe 19 June 2006
Won't it be the normal expectant result.?

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

Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 144Number 116 June 2006
Pages: 812 - 821

History

Published online: 6 June 2006
Published in issue: 6 June 2006

Keywords

Authors

Affiliations

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

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Clive Kearon, Jeffrey S. Ginsberg, James Douketis, et al; for the 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;144:812-821. [Epub 6 June 2006]. doi:10.7326/0003-4819-144-11-200606060-00007

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